Sensitization of normal and malignant tissues to cyclophosphamide by nitroimidazoles with different partition coefficients

Abstract

The ability of a range of 2-nitroimidazoles with similar electron affinities but widely differing partition coefficients (P) to enhance the cytotoxicity of cyclophosphamide (CY) in mouse tumour and normal tissues was investigated. In a preliminary study large single doses of benznidazole (BENZ), misonidazole (MISO), desmethylmisonidazole (DMM), and SR-2508 were found to give similar enhancement of the RIF-1 and SCC VII/St tumours. SR-2555 was less effective. A direct comparison was made between MISO and SR-2508 using prolonged, low-level drug exposures, achieved by multiple injections. The enhancement of CY cytotoxicity achieved in the two tumour systems (RIF-1 and SCC VII/St) was found to be similar for a given blood sensitizer concentration. In the normal tissue assays (white blood cell count, bone marrow CFU-S and testis spermatogonia) neither MISO nor SR-2508 produced significant enhancement of CY cytotoxicity, so that the therapeutic gains achieved at a given blood concentration of sensitizer were similar for SR-2508 and MISO. The main advantage of SR-2508, however, will probably lie in its lower toxicity, permitting higher blood levels to be achieved. However, the slope of the dose response curves are rather shallow so we would not predict a dramatically increased benefit.