[Enhancement of MeCCNU potency (chemosensitization) by misonidazole in a human melanoma xenograft system].

In addition to the well-known radiosensitizing properties of misonidazole its potential for chemosensitization has been investigated recently. According to results obtained mostly with conventional murine tumor systems, the degree of such chemosensitization depends on the particular tumor system, the type of antineoplastic agent and the dose of misonidazole employed. Our experiments were conducted with a human melanoma transplanted onto (nu/nu) mice. At the dose level of 1 g/kg misonidazole toxicity was enhanced by a factor of about 3, whereas antineoplastic activity was enhanced only by a factor of about 1.8. Therefore, the usefulness of such chemosensitization remains limited, especially since under clinical circumstances this dose of misonidazole would cause unacceptable neurotoxicity. The retention of radiotivity from 14C-MeCCNU is increased in neoplastic as well as in normal tissues by a factor of 1.3.DNA interstrand crosslinks measured 24 hours after drug exposure, however, are increased by a factor of about 2. Despite their nonselective reaction at the level of molecular pharmacology, drugs with sensitizing or protective properties may well constitute a valuable addition to the serial synthesis of chemical congeners in drug development. The use of oxazaphosphorines is quoted as an example where selective protection from urotoxicity is afforded by sodium-2-mercaptoethanesulfonate.