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

Abstract

Summary 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-I 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-l 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.

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide

“…This effect was first demonstrated by Clement et al, 1980 andRose et al, 1980 and is particularly marked for alkylating agents. Misonidazole increased the antitumour activity of melphalan and of cyclophosphamide by factors of 2.2 and 1.8 respectively, while myelotoxicity was increased only by 1.2 and 1.3-fold (Law et al, 1981;Hirst et al, 1984). At equimolar doses, SR2508 enhances the activity of cyclophosphamide and melphalan as effectively as misonidazole .…”