Use of growth-stimulatory hormones to improve the in vitro therapeutic index of doxorubicin for human breast tumors.

Tumor-specific growth factors that increase the proliferative rate of tumor cells should, in theory, enhance the efficacy of cytotoxic drugs that have cell-cycle-dependent activity. To test this hypothesis, we measured the cytotoxicity of doxorubicin for clonogenic breast tumor cells in the presence and the absence of hormones that stimulate their in vitro growth (17 beta-estradiol, epidermal growth factor, hydrocortisone, and insulin). These growth factors increased the sensitivity to doxorubicin of the clonogenic cell populations from 20 of 25 breast tumors. Their effect was greatest on tumors from hormone-responsive patients. In contrast, these hormones increased the clonogenicity and sensitivity to doxorubicin of bone marrow progenitor cells to a much lesser degree. Hence, under the effect of these growth factors, the in vitro therapeutic index of doxorubicin improved for most of the tumors tested, while tamoxifen citrate, a tumor growth-inhibitory hormone, had the opposite effect. We conclude that tumor tissue-specific growth-stimulatory hormones can improve the in vitro efficacy of cell cycle-active anticancer drugs.