Comparison of growth delay and cell survival as end-points of tumour response following treatment with combinations of cytotoxic agents.

The response of the B16 melanoma to the simultaneous combination of CY plus CCNU was examined using cell survival and growth delay endpoints. Combination data were evaluated either by applying the simple concept that an additive combination response is equal to the sum of the single agent responses or by constructing additivity envelopes as described recently by Steel & Peckham (1979), in order to take account of non-linear dose-response curves. Although cell survival was additive on the simple basis, tumour growth delay was greater than predicted by the simple concept, but still within the additivity envelopes. This apparent anomaly may, however, be explained by considering the relationship between the two endpoints. Although the extent of growth delay of a tumour is dependent on the level of tumor cell survival, it is also influenced by other factors such as the rate of regrowth of surviving tumour cells, which may in turn be affected by systemic host effects resulting from the same treatment. We have recently shown that tumour cell repopulation after CY treatment is much slower than after CCNU, and in this paper we demonstrate by means of a transplantation experiment that this is probably due to a systemic host effect of CY. Thus, the observed growth delay response of the combination is consistent with a model in which the agents produce additive cell killing, but the subsequent tumour cell repopulation is retarded by a systemic effect of CY.