REGRESSION OF HUMAN BREAST-TUMOR XENOGRAFTS IN RESPONSE TO (E)-2'-DEOXY-2'-(FLUOROMETHYLENE)CYTIDINE, AN INHIBITOR OF RIBONUCLEOSIDE DIPHOSPHATE REDUCTASE

(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (MDL 101,731) is a mechanism -based inhibitor of ribonucleoside diphosphate reductase (J. Stubbe, p ersonal communication), an enzyme involved in DNA synthesis and theref ore a potential target for cancer chemotherapy. In the present report, we show that MDL 101,731 inhibits the proliferation of several human breast cancer cell lines, including the estrogen-dependent cell line, MCF-7, and the estrogen-independent cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-435 in vitro at nanomolar concentrations (50% inhibitory c oncentration, 15-26 nM). Administration of MDL 101,731 caused marked r egression of tumors which formed after s.c. inoculation of all four of the cell lines in athymic (nude) mice. MDA-MB-231 tumors were found t o be most sensitive to MDL 101,731 with a 90-100% cure rate at doses o f MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p. injecti ons, 5 days/week for as little as 3 weeks. Almost complete cessation o f MDA-MB-231 tumor growth was obtained with a dose of 0.5 mg/kg MDL 10 1,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and M CF-7 tumors were not as sensitive as MDA-MB-231, but tumor regression of 50, 65, and 80%, respectively, was obtained after 5-6 weeks of trea tment. The effects of MDL 101,731 on spontaneous metastasis of MDA-MB- 435 cells from the mammary fat pad to the lung was also examined, and it was found that the number of lung metastases was significantly decr eased if mice received MDL 101,731 while the primary tumors were growi ng and after primary tumors were surgically excised. Additionally, pre liminary evidence raises the possibility that MDL 101,731 may induce a poptosis in MDA-MB-231 tumors. Our data suggest that the use of MDL 10 1,731 for the treatment of breast cancer and possibly other solid tumo rs should be pursued.