Variability of tumor response to chemotherapy. I. Contribution of host heterogeneity

Host factors that might be associated with the variable response of tumors to effective chemotherapy were studied in B6C3F1 mice bearing transplanted mammary adenocarcinoma 16/C tumors and treated with melphalan. Tumor response ranged from regression to an unpalpable size to growth under treatment. That biochemical resistance of the cell population was not primarily responsible for the variability was demonstrated by passage of responsive and nonresponsive tumors into new hosts followed by treatment with melphalan. When the implanted subcutaneous tumor weighed 1.0 g or less (usually 12 to 13 days postimplant), both the plasma levels of melphalan and the variability in plasma levels were similar to those observed in tumor-free mice. With tumor progression beyond 1.0 g, an increase in mean plasma levels and in variability, but not in plasma half-life, was observed. A correlation between the dose of melphalan administered, the schedule, and the percentage of tumor responses was found. There was no correlation between the plasma levels in individual mice following a given dose of melphalan and subsequent tumor response. Also, there was no correlation between the plasma levels of melphalan in individual mice following the second, third or fourth treatment in a multiple-dose treatment schedule and the response of the tumor in that mouse to previous treatments. Prior therapy (1, 2 or 3 doses administered 4 days apart) either prevented the increase in plasma levels that occurred in mice bearing untreated advanced tumors or reduced the plasma level (and the variability) to approximately that found in tumor-free mice. Whether this was a direct result of the effects of melphalan on the host or an indirect result of tumor inhibition is not known. A similar study in tumor-free mice indicated that prior treatment had only minimal effects on subsequent plasma levels. These studies indicate that heterogeneity of the host was not a major factor in variable tumor response if therapy was initiated when the tumors weighed 1.0 g or less.