melphalan and benzonidazole

The radiation sensitizer misonidazole (MISO) has been shown to potentiate the cytotoxic action of a variety of anti-cancer agents. Even larger enhancement ratios than those observed with MISO have been found with certain other nitroimidazoles. One agent reported to be particularly effective in combination with the chemotherapeutic agent melphalan is the sensitizer RSU 1069. The present studies therefore were designed to evaluate the effect of combining these two agents in the treatment of intramuscularly growing KHT sarcomas. Tumor response was assessed using an in vivo to in vitro clonogenic cell survival assay. When given at times ranging from 60 min before to 30 min after melphalan exposure, RSU 1069 was found to increase the tumoricidal activity of the chemotherapeutic agent. Complete dose response curves combining RSU 1069 and a range of melphalan doses then were determined. For comparison the effects of combining MISO or benznidazole (BENZO) with melphalan also were evaluated. All sensitizers were administered i.p. either 30 min before (BENZO) or simultaneously with (MISO, RSU 1069) the chemotherapeutic agent. Survival of clonogenic tumor cells assessed 22 to 24 hr after treatment was used to assay tumor response. When combined with melphalan, doses of RSU 1069 (0.38 mmol/kg), BENZO (0.3 mmol/kg) and MISO (5.0 mmol/kg) were found to yield dose modifying factors of 1.6, 1.5, and 1.4, respectively. These results indicate that potentiation of melphalan activity occurs at RSU 1069 doses which are approximately 10-fold lower than those of MISO, making this sensitizer as effective a potentiator of melphalan as so far tested in the KHT sarcoma.

Topics: Animals; Aziridines; Azirines; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Melphalan; Mice; Misonidazole; Neoplasm Transplantation; Nitroimidazoles; Radiation-Sensitizing Agents; Sarcoma, Experimental; Time Factors

We have carried out experiments to determine the response of tumours and normal tissues in the C3H mouse to the combination of lipophilic nitroimidazoles and CCNU, cyclophosphamide or melphalan. The nitroimidazoles studied were Ro 07-1902 (1902) and benznidazole (Ro 07-1051, BENZO). Maximum enhancement of CCNU response in the KHT sarcoma by 2.5 mmol kg-1 1902 or 0.3 mmol kg-1 BENZO occurred at low doses of CCNU where dose modifying factors (DMF) of 2.5-3.0 and 1.5-2.0 respectively were found. The DMFs for depression of white cell count at day 3 were 1.6 and 1.2 respectively whilst the DMFs for LD50/30 were 1.5 and 1.3. There appears, therefore, to be a therapeutic gain at low doses of CCNU of about the same magnitude as produced by 2.5 mmol kg-1 misonidazole. The production of this gain at relatively low doses of BENZO is of possible clinical significance. Some sensitization of the KHT tumour to CCNU by 0.3 mmol kg-1 BENZO was maintained even with an interval of 25 h between BENZO and CCNU injection. A multiple injection regime of BENZO administration designed to maintain plasma concentrations for prolonged periods was, however, no more effective than a single dose. The response of the RIF-1 sarcoma to cyclophosphamide was not enhanced by the lipophilic sensitizers at the doses previously stated. Considerable enhancement of tumour response to melphalan (DMF 2.0) was produced by both lipophilic sensitizers. Enhancement of acute LD50 was similar in magnitude but no large enhancement by BENZO of melphalan induced white blood cell depression was observed. The evidence regarding the therapeutic potential of this combination is, therefore, equivocal.

Topics: Animals; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Leukocyte Count; Lomustine; Male; Melphalan; Mice; Mice, Inbred C3H; Misonidazole; Nitroimidazoles; Sarcoma, Experimental; Time Factors