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 Sun, L.-Q. Articles by Coucke, P. A. Search for Related Content PubMed PubMed Citation Articles by Sun, L.-Q. Articles by Coucke, P. A.

(E)-2'-Deoxy-2'-(fluoromethylene) Cytidine Potentiates Radioresponse of Two Human Solid Tumor Xenografts¹

Laboratory of Radiobiology, Department of Radiation Oncology [L-Q. S., Y-X. L., P. A. C.] and Institute of Pathology [L. G.], University Hospital of Lausanne (CHUV), CH-1011 Lausanne, Switzerland

Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. human C33-A cervix cancer and U-87 MG glioblastoma xenografts. FMdC given once daily has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 daily i.p. administrations of 10 mg/kg over 12 days. In the case of radiotherapy (RT) alone (10 fractions over 12 days), the radiation dose required to produce local tumor control in 50% of the treated C33-A xenografts was 51.0 Gy. When combined with FMdC, the radiation dose required to produce local tumor control was reduced to 41.4 and 38.2 Gy, at respective doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation. The corresponding enhancement ratios (ERs) were 1.2 and 1.3, respectively. In U-87 MG xenografts, when 5–20 mg/kg FMdC combined with 30 or 40 Gy of RT, the combination treatment produced a significantly increased growth delay as compared with RT alone (P 0.002). The ERs of 5, 10, and 20 mg/kg FMdC at a dose of 30 Gy were 2.0, 1.4, and 1.8, respectively. At the 40-Gy level, ERs of 10 and 20 mg/kg FMdC were 1.4 and 1.7. When FMdC was combined with 50 Gy of RT, an increased long-term remission rate of 80–88.9% was observed, as compared with 25% for RT alone (P <0.05). FMdC produced moderate myelosuppression in the mice bearing cervix cancer, whereas leukocytosis occurred in the mice bearing glioblastoma at a low dose. Slightly increased skin toxicity (only with U-87 MG tumor) was observed, as compared with RT alone. In conclusion, FMdC is a potent cytotoxic agent and able to modify the radiation response of C33-A and U-87 MG xenografts.

¹ Supported by the Foundation Radiobiologie 2000 and Ligue Vaudoise Contre Le Cancer, Lausanne, Switzerland.

² Present address: Division of Hematology/Oncology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039.

³ Present address: Department of Clinical Investigation, Box 71, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

⁴ To whom requests for reprints should be addressed, at Laboratory of Radiobiology, Department of Radiation Oncology, University Hospital of Lausanne (CHUV), CH-1011 Lausanne, Switzerland. Phone: 41-21-314-4603; Fax: 41-21-314-4601; E-mail: philippe.coucke@chuv.hospvd.ch.

Received 6/15/98. Accepted 9/30/98.

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]

				K. Zaugg, S. Rocha, H. Resch, I. Hegyi, C. Oehler, C. Glanzmann, D. Fabbro, S. Bodis, and M. Pruschy Differential p53-dependent Mechanism of Radiosensitization in Vitro and in Vivo by the Protein Kinase C-specific Inhibitor PKC412 Cancer Res., January 1, 2001; 61(2): 732 - 738. [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]