Clinical Cancer Research, Vol 4, Issue 2 493-497, Copyright © 1998 by American Association for Cancer Research

ARTICLES

High susceptibility of human cancer xenografts with higher levels of cytidine deaminase to a 2'-deoxycytidine antimetabolite, 2'-deoxy-2'-methylidenecytidine

M Miwa, H Eda, M Ura, KF Ouchi, DD Keith, LH Foley and H Ishitsuka
Nippon Roche Research Center, Kanagawa, Japan.

2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd) antimetabolite. The present study compared its antitumor activities with those of 2',2'-difluorodeoxy-cytidine (gemcitabine) in 15 human cancer xenograft models. DMDC was highly resistant to cytidine (Cyd) deaminase, which deaminates the dCyd analogues to inactive molecules, whereas gemcitabine was susceptible to the enzyme. Given p.o., high antitumor activity with therapeutic index of more than 10 was found with DMDC in 7 of 15 xenograft lines. In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although their molecular targets are reported to be similar. DMDC was highly effective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deaminase. In contrast, gemcitabine appeared to be less effective in tumors with high levels of Cyd deaminase. We also investigated the correlation with the susceptibility to the two dCyd antimetabolites and dCyd kinase activity in tumors, but none was observed. Cyd deaminase activity was found to be high in tumor tissues from various types of human cancers thus far tested, such as colorectal cancer and non-small cell lung cancer. Such cancer types or individual patients who have tumors with high activity of the enzyme may be targets for DMDC therapy.

This article has been cited by other articles:

				J. A. Gilbert, O. E. Salavaggione, Y. Ji, L. L. Pelleymounter, B. W. Eckloff, E. D. Wieben, M. M. Ames, and R. M. Weinshilboum Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin. Cancer Res., March 15, 2006; 12(6): 1794 - 1803. [Abstract] [Full Text] [PDF]

				R. Danesi, F. De Braud, S. Fogli, T. M. De Pas, A. Di Paolo, G. Curigliano, and M. Del Tacca Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer Pharmacol. Rev., March 1, 2003; 55(1): 57 - 103. [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]

				H. Gourdeau, M. L. Clarke, F. Ouellet, D. Mowles, M. Selner, A. Richard, N. Lee, J. R. Mackey, J. D. Young, J. Jolivet, et al. Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines Cancer Res., October 1, 2001; 61(19): 7217 - 7224. [Abstract] [Full Text] [PDF]