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Purpose: The relationship between the pharmacokinetics and effects of gefitinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is unknown. In this study, we examined the correlation between gefitinib plasma concentration and progression-free survival (PFS) in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R.Methods: The retrospective analysis examined 40 patients who were administered 250 mg of gefitinib daily. All patients were diagnosed with and treated for advanced non-small cell lung carcinoma with sensitive EGFR mutations between January 2011 and November 2013 at Akita University Hospital, Akita, Japan. The 40 patients were divided into four groups by trough plasma concentration (high or low) and mutation type (exon 19 deletions or exon 21 L858R point mutations). PFS, response rate, and toxic effects were analyzed in all four groups.Results: After excluding 5 patients, the remaining 35 were successfully analyzed. For the patients with exon 19 deletions, there was no significant difference in PFS between the high and low plasma concentration groups (median survival: 12.0 vs. 17.0 months, P = 0.9548). In contrast, the PFS was significantly shorter for patients with exon 21 point mutations and low vs. high concentrations of gefitinib (median survival: 8.0 vs. 16.0 months, P < 0.05).Conclusions: The results suggest that low gefitinib plasma concentrations in patients with exon 21 L858R point mutations may be associated with shorter PFS in NSCLC patients. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone ( n = 55) or ACNU + PCZ ( n = 56) in the intention-to-treat population were 27.4 and 22.4 months ( p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone ( n = 40) or ACNU + PCZ ( n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM. [ABSTRACT FROM AUTHOR]

The efficacy and toxicity of combined paclitaxel (PTX) and gemcitabine (GEM) was evaluated as a protocol for first-line chemotherapy in 40 patients with advanced non-small-cell lung cancer (NSCLC). Paclitaxel, 100 mg/m2, was administered intravenously (IV) as a 1-h infusion, followed by GEM, 1,000 mg/m2, IV over 30 min on days 1 and 8 of a 21-day cycle. The median age of patients was 66 years with a range of 33–75 years. Nearly all patients (39/40) had an ECOG performance status of 0 or 1. Thirteen patients (32%) had initial stage IIIB disease and 27 patients (68%) had stage IV disease. Histological subtypes were adenocarcinoma (73%) and squamous cell carcinoma (25%). Twenty-two patients (55%) achieved a partial response and none achieved a complete response, giving an overall response rate of 55% (95% confidence interval: 38.2–71.8%). Disease stability was achieved in 14 patients (35%), and 4 patients (10%) had progressive disease. The median survival time was 11.9 months (95% CI: 10.3–14 months), with a 1-year survival rate of 47.5%. Grade 3 or 4 hematological toxicities observed included neutropenia in 37.5%, anemia in 2.5%, and thrombocytopenia in 5.0% of these patients. Non-hematologic toxicities were mild, with the exception of grade 3 and 4 pneumonitis. There were no deaths due to toxicity. Weekly chemotherapy with PTX plus GEM is effective and is acceptable for the first line treatment of advanced NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Methods: The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m-² and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m-² day-± beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610. Results: Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3–4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77–1.37). Similarly, the ratio of the mean AUC0-last for carboplatin was 1.04 (0.73-1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03–1.31), and the ratio of the mean AUC0-last was 1.17 (1.04–1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer). Conclusions: These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the metabolic fate of UCN-01, a signal transduction inhibitor, blood and plasma concentrations, distribution, metabolism and excretion were investigated in rats and dogs after intravenous administration of [3H]UCN-01. Methods: The radioactivity in plasma, blood and tissues was measured after intravenous administration of UCN-01. In addition, the radioactivity excreted in bile, urine and feces was also determined. Results: The radioactivity in rat and dog plasma disappeared triphasically with terminal half-lives of 21.3 and 27.2 h, respectively. The ratios of the blood-to-plasma concentrations ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [3H]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The highest concentration was observed in the lungs followed by the liver and kidneys. The radioactivity was mainly excreted in feces, reaching 96.0% of the radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct-cannulated rats, most of the radioactivity excreted in feces was from biliary radioactivity. There were several metabolites in bile samples, but little UCN-01. Conclusions: UCN-01 is mainly eliminated by the liver, and there are high concentrations of radioactivity derived from [3H]UCN-01 in all tissues except the brain and testes. [ABSTRACT FROM AUTHOR]

Purpose: 7-Hydroxystaurosporine (UCN-01) is a potent protein kinase inhibitor and is being developed as a novel anticancer agent. We describe here its pharmacokinetics and pharmacodynamics in experimental animals. Methods: The pharmacokinetics of UCN-01 were studied following intravenous (i.v.) administration to mice, rats and dogs at doses of 1–9, 0.35–3.5 and 0.5 mg/kg, respectively. We also studied the pharmacodynamics of UCN-01 (9 mg/kg per day) during and after five consecutive i.v. administrations to nude mice bearing xenografted human pancreatic tumor cells (PSN-1). The concentrations of UCN-01 in plasma and tumor were measured by HPLC using a fluorescence detector. Results: UCN-01 in plasma after i.v. administration was eliminated biphasically in mice and rats, and triphasically in dogs. The elimination half-lives in mice, rats and dogs were 3.00–3.98, 4.02–4.46 and 11.6 h, respectively. The total clearance (Cltotal) values in mice, rats and dogs were high (1.93–2.64, 2.82–3.86 and 0.616 l/h per kg, respectively). The hepatic clearance (Clhepatic) in rats represented 54.0–81.3% of Cltotal. The volumes of distribution at steady-state in mice, rats and dogs were large (7.89–8.42, 13.0–16.9 and 6.09 l/kg, respectively). These pharmacokinetic parameters were dose-independent in mice and rats. UCN-01 produced significant inhibition of tumor growth during five consecutive i.v. administrations in mice bearing the xenografted PSN-1 cells, and the inhibitory effect continued for 3 days after the final administration. UCN-01 concentrations in tumor tissue were much higher than those in the plasma, and the ratio of tumor to plasma concentrations was about 500 at 24 h after five consecutive doses. Conclusions: The pharmacokinetic studies showed that UCN-01 has a high clearance and large distribution volume in various experimental animals, and its disposition is linear over the range of doses tested. The pharmacodynamic study showed that UCN-01 is distributed at much higher concentrations in tumor than those in plasma and that it significantly inhibits tumor growth. The high distribution of UCN-01 into tumor cells may contribute to the potent inhibition of tumor growth in vivo. [ABSTRACT FROM AUTHOR]

ZD9331 is a non-polyglutamatable, potent quinazoline antifolate inhibitor of thymidylate synthase (TS). In an effort to clarify the exact mechanism of resistance to this novel TS inhibitor, we examined the molecular alterations in its target enzyme TS, the transport protein (reduced folate carrier, RFC), and folylpolyglutamate synthetase (FPGS) in a human acute lymphoblastic leukemia cell line, MOLT-3, made resistant to ZD9331. A 310-fold resistant subline was established after 6 months exposure to the drug at concentrations up to 7 μ M, and was designated MOLT-3/ZD9331. MOLT-3/ZD9331 showed crossresistance to CB3717 (4.8-fold), raltitrexed (63-fold) and methotrexate (MTX) (120-fold), but retained sensitivity to trimetrexate (0.88-fold). The resistant cells demonstrated impaired initial cellular uptake and low accumulation of [3H]MTX in accordance with a decreased expression of RFC1, suggesting the downregulation of RFC. However, Southern blot analysis demonstrated no change in gene copy number nor gross rearrangement of RFC1 in the resistant cells. In addition, MOLT-3/ZD9331 showed amplification of the TS gene with a concomitantly increased level in the gene expression. In contrast, the expression of FPGS did not alter. These results demonstrate that continuous exposure of the cells to ZD9331 leads not only to a decreased expression of RFC1 but also to TS gene amplification and overexpression. The resistant mechanisms are likely to be regulated both at a genetic and a transcriptional level for different resistance phenotypes in the ZD9331-resistant MOLT-3 cells. [ABSTRACT FROM AUTHOR]

Purpose: Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. We examined whether cationic liposome-mediated transfer of a ribozyme could reverse MDR. Methods: A ribozyme which cleaved codon 196 of MDR1 mRNA was constructed from synthetic oligonucleotides. The MDR1 ribozyme was mixed with N-(1-(2,3-dileoyloxy)propyl)- N, N, N-trimethylammonium methyl sulfate (DOTAP) to form a liposomal complex. The complex was used to treat two P-glycoprotein-producing MDR cell lines: MCF-7/R human breast cancer cells resistant to doxorubicin and MOLT-3/TMQ800 human ALL cells resistant to trimetrexate (TMQ). In order to investigate the differential sensitivity of these two cell lines to the liposome-ribozyme complex, cellular pharmacological studies including phase-contrast and confocal microscopic studies were performed. Results: Treatment with the liposome-ribozyme complex resulted in reversal of vincristine (VCR) resistance in MCF-7/R cells, but not in MOLT-3/TMQ800 cells. In MCF-7/R cells the treatment resulted in decreases in MDR1 mRNA expression and P-glycoprotein production, whereas no changes in these parameters were seen in MOLT-3/TMQ800 cells. Phase-contrast microscopy revealed that in MCF-7/R cells treatment with DOTAP led to the formation of cytoplasmic vacuoles, and treatment with latex beads resulted in the development of a shiny material in the cytoplasm. In contrast, in MOLT-3/TMQ800 cells hardly any morphological changes occurred. Confocal microscopic imaging showed cytoplasmic fluorescence in MCF-7/R cells after treatment with DOTAP/FITC-dextran or FITC-conjugated latex beads. In MOLT-3/TMQ800 cells no fluorescence was detected. Treatment with cytochalasin B abolished fluorescence in MCF-7/R cells after treatment with DOTAP/FITC-dextran or FITC-conjugated latex beads. These studies show that MCF-7/R cells have high endocytotic activity whereas MOLT-3/TMQ800 cells have little activity. Conclusions: Endocytotic activity was correlated with the success of cationic liposome-mediated transfer of MDR1 ribozyme. Determination of endocytotic activity of target tumor cells may be predictive of efficacy of liposome-mediated gene transfer. [ABSTRACT FROM AUTHOR]

When tumor cell density increases, the cytotoxic activity of certain anticancer agents, such as vincristine (VCR) and doxorubicin (DXR), progressively decreases. This phenomenon is termed the inoculum effect. Since VCR and DXR are less active in an acidic environment, we questioned whether the inoculum effects could have resulted from acidification of the medium that may have developed due to the high cell density. However, measurements of the cytotoxic activity of these agents in a pH-controlled medium revealed only a minor correction of the inoculum effects. Second, we wondered whether the inoculum effects that occurred at the high cell density might have been attributable to insufficient amounts of drugs to bind all the binding sites of the cells. To test this hypothesis, we used drug-resistant sublines, which required higher VCR or DXR concentrations for cell killing than did the parent cell line. When higher drug concentrations were used, the dose-response curves generated for low- and high-density cell populations became closer and overlapped each other, resulting in virtual disappearance of the inoculum effects. Measurements of cellular drug levels revealed that at a high cell density, cells accumulated much smaller amounts of both VCR and DXR in parallel with the positive inoculum effect. In contrast, when high concentrations of the drugs were used in drug-resistant cells, differences in the cellular drug contents between low and high cell densities became narrow. Cisplatin (DDP) belongs to a group of drugs that do not produce inoculum effects, and DDP's cytotoxic effects were not influenced by the pH-controlled medium or by the use of drug-resistant cell lines. These observations indicate that the inoculum effects are the result of the unavailability of VCR or DXR molecules to all cellular binding sites when cells at high densities are exposed to drugs. The drug concentration relative to cell density was apparently the major determinant for the inoculum effects seen in VCR- or DXR-induced cell killing. [ABSTRACT FROM AUTHOR]

The effect of tumor cell density on the cellular pharmacokinetics of doxorubicin (DXR) and cisplatin (CDDP) was studied using MOLT-3 human acute lymphoblastic leukemia cells. As determined by the MTT assay, the growth-inhibitory effect of DXR was approx. 40 times lower when cell density was increased from 10(6) to 10(8) cells/ml (positive inoculum effect), whereas little or no influence of cell density was observed in CDDP-induced cell-growth inhibition. As measured by high-performance liquid chromatography using a fluorescence detector, the cellular accumulation of DXR showed 6- and 18-fold decreases after 1 h incubation when the cells were concentrated from 10(6) to 10(7) and 10(8) cells/ml, respectively. Only at low cell density (10(6) cells/ml) did the amount of DXR in the cells increase with increasing exposure times of up to 6 h. The DXR concentration in the supernatant that was separated from a cell suspension showing a density of 10(8) cells/ml fell to 20% of that obtained at 10(6) cells/ml. The metabolites of DXR, including Adriamycinol and Adriamycinone, were not detectable in the cell extracts or supernatants at any cell density examined. In contrast, the cellular accumulation of CDDP calculated from the platinum concentration, which was measured with a flameless atomic absorption spectrophotometer, was essentially identical at all cell densities examined; moreover, extension of the exposure period resulted in a linear increase in the amount of CDDP in the cells. CDDP concentrations in the supernatants were equally retained, irrespective of cell densities. These observations indicate that the positive inoculum effect shown in DXR-induced cell-growth inhibition results from the decreased cellular accumulation of the drug at high cell densities. We found no influence for cell density on the cellular accumulation of CDDP that might be relevant to the therapeutic potentiation of this drug at high tumor-cell density. [ABSTRACT FROM AUTHOR]