Chemosensitization by lipophilic nitroimidazoles

Abstract

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.