In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts.

New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblastoma (IGRG88, 93, 121) xenografts treated at an advanced stage of tumor growth in comparison with that of doxorubicin. Animals were randomly assigned to receive i.v. S16020 or doxorubicin weekly for three consecutive weeks. The optimal dose was 80 mg/kg per week. S16020 demonstrated a significant antitumor activity in two out of three medulloblastoma xenografts. IGRM57 xenografts were highly sensitive with 100% tumor regressions and a tumor growth delay (TGD) of 102 days, while one of eight IGRM34 xenografts showed a partial regression with a TGD of 16 days. Doxorubicin was significantly more active than S16020 in these two models. IGRM33, a model established from a tumor in relapse after chemotherapy and radiotherapy, was refractory to both drugs. S16020 demonstrated a significant antitumor activity in the three glioblastoma xenografts evaluated. The wild-type p53 IGRG93 xenograft was highly sensitive with 100% tumor regressions and a TGD of 54 days. IGRG121 (wt p53) and IGRG88 (mutant p53) were moderately sensitive with TGDs of 33 and 23 days, respectively. Doxorubicin showed greater activity in two of these models. All six xenografts exhibited low expression of mdr1 as quantitated by RT-PCR, and no correlation was found with the activity of either drug. Conversely, a low activity of the two drugs was significantly associated with a high expression of MRP1 in medulloblastomas. Finally, no relationship was observed between drug sensitivity to either drug and expression of their target, topoisomerase IIalpha. In conclusion, S16020 and doxorubicin showed significant antitumor activity in brain tumor xenografts treated at an advanced stage of tumor growth. Their activity was related to MRP1 expression in medulloblastomas.

Enhancement of fotemustine (Muphoran) cytotoxicity by amifostine in malignant melanoma cell lines.

Fotemustine (Muphoran, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC(50) of fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of fotemustine as a significant decrease in IC(50) was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation of O(6)-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.