Response of Aerobic and Hypoxie Cells in a Solid Tumor to Adriamycin and Cyclophosphamide and Interaction of the Drugs with Radiation1

I have assessed the relative sensitivity of aerobic and hypoxic cells to Adriamycin (ADR) and Cyclophosphamide (CY) in the drug-sensitive murine 16/C tumor. The end point used was tumor response to subsequent radiation given under aerobic or acutely hypoxic conditions. Delay in tumor growth following 15 gray radiation alone to ~0.4 g tumors was about 3 days longer after aerobic than after hypoxic radiation. Prior treatment with CY had little effect on this difference, implying little selectivity of CY for killing aerobic or hypoxic cells, and the effects of CY and radiation were additive. Treatment with ADR abolished the difference in response to aerobic and hypoxic radiation given from 0.5 to 2 hr after the drug, suggesting that most of the cells which survived treatment with ADR were hypoxic. Difference in response to aerobic and hypoxic radiation at 6 to 24 hr after ADR was equal to or greater than that in non-drug-treated mice, implying rapid reoxygenation after ADR. Experiments on small, nonpalpable tumors with a low proportion of hypoxic cells showed that ADR was slightly more effective than against larger tumors and that some aerobic cells were spared by the drug when the hypoxic fraction was small. Misonidazole is known to be selectively toxic for hypoxic cells, and a high dose of misonidazole gave a small increase in antitumor effects of ADR without increased toxicity. My results suggest that ADR (but not CY) may spare hypoxic cells in a solid tumor and are consistent with limited diffusion of ADR from tumor blood vessels.