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The Ohio State University College of Medicine, General Surgery Research Laboratories, Department of Surgery, Columbus, Ohio 43210 [L. G. B., J. L. B., F. I. Y., P. M., W. S. M., W. J. S.]; Department of Biochemistry and Molecular Biology, University of Barcelona, C/Marti 1 Franques 1, 08028 Barcelona, Spain [J. P., M. C.]; Research and Education Institute, Harbor-UCLA Medical Center, Torrance, California 90502 [W-N. P. L., S. B.]; and University Reference Laboratories, The Ohio State University Medical Center, Columbus, Ohio 43210 [R. D. W.]
This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-13C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone-sulfate (0.5 µM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.
1 This work was supported by Grant 536566 LGB1 from the Medical Research and Development Fund of the Ohio State University Department of Surgery. Grant PHS M01-RR00425 of the General Clinical Research Unit, and Grant P01-CA42710 of the UCLA Clinical Nutrition Research Unit Stable Isotope Core.
2 To whom requests for reprints should be addressed, at The Ohio State University College of Medicine, Department of Surgery, N217 Wiseman Hall, 400 West 12th Avenue, Columbus, OH 43210. Phone: (614) 292-0828; Fax: (614) 293-4030; E-mail: lboros@magnus.acs.ohio-state.edu.
Received 5/13/97. Accepted 8/ 1/97.
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