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The main objective of the present work was to ensure quality of radiopharmaceuticals syringes withdrawn with a "Spinal needle/obturator In-Stopper" system. Methods: Visual examinations and physicochemical tests are performed at T0 and T+4h for [ 99m Tc]albumin nanocolloid and T+7h for [ 99m Tc]eluate, [ 99m Tc] HydroxyMethylene DiPhosphonate and [ 99m Tc]Human Serum Albumin. Microbiological validation was performed according to European pharmacopoeia. Fingertip radiation exposure was evaluated to confirm the safety of the system. Results: Results show stable visual and physicochemical properties. The integrity of the connector was not affected after 30 punctures (no cores). No microbiological contamination was found on tested syringes. Conclusion: The system could be used 30 times. The stability of syringes drawing with this method is guaranteed up to 4 hours for [ 99m Tc]albumin nanocolloid and 7 hours for [ 99m Tc]eluate, [ 99m Tc]HydroxyMethylene DisPhosphonate and [ 99m Tc]Human serum albumin., (Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms., Patients and Methods: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments., Results: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%])., Conclusion: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population., Trial Registration Id: NCT01589861., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies., (© 2016 UICC.)

Aims: Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab., Methods: Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4 mg kg(-1) loading dose followed by 5 weekly 2 mg kg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate., Results: A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1 l (23%), peripheral volume of distribution =1.3 l (38%), intercompartment clearance =0.36 l day(-1) , with an elimination half-life of 11.8 days. Typical clearance was 0.22 l day(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size., Conclusions: In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied., (© 2015 The British Pharmacological Society.)

Background: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort)., Methods: In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582., Findings: Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria., Interpretation: The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects., Funding: Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results of patients with acute leukaemia (leukaemia cohort)., Methods: In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France [five], UK [one], and Canada [one]). Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate. OTX015 was given orally at increasing doses from 10 mg/day to 160 mg/day (14 of 21 days), using a conventional 3 + 3 design. In this open-label trial, OTX015 was initially administered once a day, with allowance for exploration of other schedules. The primary endpoint was dose-limiting toxicity (DLT), assessed during the first treatment cycle (21 days). The study is ongoing and is registered with ClinicalTrials.gov, NCT01713582., Findings: Between Jan 18, 2013, and Sept 9, 2014, 41 patients, 36 with acute myeloid leukaemia, a median age of 70 years (IQR 60-75) and two lines of previous therapy, were recruited and treated across six dose levels of OTX015. No DLT was recorded until 160 mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120 mg doses hampered patient compliance and 80 mg once a day was judged the recommended dose with a 14 days on, 7 days off schedule. Common toxic effects for all OTX015 doses were fatigue (including grade 3 in three patients) and bilirubin concentration increases (including grade 3-4 in two patients). OTX015 plasma exposure increased proportionally up to 120 mg/day with trough concentrations in the in-vitro active range from 80 mg/day (274 nmol/L). Three patients (receiving 40 mg/day, 80 mg/day, and 160 mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting 2-5 months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far., Interpretation: The once-daily recommended dose for oral, single agent oral OTX015 use in patients with acute leukaemia for further phase 2 studies is 80 mg on a 14 days on, 7 days off schedule., Funding: Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Objectives: OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling., Methods: A dose-escalation, phase Ib study was performed with oral OTX015 in patients with haematologic malignancies, at doses starting from 10 mg once daily (QD) with continuous or discontinuous schedules. Five or eight blood samples were collected per patient for pharmacokinetic analysis. OTX015 plasma concentrations were determined using validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and analysed using a nonlinear mixed-effects modelling software program. A population pharmacokinetic model was fitted to the data, and patient demographics and clinical chemistry parameters were tested as predictive covariates on the model parameters., Results: Blood samples were analysed from 81 patients treated with OTX015 at doses ranging from 10 to 160 mg QD or 40 mg twice daily (BID), and 633 time-plasma concentrations were available for analysis. A one-compartment open model with linear elimination adequately described OTX015 pharmacokinetics. The most significant covariate was lean body mass (LBM), which decreased the between-subject variability in apparent total body clearance (CL) and the volume of distribution (V). The estimated pharmacokinetic parameters were the absorption rate constant (k a) = 0.731 h(-1), V = 71.4 L and CL = 8.47 L·h(-1)., Conclusion: The pharmacokinetics of oral OTX015 in patients with haematologic malignancies can be described with a one-compartment model. Population pharmacokinetic modelling of OTX015 plasma concentrations showed that LBM influences V and CL. These findings do not suggest the need for dose adjustment.

Background: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen., Methods: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide., Results: The maximum tolerated dose was established at 9.0 mg/m2 on a 5-day regimen, analogously to what was reported for topotecan monotherapy. One toxic death from septic shock and multiorgan failure occurred. Although hematopoietic toxicities were overcome by peripheral blood stem cell transplantation, superior nonhematological toxicities were observed as compared to the initial trial., Conclusion: Response rates were generally short and survival rates were poor. Results of the ITOV 01bis study demonstrate that, in the setting of recurrent ovarian cancer, intensive chemotherapy based on topotecan-cyclophosphamide association is not currently clinically indicated., (© 2015 S. Karger AG, Basel.)

Objectives: Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration., Methods: Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded., Results: All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml., Conclusions: ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability., Methods: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods., Results: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose., Conclusion: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC)., Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day., Results: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months., Conclusions: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors. All of these considerations have to stay in the frame of guideline recommendations which represent evidence-based medicine. The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, and to define targeted populations according to prognostic indexes., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs)., Methods: Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials., Results: Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population., Conclusions: These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101). Pathological response was assessed using the Sataloff classification. Pharmacokinetic analysis was performed for the first course of docetaxel (n = 84). No significant association was found between ABCB1 polymorphisms or docetaxel pharmacokinetics and pathological complete response. C3435T genotype was an independent predictive factor of good response in breast (response >50 %, i.e., Sataloff T-A and T-B): OR: 4.6 (95 % CI: 1.3-16.1), p = 0.015, for TT patients versus CT and CC patients. Area under the plasma concentration-time curve (AUC) of docetaxel was the only independent predictive factor of the total absence of response in breast (Sataloff T-D): OR: 14.3, (95 % CI: 1.7-118), p = 0.015, for AUC of docetaxel <3,500 μg h/L versus ≥3,500 μg h/L. These results suggest that C3435T polymorphism and docetaxel exposure are involved in the response to neoadjuvant chemotherapy in breast cancer patients and may be useful to optimize individualized therapy.

Background: The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP., Methods: First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria., Results: In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent., Conclusions: GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.

Background: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors., Methods: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m(2) and 25 mg/m(2) once every 21 days., Results: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m(2)) and without (10 mg/m(2)) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m(2) with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m(2)). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥ 4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥ 4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer., Conclusions: EZN-2208 was well tolerated and produced stable disease that lasted for ≥ 4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy., (Copyright © 2012 American Cancer Society.)

Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0-24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0-24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed.

High-dose methotrexate treatment requires pharmacological monitoring in order to tailor administration of folinic acid to reduce side effects. The aim of the study was to validate the adaptation of the EMIT reagent on the l'Unicel DxC 600® Beckman Coulter. The establishment of two assays was necessary to obtain a quantification limit as low as possible (0.05 μmol/L). The linearity of the adapted methods extends from 0.05 to 0.25 μmol/L on the one hand, and from 0.25 to 1 μmol/L on the other hand. For each method, fidelity and accuracy were studied and the limits of detection and quantification were quantified. The correlation with the FPIA method was performed on the Abbott TDX(®). The results of all tests are satisfactory with coefficients of variation (CV) of repeatability and reproducibility of less than 6%. However the daily assays are heavy as 66% of blood samples require at least two dosages and 30% a manual dilution.

Background: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab., Methods: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated., Results: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1., Conclusion: The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.

Purpose: Doxorubicin and ifosfamide are highly active drugs for the treatment of high-grade sarcomas, but little is known on the optimal management of young patients who develop such malignancies during pregnancy., Methods: We report on a single-institution series of patients (n = 9) with high-grade sarcoma diagnosed during the third trimester of pregnancy. Neoadjuvant chemotherapy combining doxorubicin (50 mg/m(2) day 1) and ifosfamide (2.5 g/m(2) days 1-2) with standard mesna rescue every 3 weeks was administered during the third trimester of pregnancy in five patients., Results: We observed a favourable outcome for both the mother and the offspring in all cases. Maternal and neonatal pharmacokinetic data for ifosfamide were obtained from one patient and did not evidence a transplacental transfer of this drug. The use of other active drugs (cisplatin, etoposide, dactinomycin and cyclophosphamide) in sarcoma during pregnancy is discussed on the basis of a comprehensive review of the English literature., Conclusions: In view of this single-centre experience, we suggest that the treatment of high-grade sarcoma during the third trimester of pregnancy should include an adapted regimen tailored to the pharmacological specificities of the pregnant patients.

Purpose: The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients., Methods: Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s)., Results: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib., Conclusions: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8.

Although testicular cancers are highly curable malignancies, conventional cisplatin based therapy often causes important toxicities, not often easily manageable. Nephrotoxicity occurs in almost all patients, and is potentialized in patients suffering from renal failure. Monitoring of residual levels of unbound platinum was used to define guidelines for cisplatin administration. Monitoring of cisplatin was initiated in a patient treated for metastatic testicular cancer and acute renal failure. Reduced doses of cisplatin were first administered in conjunction with hemodialysis. Unbound and total platinum levels were determined by flameless atomic absorption spectrophotometry. The data found allowed us to adapt and increase sequentially cisplatin doses, accordingly with the renal function. Full regimen doses were eventually administered when useful renal function returned. This simple approach may be useful in monitoring cisplatin administration during acute renal failure.

Tyrosine kinase inhibitors (TKI) of EGFR are used in advanced non-small cell lung cancer (NSCLC) in 2(nd) and 3(rd) line, and for gefitinib in first line in case of EGFR mutations. These drugs are particularly active in presence of these mutations, with response rate around 60-70%. Pharmacological data suggest an equivalent effect of erlotinib and gefitinib. One phase II study has directly compared the two drugs in 2(nd) line, with a non significant advantage for gefitinib in term of response and progression-free survival. However, skin tolerance profile was statistically better with gefitinib. Indirect comparisons between erlotinib and gefitinib in the phase III trials vs chemotherapy 1(st) line have to be interpreted, with caution and take under consideration the impact of the chemotherapy arm on the Hazard Ratio for Progression-free and overall survival. However, response rates seem to be equivalent. Cohort and phase IV studies have shown no significant difference for response and survival, and a similar tolerance profile., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Purpose: To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials., Patients and Methods: Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m(2)/day: 4 patients; 15 mg/m(2)/day: 4, 20 mg/m(2)/day: 5 and 25 mg/m(2)/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level., Results: The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m(2) level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m(2) level (grade 3 GI disorders), one at 10 mg/m(2) level (grade 4 mucositis). PK analysis showed no significant difference of C(max) values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum)., Conclusion: Due to 3 DLTs experienced at 25 mg/m(2)/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m(2)/day., (Copyright © 2010. Published by Elsevier Ireland Ltd.)

Background: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone., Methods: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86)., Results: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001)., Conclusion: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

Acquired resistance to protein kinase C (PKC) modulators may explain the failure of clinical trials in patients with cancer. Herein, we established a human colon cancer cell line resistant to PEP005, a drug that inhibits PKCalpha and activates PKCdelta. Colo205-R cells, selected by stepwise exposure to PEP005, were >300-fold more resistant to PEP005 than parental Colo205-S cells and were cross-resistant to phorbol 12-myristate 13-acetate, bryostatin, bistratene A, and staurosporine. No PKCalpha or PKCdelta mutation was detected in Colo205-S and Colo205-R cells. Changes in Colo205-R cells were reminiscent of the epithelial-to-mesenchymal transition (EMT) phenotype. Accordingly, Colo205-R cells were more invasive than Colo205-S in Matrigel assays and in mouse xenografts. We also found an increased mRNA expression of several EMT genes, such as those encoding for transforming growth factor-beta and vimentin, along with a decreased mRNA expression of genes involved in epithelial differentiation, such as CDH1 (E-cadherin), CLDN4 (claudin 4), S100A4, and MUC1, in Colo205-R compared with Colo205-S cells in vitro and in vivo. Interestingly, high expression of ET-1 was shown in Colo205-R cells and correlated with low sensitivity to PEP005 and staurosporine in a panel of 10 human cancer cell lines. Inhibition of the ET-1 receptor ETR-A with bosentan restored the antiproliferative effects of PEP005 in Colo205-R cells and decreased the invasive properties of this cell line. Exogenous exposure to ET-1 and silencing ET-1 expression using small interfering RNA modulated cell signaling in Colo205-S and Colo205-R. In summary, acquired resistance to PEP005 was associated with expression of EMT markers and activates the ET-1/ETR-A cell signaling.

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC(50) of PEP005 ranged from 0.01-140 microM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

Based on the observation of a high incidence of breast cancer in the upper outer quadrant adjacent to the usual area of application of deodorants and/or antiperspirants, several scientific teams have advanced the hypothesis of a possible link between antiperspirants and breast cancer. The possibility of the involvement of parabens and aluminium salts, traditional components of a number of cosmetic products, has been advanced by the same teams. In order to ascertain whether this hypothesis could or could not be confirmed, a group of clinical experts in oncology was set up to search and analyse the literature data relating to the problem raised with the aim of answering three predefined questions: 1) does it exist experimental or biological arguments supporting a potential link between the use of deodorants/antiperspirants and breast cancer? 2) Does the use of deodorants/antiperspirants have any effect on the increase in the risk of breast cancer? 3) Could a causal relationship between the use of deodorants/antiperspirants and breast cancer be accepted? The scientific data were searched systematically in the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez) using standardised search equations. Fifty-nine studies resulting from the literature search were reviewed and nineteen articles with various methodologies were selected for in-depth analysis. In view of the fact that parabens are generally not present in deodorants/antiperspirants, the reflection group's search related purely to the question of aluminium salts. Among these nineteen articles, many are methodologically unsound, do not answer to the questions posed or deal with the question of parabens and were therefore discarded by the reflection group. The expert group's conclusion coincides with those of the French, European and American health authorities. After analysis of the available literature on the subject, no scientific evidence to support the hypothesis was identified and no validated hypothesis appears likely to open the way to interesting avenues of research.

Purpose: Recent data suggested that combining targeted therapies with chemotherapy may counteract drug resistance. Activation of the PI3K/AKT/mTOR pathway downstream to kinase receptors, such as EGFR, was found in 57-81% of head and neck squamous cell carcinoma (HNSCC), and was eventually associated with a loss of PTEN function. mTOR was shown to modulate cell proliferation, apoptosis, invasion, and angiogenesis. This study aimed to evaluate molecular and cellular effects of rapamycin in a panel of cell lines either as single agent or in combination with cytotoxics commonly used in HNSCC., Methods: Antiproliferative effects of rapamycin, carboplatin, and paclitaxel were evaluated in a panel of three HNSCC cell lines (SCC61, SQ20B and HEP2). Cells were exposed to rapamycin for 48 h, to carboplatin for 48 h, or to paclitaxel for 24 h. Antiproliferative effects of simultaneous and sequential rapamycin-based combinations were studied using MTT assay and median effect plot analysis. Cell cycle effects were analysed using flow cytometry., Results: Rapamycin induced concentration dependent antiproliferative effects in HNSCC cell lines with IC(50) of 5 +/- 1, 12 +/- 2 and 20 +/- 2 microM in SCC61, SQ20B, and HEP2 cells, respectively. Higher antiproliferative effects were observed in SCC61 cells overexpressing NOXA and cyclin D1 than in HEP2 that overexpressed MDR1 and BCL2. In our panel, antiproliferative effects of rapamycin were associated with G0/G1 cell cycle accumulation and apoptosis induction, at concentrations ranging 3-30 microM. Combinations of rapamycin with paclitaxel and carboplatin displayed synergistic and additive effects. Synergistic effects were observed with paclitaxel in SQ20B and HEP2 cells and with carboplatin in SQ20B cells, when cells were exposed to cytotoxics prior to rapamycin., Conclusion: Our results show that rapamycin displays antiproliferative effects and induces apoptosis in HNSCC cell lines, cellular effects being more potent in cells that do not express BCL2 and MDR1. Additive and synergistic effects were observed when rapamycin was combined with carboplatin and paclitaxel.

Management of cancer in the older-aged patient is an increasingly common problem in our occidental societies. Cancer is a disease primarily of older persons: over 60% of all cases of cancer are diagnosed after age 65 - an age group that constitutes less than 20% of the western population and the risk of persons over 65 years of age developing cancer is at least 10 times that of those under 65. Cancer in older persons may be considered a different disease from cancer in the younger in that way that biology of the host could influence the growth of cancer, that the management of the disease deserved an individualized approach. Indeed, the normal process of aging is associated with a progressive age-related reduction in function of many organs, including losses such as renal, pulmonary, cardiac, immune, hepatic, haematological, muscles, osseous, sight, hearing and brain functions. The consequences of these changes with age, added to comorbid diseases, have major implications on toxicities of anti-cancer therapies, surgery, radiotherapy as well as chemotherapy. However chronologic age should not be used as a guide to cancer therapy. Performance status and physiologic performance of the older patient are of prime importance to decide and conduct chemotherapy.

Chemotherapy-induced cardiotoxicity can concern major effects, inducing severe impairments of vital functions: systolic or diastolic function, hypertension, rhythmic or conducting pathology, Elsewhere, cardiac and vascular aging induces alterations, which concern roughly the same points and are enhanced by vascular risk factors. We wish to analyse the correlation and increase of the consequences of the first one toward the second one and the safe attitude we must have for those patients (prevention and early treatment). Echocardiography seems to have more and more a major status to assess cardiac function, chiefly in systolic and diastolic manor. We insist on the interest of stress echo for assessment of impaired contractility and for evaluation of vascular risk in ischemic disease. We suggest a vulnerability score to predict the risk of complication due to chemotherapy.

What Is Already Known About This Subject: * The optimal infusion duration for ifosfamide remains to be determined. * No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve. * The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics., What This Study Adds: * The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration. * Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles., Aims: To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary beta(2)-microglobulin (BMG) and absolute neutrophil count (ANC), respectively., Methods: Seventeen patients were enrolled into an n = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m(-2) during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM., Results: Ifosfamide and metabolite concentration-time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models., Conclusions: This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.

PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCdelta, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCdelta was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCalpha and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCdelta and reduced expression of PKCalpha resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents.

Background: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy., Methods: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection., Results: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone., Conclusion: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.

Purpose: To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients., Experimental Design: Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000., Results: Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug-drug interactions., Conclusions: Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m2/day.

Purpose: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule., Methods: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide., Results: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules., Conclusion: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

The aim of this study was to evaluate the safety and efficacy of radiolabelled rabbit polyclonal antiferritin antibody in relapsed or refractory Hodgkin's lymphoma. The protocol included a first intravenous injection of In-labelled antiferritin antibody, followed by immunoscintigraphy at 4, 48 and 72 h, and an intravenous injection of Y-labelled antiferritin antibody in the case of tumour targeting. Ten patients were included in the study: median number of chemotherapy regimens: 3; number of autografted patients: 8; number of previously irradiated patients: 9; response to last chemotherapy: six partial response and four progressions. All immunoscintigraphies showed tumour targeting. Nine patients were treated, as the last patient died from progressive Hodgkin's lymphoma before therapeutic injection. Median injected activity was 12 MBq/kg (0.32 mCi/kg). Among the 10 patients who were included in the study, one complete response and six partial responses were observed (overall response rate 70%) with a median duration of response of 8 months (range: 7-12 months). Toxicity was mainly haematological, with grade 1 or 2 neutropenia and anaemia, and grade 2 and 3 thrombocytopenia. The pharmacokinetic study showed that the half-lives of In and Y were almost identical. These results confirm those previously reported and show the therapeutic potential of rabbit polyclonal antiferritin antibody in relapsed or refractory Hodgkin's lymphoma. They therefore justify further multicentre prospective trials.

This study was undertaken to review our approach to diagnosis and treatment in a series of 11 patients (mean age 8.2 years) with primary pyomyositis, who had neither an underlying disease nor a compromised immune system. Nine of the children had positive blood cultures, Staphylococcus aureus (eight) and Streptococcus group A (one). The sites of infection were iliopsoas (four), obturator (two), hip adductors (two), levator scapula (one), thoracolumbar paraspinal (one) and gastrocnemius (one) muscles. Antibiotic treatment was initially intravenous, followed by oral administration. Of five patients with evidence of abscess formation, three underwent percutaneous drainage, whereas two required open surgical drainage. The infection resolved completely without any sequela in 10 children. One patient who developed acute compartment syndrome showed late signs of osteonecrosis of the tibial shaft segment.

The pemetrexed (Alimta) is a new generation antifolate prescribed in the treatment of mesothelioma in association with cisplatin and in the 2nd line treatment of locally advanced or metastatic non-small lung cancer. Pemetrexed is an original molecule, different from the other antifolates. On the opposite methotrexate, pemetrexed inhibits several enzymes involved in the synthesis of purines and pyrimidines, in particular thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. Pemetrexed is transported in cells by three receptors, which make easier its cellular penetration. On the other hand, the polyglutamation of the product by the folylpolyglutamate synthetase increases considerably its activity notably towards the thymidylate synthase. Finally, unlike methotrexate, pemetrexed presents an atypical effect on cellular synchronisation. The wide spectre of activity of pemetrexed confers it a therapeutic advantage with regard to the other antifolates specific of one or other one enzymes. The clinical results show an anti-tumoral activity against non-small lung cancer and in mesothelioma and recently towards other solid tumours, in particular in head an neck, colon and mammary cancers.

Gemcitabine or Gemzar forms part of the class of the anti-cancer drugs antimetabolites. Gemcitabine is a structural analogue of the deoxycytidine with 2 fluorine atoms. There is a strong analogy between gemcitabine and cytosine arabinoside (Aracytine or Depocyt), at the same time structural, mechanistic and metabolic. However, if the intracellular derivatives triphosphate of gemcitabine seem more stable than those of the cytarabine, the two molecules move away from share their therapeutic activity. Indeed, if the cytosine arabinoside finds its place in the treatment of hematologic diseases, myeloblastic or lymphoblastic acute leukaemia and in acute myeloid leukaemias and myelodysplasy, gemcitabine sees its indications in the treatment of solid tumours such as non small cell lung cancer, adenocarcinoma of the pancreas, cancer of the bladder and metastatic breast cancer.

Irofulven is currently in Phase 2 clinical trials against a wide variety of solid tumors and has demonstrated activity in ovarian, prostate, gastrointestinal, and non-small cell lung cancer. The objectives of this study were to determine its pharmacokinetics and route of excretion and to characterize its metabolites in human plasma and urine samples after a 30-min i.v. infusion at a dose of 0.55 mg/kg in patients with advanced solid tumors. Three patients were administered i.v. 100 microCi of [14C]irofulven over a 30-min infusion on day 1 of cycle 1. Serial blood and plasma samples were drawn at 0 (before irofulven infusion) and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 144 h after the start of infusion. The mean urinary and fecal excretion of radioactivity up to 144 h were 71.2 and 2.9%, respectively, indicating renal excretion was the major route of elimination of [14C]irofulven. The C(max), AUC(0-infinity), and terminal half-life values for total radioactivity were 1130 ng-Eq/ml, 24,400 ng-Eq . h/ml, and 116.5 h, respectively, and the corresponding values for irofulven were 82.7 ng/ml, 65.5 ng . h/ml, and 0.3 h, respectively, suggesting that the total radioactivity in human plasma was a result of the metabolites. Twelve metabolites of irofulven were detected in human urine and plasma by electrospray ionization/tandem mass spectrometry. Among these metabolites, the cyclopropane ring-opened metabolite (M2) of irofulven was found, and seven others were proposed as glucuronide and glutathione conjugates.

Protein kinase C (PKC) family comprises more than 12 serine-/threonine-specific isoenzymes. PKC isoenzymes play a complex role in the transduction of signal from tyrosine kinase receptor modulating proliferation, cell cycle, apoptosis, invasion, differentiation, and senescence in both cancer cells and endothelial cells. Thereby, inhibition and/or activation of specific PKCs is thought to control tumor growth by interacting directly with cancer cells and indirectly by blocking tumor angiogenesis. Furthermore, PKCs are known to modulate multi-drug resistance, providing a rational for the combination of PKCs modulators with classical cytotoxic drugs. During the past few years, preclinical and clinical data with first-generation PKC inhibitors/activators provided insight that PKCs may indeed represent attractive targets for the discovery of small molecules with new anticancer properties. In this review, we will provide an overview on the current understanding of PKC participation in chemotherapeutic resistance, the possible implications in cancer treatment, and the potential of most recent PKC inhibitors in molecular cancer therapeutics.

Background: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients., Patients and Methods: Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay > 1 week. MTD was the DL with DLT in 2/2 or > or = 2/6 patients during cycle 1-2., Results: Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1-2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations > 3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions., Conclusion: Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.

Soluble Fas (sFas) and cytokeratin 18-Asp396 neoepitope (CK18-NE) were measured by ELISA in serial samples from 42 patients with different cancers under chemotherapy and were compared with pharmacokinetic results. Baseline sFas (median 6146 pg/ml, range 3123-16294 pg/ml) was higher in cancer patients than in normal subjects (median 4954 pglml, range 2595-10565 pg/ml, n =95) (p <0.01) and increased with the number of previous chemotherapy lines (p =0.008). During pharmacokinetics, the median sFas response differed significantly with tumour histology (p<0.001) and was correlated to 5-Fluorouracil (rho=0.366, p=0.015, n=45) or cisplatin (rho=0.509, p=0.025, n=21) concentrations but not to anthracyclines or oxazaphosphorine. By Kaplan-Meier analysis, patients with baseline sFas <6146 pg/ml had a longer survival probability (p=0.002). The median baseline CK18-NE did not differ from normal subjects, but its maximum increase differed according to histology (p=0.007) and to drug type (p=0.028). Patients with a maximum increase >67.5% (median) during chemotherapy had a better univariate overall survival (p=0.021). As measured by sFas concentration, chemotherapy induces an anti-apoptotic response of differing intensity according to tumour types and drugs, which has a prognostic value for survival. A CK18-NE elevation, indicative of chemotherapy-induced apoptosis, is linked to good prognosis.

The incidence of central nervous system (CNS) recurrence in patients with lymphoma is about 5%. Nevertheless, this complication is very serious because it is almost always fatal. Its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The identification of subgroups for whom CNS prophylaxis may be of benefit is therefore important and the age-adjusted international prognostic index (aa-IPI) may be useful in this respect. Ifosfamide (IFO) is a widely used antitumor agent, requiring activation to isophosphoramide mustard (IPM) for DNA alkylation. IFO anabolism occurs through the hepatic microsomal cytochrome P450 system. As with the majority of antineoplastic agents, IFO has toxic side-effects. These include neurotoxicity due to the chloroacetaldehyde (CAA) catabolite. However, the incidence of neurotoxicity is low when IFO is administered as a continuous intravenous infusion. Both inactive IFO and active IPM cross the blood-brain barrier, making IFO treatment effective in the prevention of CNS metastasis in lymphoma patients at high risk of recurrence. The benefit/risk ratio for such patients should evaluated.

Purpose: This study assessed the cytotoxic effects of irofulven in combination with oxaliplatin and cisplatin in a panel of human cancer cell lines., Methods: Growth inhibition studies were performed using the human HT29 colon cancer cell line, irofulven-resistant derivative HT29/IF2, breast cancer cell line MCF7, and ovarian cancer line CAOV3. Irofulven-oxaliplatin combinations were compared with irofulven-cisplatin combinations in the same cell lines using similar experimental settings. Cells were exposed for 1 h to irofulven and then for 24 h to oxaliplatin or cisplatin and vice versa., Results: Single agent irofulven displayed cytotoxic effects against human colon HT29 cells, human breast cancer cell lines including MCF7, SKBR3, and ZR-75-1, and human ovarian cancer cell lines CAOV3, OVCAR3, and IGROV1, with OVCAR3 being the most sensitive cancer cell line (IC50: 2.4 microM). In all tested cell lines the oxaliplatin-irofulven combination led to clear evidence of synergistic activity. In HT29 and HT29/IF2, the sequence oxaliplatin followed by irofulven appears to be the most effective whereas in MCF7 cells, irofulven given prior to or simultaneously with oxaliplatin is more effective than the other schedule. The combination displays additive activity toward CAOV3 ovarian cells when irofulven was administered prior to or simultaneously with oxaliplatin and partially synergistic when oxaliplatin was followed by irofulven. In most of the cell lines, the sequence oxaliplatin followed by irofulven appears to be the most effective as compared to other schedules. A combination of irofulven with cisplatin has the same efficacy as with oxaliplatin for the same cell lines. Cell cycle studies show that irofulven increases the proportion of cells in the S phase. Cisplatin-irofulven and oxaliplatin-irofulven combinations block cells in G1/S and potently induce apoptosis., Conclusion: Irofulven displays synergistic antiproliferative and pro-apoptotic effects when combined with oxaliplatin over a broad range of concentrations in human colon and breast cancer cells. Acquired resistance to irofulven has limited impact on the effects of cisplatin-irofulven and oxaliplatin-irofulven combinations. Based on these data, irofulven-oxaliplatin and cisplatin-irofulven combinations will be further explored in clinical trials, favoring the use schedules of oxaliplatin given prior to irofulven in patients with cancer.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.