POTENT GROWTH-INHIBITORY ACTIVITY OF ZIDOVUDINE ON CULTURED HUMAN BREAST-CANCER CELLS AND RAT MAMMARY-TUMORS

Originally designed as an antitumor agent, zidovudine (AZT) has exhibi ted only marginal tumor growth inhibitory activity. Recently, three ab stracts have described positive clinical outcomes for a small number o f patients with advanced breast cancer treated with weekly infusions o f either methotrexate or cisplatin and AZT. Consequently, we conducted a preclinical study of the anti-breast cancer and anti-mammary tumor activity of AZT. Here we have demonstrated that AZT, alone, has a pref erential in vitro and in vivo effect on breast and mammary cancer cell s. It is 1000 times as potent as an inhibitor of the in vitro growth o f the human breast cancer cell line MCF-7 (IC50 = 10 +/- 5 nM) than of the growth of the T-cell leukemia cell line CEM (IC50 = 14 +/- 2 mu M ). A novel mechanism for this preferential effect on growth is indicat ed by the 3-4-fold increase in production of phosphorylated AZT (mono- , di-, and triphosphate) in MCF-7 relative to CEM. We extended these i n vitro observations to iii vivo studies in rats and found that AZT is a potent ill vivo inhibitor of the growth of methylnitrosourea-induce d rat mammary tumors without any apparent toxic effects on internal or gans. These preclinical results demonstrate, for the first time, that AZT has significant anti-breast cancer activity and strongly suggest t hat the clinical usefulness of this drug is worthy of investigation.