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The clinical development of interleukin 12 (IL-12) as a single agent for systemic cancer therapy has been hindered by its significant toxicity and disappointing anti-tumor effects. The lack of efficacy was accompanied by, and probably related to, the declining biological effects of IL-12 in the course of repeated administrations at doses approaching the maximum tolerated dose (MTD). Nevertheless, IL-12 remains a very promising immunotherapeutic agent because recent cancer vaccination studies in animal models and humans have demonstrated its powerful adjuvant properties. Therefore, IL-12 may re-enter the arena of cancer therapy. Here, we review the immune modulating characteristics of IL-12 considered responsible for the adjuvant effects, as well as the results of animal and human cancer vaccination studies with IL-12 applied as an adjuvant. In addition, we discuss how studies with systemic IL-12 in cancer patients, and several other lines of evidence, indicate that IL-12 may exert optimal adjuvant effects only at low dose levels. Therefore, the MTD may not constitute the maximum effective dose of IL-12 for adjuvant application.

In a phase I study we demonstrated the feasibility of a bi-weekly combination of paclitaxel 180 mg m−2 with cisplatin 60 mg m−2. In this study we further assessed toxicity and efficacy of this schedule in the treatment of advanced cancer of the oesophagus or the gastro-oesophageal junction. Patients received paclitaxel 180 mg m−2 administered over 3 h followed by a 3-h infusion of cisplatin 60 mg m−2. Patients were retreated every 2 weeks unless granulocytes were

The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --T and C --S), and (3) TPT or SN-38 followed by cisplatin (T --C and S --C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. In addition, a significant schedule-dependent synergistic cytotoxicity was found in three of the cell lines used, with C --T (or C --S) being the most active schedule. The formation and repair of total cisplatin-DNA adducts in the IGROV-1 ovarian cancer cell line and its cisplatin-resistant subline IGROV(CDDP) was not significantly affected by TPT on simultaneous incubation. In contrast, the number of cisplatin-DNA interstrand cross-links detected in the IGROV-1 and IGROV(CDDP) lines at certain time points was significantly lower after coincubation of the cells with TPT. Assessment of the cell-cycle distribution revealed an accumulation of cells in the G2/M phase after exposure to cisplatin. After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.

A retrospective study on the incidence of catheter-related complications and catheter indwelling time (tCI) during treatment with continuous interleukin-2 (IL-2) infusion in patients with metastatic renal cell cancer, who were equipped with tunnelled central venous catheters (CVC). A group of 72 patients were treated with IL-2-based immunotherapy. Two induction treatment cycles of 35 days each were used. Treatment consisted of IL-2 as a continuous intravenous infusion (c.i.v.) with lymphokine-activated killer cells and interferon alpha intramuscularly. A tunnelled CVC was inserted at the start of treatment and was kept in place for the duration of the therapy or until the occurrence of complications. Out of 72 CVC, 30 (42%) functioned uneventfully for a median tCI of 64 days. In another 12 clinically uncomplicated cases (16%), catheter tips were positive in routine culture after a median tCI of 33 days. In 18 patients (25%), CVC-related infections were noted, including 8 (11%) local tunnel infections and 10 (14%) septic episodes. These complications occurred at a median tCI of 28 and 20 days respectively. In 15 (83%) of these 18 catheter infections, Staphylococcus aureus was isolated, whereas in the remaining 3 (17%) Staphylococcus epidermidis was found. Subclavian vein thrombosis was noted in 12 (17%) CVC at a median tCI of 31 days: 5 (36%) of these were diagnosed in the first 14 patients. This prompted us to administer prophylactic heparin 15,000 i.u. c.i.v. daily during IL-2 treatment. Thereafter the incidence of thrombosis dropped to 7 (12%) in the subsequent 58 CVC inserted (P = 0.03). In conclusion, in contrast to previous reports on the high incidence of CVC-related septicaemia and thrombosis, we observed a relatively low incidence of these complications, which we ascribe to the use of tunnelled catheters and prophylactic heparin.

Purpose: This study was performed to deter mine the correlation of CA15.3 and TPS with disease course in patients with metastatic breast cancer.Methods: Levels of CA15.3 and tissue polypeptide antigen using the M3 monoclonal antibody (TPS) were determined in the serum of 60 patients with metastatic breast cancer. CA15.3 and TPS were measured at two assay times.Results: A change of more than 25% in the serum level of CA15.3 or TPS was highly correlated with tumor response. The association between response and change in marker levels was stronger for CA15.3 (P=0.0001) than for TPS (P=0.0005). Distinct mismatches between marker changes and the tumor response were observed for both CA15.3 and TPS.Conclusion: CA15.3 and TPS are useful in the determination of response to treatment. Because of observed disagreement, marker changes can only be regarded as indicative of disease course.

The aims of the trial were to establish the response rate and determine the toxicity of combination chemotherapy with ifosphamide, vincristine and cisplatin (HOP regimen) in advanced metastatic seminoma and to study the role of post-chemotherapy consolidation treatment. Patients with bulky metastatic non-alpha-fetoprotein-producing seminomas were eligible for this phase II study [serum human chorionic gonadotropin or = 10 cm or had extra-gonadal seminoma or had relapsed after previous radiotherapy. The HOP regimen consisted of four 3-weekly cycles of the following drug combination: ifosphamide (days 1-5, 1.2 mg m-2 day-1), vincristine (day 1, 2 mg) and cisplatin (days 1-5, 20 mg m-2 day-1). Residual masses persisting 6 months after chemotherapy could be considered for consolidation surgery or radiotherapy. Maximal response to the HOP chemotherapy (evaluated at any time) was based on the WHO criteria. The median observation time was 2.5 years (range 1.8-5.5 years). Thirteen institutions treated 42 eligible patients within the study (testicular cancer stage > or = IID, 25; extragonadal, 5; relapse after previous radiotherapy, 12). Two patients were not evaluable for response owing to premature treatment discontinuation. Maximal response was as follows: complete remission (CR), 26 (65%); partial remission (PR) 11 (28%); no change (NC), 2 (5%); progressive disease (PD), 1 (3%). Four patients have died, three from their malignancy (two without previous irradiation and one with prior radiotherapy). The fourth patient died of treatment-related toxicity. The 3 year survival for all 42 eligible patients was 90%. Dose reduction and treatment postponement were necessary in 25 and 14 patients respectively. Ten patients experienced granulocytic fever. Previously irradiated patients tolerated chemotherapy as well as non-irradiated patients. Immediately after HOP chemotherapy a mass persisted in 16 of 17 patients with retroperitoneal masses of > or = 100 mm at presentation. Three of these residual lesions were resected within the following 6 months showing complete necrosis. Four lesions dissolved spontaneously during the first year of follow-up. Nine lesions persisted for > or = 1 year (one after consolidation radiotherapy) without leading to relapse. Four of seven patients with mediastinal lesions achieved CR and three a PR after HOP chemotherapy. The HOP chemotherapy regimen is highly effective in patients with advanced metastatic seminoma or those relapsing after previous radiotherapy, but is associated with a high risk of toxicity, in particular myelotoxicity.

Drugs used in anti-cancer chemotherapy are thought to exert their cytotoxic action by induction of apoptosis. Genes have been identified which can mediate or modulate this drug-induced apoptosis, among which are c-myc, p53 and bcl-2. Since expression of oncogenic ras genes is a frequent observation in human cancer, we investigated the effects of the c-H-ras oncogene on anti-cancer drug-induced apoptosis. Apoptosis induced by a 2 h doxorubicin exposure was measured by in situ nick translation and flow cytometry in a rat cell line (R2T24) stably transfected with the c-H-ras oncogene and in a control cell line (R2NEO) transfected only with the antibiotic resistance gene neo. Both cell lines (R2T24 and R2NEO) had nearly identical growth characteristics, including cell doubling time, distribution over the cell cycle phases and plating efficiency in soft agar. Doxorubicin exposure of the R2NEO cells led to massive induction of apoptosis. In contrast, R2T24 cells, expressing the c-H-ras oncogene, showed significantly less apoptosis after doxorubicin incubation. Doxorubicin induced approximately 3- to 5-fold less cytotoxicity in the R2T24 cells than in the R2NEO cells, as determined by clonogenic assay in soft agar. No difference was observed in intracellular doxorubicin accumulation between the two cell lines, indicating that the classical, P-glycoprotein-mediated multidrug resistance phenotype is not involved in the observed differences in drug sensitivity. In conclusion, our data show that constitutive expression of the c-H-ras oncogene suppresses doxorubicin-induced apoptosis and promotes cell survival, suggesting that human tumours with ras oncogene expression might be less susceptible to doxorubicin treatment.

The purpose of this study was to determine the mechanism of the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin. Cisplatin- induced DNA-adducts and cisplatin accumulation were quantitated in peripheral blood leukocytes (WBC). The WBC were obtained from patients treated with docetaxel or paclitaxel in phase I/II studies and were incubated in vitro with cisplatin. In addition, blank whole-blood samples were obtained from pa- tients and healthy subjects and incubated in vitro with cisplatin or docetaxel/paclitaxel and cisplatin. The cis- platin-induced DNA-adduct levels measured in WBC after treatment with docetaxel or paclitaxel were signif- icantly lower than those determined in non-pretreated WBC. Docetaxel and paclitaxel reduced the intracellu- lar accumulation of cisplatin in WBC by 46—47%. If the pharmacodynamic interaction between docetaxel/pac- litaxel and cisplatin also occurs in other normal tissues such as bone marrow, it may well contribute to the sequence dependent toxicity that has been observed in clinical studies.

The ether lipid miltefosine (hexadecylphosphocholine) was orally given to patients with various tumours in a dose-finding study. All patients initially received a daily total dose of 100 mg, which in the absence of side-effects was increased to 150 mg and further to 200 mg. A total of 54 patients were entered and were evaluable for gastrointestinal toxicity. Nausea and vomiting were found to be dose-limiting; 22% of patients ultimately tolerated a dose of 100 mg, 59% tolerated a dose of 150 mg and 19% tolerated a dose of 200 mg. In addition 30% of patients developed renal dysfunction, which was thought to be related to the drug. No other toxicities were observed. For further phase II studies it is recommended that one starts with a dose of 150 mg daily, divided over three administrations.

Background In view of their small therapeutic window, cytotoxic drugs for adults are dosed based on body-surface area (BSA), aiming to reduce interpatient variability in drug exposure. In a retrospective analysis no rationale was found for continuing of BSA-based dosing for cisplatin (CDDP) in the average patient[JCO 19 (2001), 3733]. Here, we studied the usefulness of this dosing strategy in patients at lower and upper extremes of BSA values. Methods Patients were randomized to receive a fixed dose of CDDP (based on an average BSA of 1.86m2) in course 1 and a BSA-adjusted dose in course 2 or vice versa. Plasma concentrations of unbound platinum (Pt) were determined and analyzed by noncompartmental analysis. Results 18 Patients are evaluable so far; 10 large patients (9 M> 2.05m2, 1 F >1.90m2) and 8 small patients (5 M 0.37), however with a large variability in CL. The average CL in large patients was approximately 30% faster than the average CL in small patients. Correction of CL for the BSA in both populations, resulted in a reduction of only 10–13% in the variability. Conclusion Unless better predictors for CL are identified, fixed dose regimens per BSA-cluster are recommended. Clinical Pharmacology & Therapeutics (2005) 77, P37–P37; doi: 10.1016/j.clpt.2004.12.033