Enhancement of cytotoxic drugs by misonidazole (MISO) in Lewis lung tumors of different sizes, and mouse bone marrow.

MISO substantially enhances the cell killing action of a variety of cytotoxic drugs in large intramuscular Lewis lung tumors, but not in normal bone marrow. This differential response could be explained if an hypoxic environment is a necessary requirement for MISO enhancement. To test this hypothesis, we have directly determined enhancement factors for the cytotoxicity of melphalan, cyclophosphamide (CYC) and 5-fluorouracil (5-FU) administered simultaneously with MISO (750 mg/Kg for melphalan and CYC, 1000 mg/Kg for 5-FU) in four experimental systems which are known to differ in oxygenation status, 250 mg intramuscular (i.m.) Lewis lung tumors, less than 2 mg lung tumors, single tumor cells trapped in pulmonary capillaries and normal bone marrow. Clonogenic cell assays were used to produce dose response curves and enhancement factors were expressed as the survival curve slope ratio (SR) for drug alone versus drug + MISO. In the more hypoxic i.m. tumors SR's from 1.6 to 1.9 wee obtained, whereas in the other, better oxygenated test systems SR's ranged from 1.0 to 1.3. Although these results are consistent with the proposal that hypoxia might be important for MISO enhancement of cytotoxic drug action, they do not exclude the possibility that other factors may be responsible.