Tumor subpopulation interactions affecting melphalan sensitivity in palpable mouse mammary tumors.
Paired mixtures of melphalan-sensitive and relatively insensitive tumor cell subpopulation lines, originally derived from the same mammary tumor, were injected s.c. into syngeneic mice. When tumors were palpable, the mice were treated with melphalan at doses shown to be effective against the melphalan-sensitive subpopulations. Sensitivity was assessed by the loss of colony-forming ability of tumor cells harvested 1 to 14 days after treatment. When growing in tumors mixed with melphalan-sensitive line 4TO7 cells, line 66 (less sensitive) appeared much more sensitive than when it was grown alone. Line 66 tumors growing on the opposite sides of mice bearing line 4TO7 tumors were not more sensitive than when grown alone, indicating the lack of a systemic mechanism in the transfer of sensitivity from 4TO7 to 66. Furthermore, line 66 was not more sensitive when mixed with line 168TFAR (another melphalan-sensitive subpopulation) than when alone. The "transfer of sensitivity" from line 4TO7 to line 66 could be reproduced in collagen gel cultures but not in monolayer. Interestingly, line 4TO7, unlike line 168TFAR, is more sensitive to melphalan in collagen culture than in monolayer. This difference in sensitivity does not appear to be influenced by differences in cell density between the two culture systems. In collagen culture, the increased sensitivity of line 66 in the presence of line 4TO7 did not require cell contact and so appeared to act through diffusible factors(s). Collectively, these data suggest that the transfer of sensitivity is not dependent upon host factors or upon drug sensitivity per se but rather upon some mechanism requiring tumor cell-tumor cell interaction between specific subpopulation pairs. In additional studies, pH was ruled out as a factor in the transfer of sensitivity.