(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (
MDL 101,731) is a mechanism-based inhibitor of
ribonucleoside diphosphate reductase (J. Stubbe, personal communication), an
enzyme involved in
DNA synthesis and therefore 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 concentration, 15-26 nM). Administration of
MDL 101,731 caused marked regression 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 to be most sensitive to
MDL 101,731 with a 90-100% cure rate at doses of
MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p.
injections, 5 days/week for as little as 3 weeks. Almost complete cessation of MDA-MB-231
tumor growth was obtained with a dose of 0.5 mg/kg
MDL 101,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and MCF-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 treatment. 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 decreased if mice received
MDL 101,731 while the primary
tumors were growing and after primary
tumors were surgically excised. Additionally, preliminary evidence raises the possibility that
MDL 101,731 may induce apoptosis in MDA-MB-231
tumors. Our data suggest that the use of
MDL 101,731 for the treatment of
breast cancer and possibly other solid
tumors should be pursued.