This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bitonti, A. J. Articles by Kaplan, D. A. Search for Related Content PubMed PubMed Citation Articles by Bitonti, A. J. Articles by Kaplan, D. A.

Regression of Human Breast Tumor Xenografts in Response to (E)-2'-Deoxy-2'-(fluoromethylene)cytidine, an Inhibitor of Ribonucleoside Diphosphate Reductase

Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215

(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.

¹ To whom requests for reprints should be addressed, at Marion Merrell Dow Research Institute, 2110 East Galbraith Road, Cincinnati, OH 45215.

Received 8/25/93. Accepted 1/17/94.

This article has been cited by other articles:

				G. I. Rodriguez, R. E. Jones, E. K. Orenberg, M. L. Stoltz, and D. J. Brooks Phase I Clinical Trials of Tezacitabine [(E)-2'-Deoxy-2'-(fluoromethylene)cytidine] in Patients with Refractory Solid Tumors Clin. Cancer Res., September 1, 2002; 8(9): 2828 - 2834. [Abstract] [Full Text] [PDF]

				Y. Zhou, G. Achanta, H. Pelicano, V. Gandhi, W. Plunkett, and P. Huang Action of (E)-2'-Deoxy-2'-(fluoromethylene)cytidine on DNA Metabolism: Incorporation, Excision, and Cellular Response Mol. Pharmacol., January 1, 2002; 61(1): 222 - 229. [Abstract] [Full Text] [PDF]

				A. Gijsens, L. Missiaen, W. Merlevede, and P. de Witte Epidermal Growth Factor-mediated Targeting of Chlorin e6 Selectively Potentiates Its Photodynamic Activity Cancer Res., April 1, 2000; 60(8): 2197 - 2202. [Abstract] [Full Text]

				P. A. Coucke, L. A. Decosterd, Y.-X. Li, E. Cottin, X. Chen, L.-Q. Sun, S. Stern, N. Paschoud, and J. Denekamp The Ribonucleoside Diphosphate Reductase Inhibitor (E)-2'-Deoxy-(fluoromethylene)cytidine as a Cytotoxic Radiosensitizer in Vitro Cancer Res., October 1, 1999; 59(20): 5219 - 5226. [Abstract] [Full Text] [PDF]