Interactions between Tumor Subpopulations Affecting Their Sensitivity to the Antineoplastic Agents Cyclophosphamide and Methotrexate1

The hypothesis that individual tumor subpopulations which differ in sensitivity to chemotherapeutic agents can influence each other's drug sensitivity was investigated using a set of mouse mammary tumor subpopulations derived from the same tumor. In one set of experiments, syngeneic mice were given injections of cyclophosphamide (CY)-sensitive line 168 cells and relatively insensitive line 410 cells on opposite flanks. Other mice received bilateral injections of only 168 or only 410 cells. CY administration was begun 2 days later and continued once a week for 4 weeks. The sensitivity of line 168 tumors was not affected by line 410 tumors, but the sensitivity of line 410 tumors was increased by the presence of line 168 tumors. The ability of line 168 tumors to increase the CY-sensitivity of line 410 tumors was not altered by irradiating (400 rads) the hosts 2 days before tumor cell injection. Mice bearing line 168 tumors only or both line 168 and line 410 tumors were more sensitive to the acute toxic effects of single, high doses of CY than were the line 410 tumor-bearing mice, suggesting that effects on CY activation are responsible for the drug sensitivity interaction. In a second set of experiments, cells of subpopulations which differed in sensitivity to methotrexate (MTX) were cocultured in vitro in the presence or absence of MTX. In the presence of MTX-sensitive line 410.4 cells, the sensitivity of cells of lines 67 and 168 was increased. The sensitivity of cells of another relatively insensitive population, T68H clone 8, was not af fected. Thus, the sensitivity of some mammary tumor subpopulations to both CY and MTX can be influenced by the presence of other subpopulations that differ, when tested alone, in sen sitivity to these agents.