Potentiation of cyclophosphamide cytotoxicity in vivo: a study with misonidazole and fifteen other 1-substituted 2-nitroimidazoles.
It has recently been reported that compounds more lipophilic than misonidazole are better potentiators of CCNU tumor cytotoxicity in vivo. There is now a need to extend these studies to include other tumors and cytotoxic drugs. In the present study we have shown that misonidazole (MISO) can potentiate cyclophosphamide cytotoxicity in the Lewis lung carcinoma but not in the B16 melanoma. Further studies in the Lewis lung carcinoma, using 15 1-substituted 2-nitroimidazoles possessing a range of octanol:water partition coefficient (P) (from 0.18- greater than 100) have shown that potentiation increases with increasing lipophilicity. The most efficient compounds at administered dose levels of 1.0 and 2.0 mumol/g were Ro-07-1902, benznidazole (Ro-07-1051) and RSU 1050 which possess octanol:water partition coefficients in the range of 2.5-10. However, on the basis of an equitoxic administered dose (1/2LD50/2d), little difference in potentiation is seen over the range of P studied.
D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008920:Misonidazole / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D013997:Time Factors
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008920:Misonidazole; D003520:Cyclophosphamide