In vivo evaluation of the radiosensitizing and cytotoxic properties of newly synthesized electron-affinic drugs.

We are synthesizing and testing various 2-nitroimidazole analogs with different octanol/water partition coefficients for their radiosensitizing and cytototoxic properties. Our hypothesis is that, unlike the situation in vitro, lipophilicity will play a major role in determining the extent of radiosensitization of hypoxic tumour cells in vivo and also the degree of animal toxicity. The radiosensitivity testing involves determination of the surviving fraction of EMT6 tumour cells irradiated in vivo under different conditions following drug injection, and subsequent assay in vitro. Data obtained to date on eight 2-nitroimidazoles do not indicate any compound clearly superior to misonidazole (Ro-07-0582), although one or two are close and may prove better at the completion of testing. Cytotoxicity of the compounds is assayed by cell survival and histologically. Data obtained on the toxicity of misonidazole to the cells of EMT6 tumours suggest that a large proportion of the anoxic cells in these tumours are not near necrotic areas, but rather result from the temporary closure of blood vessels.