This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Piepmeier, J. M. Articles by Bush, T. L. Search for Related Content PubMed PubMed Citation Articles by Piepmeier, J. M. Articles by Bush, T. L.

In Vitro and in Vivo Inhibition of Glioblastoma and Neuroblastoma with MDL101731, a Novel Ribonucleoside Diphosphate Reductase Inhibitor

Department of Surgery/Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520-8039 [J. M. P., N. R.]; Department of Neurology, University of Texas/Southwestern Medical Center, Dallas, Texas 75235-9036 [S. C. S.]; and Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215-6300 [A. J. B., N. J. P., T. L. B.]

We examined the effects of MDL101731, a novel ribonucleoside reductase inhibitor, against human glioblastomas and neuroblastoma, both in vitro and in xenograft models, to determine its activity against malignant brain tumors. MDL101731 produced a concentration-dependent inhibition of both glioblastoma cell lines (HS683 and J889H) and neuroblastoma (SK-N-MC) in nanomolar concentrations (IC₅₀, 30–90 nM), s.c. xenografts of human glioblastoma (D54) in athymic mice increased to five times their initial volume at a median of 7.4 days in control animals, while tumor regression occurred in 12 of 12 animals treated with MDL101731 (100 mg/kg, i.p., two times/week) during 22 days of treatment (P < 0.0001). Intracerebral implants of D54 carried a median survival of 20 days in control animals, whereas animals receiving MDL101731 (100 mg/kg, i.p., two times/week, days 10–35) had a median survival of 46.5 days (P < 0.0001). Intracerebral xenografts of SK-N-MC in athymic mice resulted in a median survival of 23 days in control animals and 26 days in animals treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea 20 mg/kg/week, i.v. x 2; difference not significant). There was 90% survival in animals treated with MDL101731 (200 mg/kg, i.v., two times/week, days 7–35) up to 90 days after implant. These studies indicate that MDL101731 has potent antiproliferative activity against human malignant brain tumors.

¹ To whom requests for reprints should be addressed, at Department of Surgery/Neurosurgery, Yale University School of Medicine, P.O. Box 208039, New Haven, CT 06520-8039.

Received 8/24/95. Accepted 11/13/95.

This article has been cited by other articles:

				M. S. Kim, M. Blake, J. H. Baek, G. Kohlhagen, Y. Pommier, and F. Carrier Inhibition of Histone Deacetylase Increases Cytotoxicity to Anticancer Drugs Targeting DNA Cancer Res., November 1, 2003; 63(21): 7291 - 7300. [Abstract] [Full Text] [PDF]

				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]