Evaluation of radiosensitizers in combination with chemotherapeutic agents in solid tumors

The electron-affinic compounds misonidazole (MISO), metronidazole (MET), desmethylmisonidazole (DMM), and CB1954 were shown to enhance the activity of alkylating agents in M5076 ovarian tumor. MISO, MET, and DMM enhanced the antitumor activity of cyclophosphamide by factors of 1.7, 1.5, and 1.7, respectively. MIS, MET, and CB1954 enhanced the antitumor activity of melphalan by factors of 2.2, 2.4, and 1.8, respectively. MISO also enhanced the antitumor activity of mitomycin C by a factor of 2.0. MISO did not enhance the activity of chlorozotocin given as a single dose and only slightly enhanced the antitumor activity of this agent when the combination was given on a q4D x 3 schedule. MISO administered 1 hr prior to the antimetabolite 5-FU on a q7D x 3 schedule was no more effective than 5-FU alone against colon carcinoma 38. MISO given simultaneously with or 1 hr after 5-FU strongly inhibited the antitumor activity of 5-FU in this tumor. Data obtained in this study indicate that several radiation sensitizers including three nitroimidazoles and a dinitrobenzamide can enhance the antineoplastic activity of alkylating agents. The degree of enhancement in the M5076 tumor appears to be independent of the electron affinity of the sensitizer. Enhancement was observed with relatively ineffective as well as highly active alkylating agents.