Oxythiamine and dehydroepiandrosterone induce a G(1) phase cycle arrest inEhrlich's tumor cells through inhibition of the pentose cycle

Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxyt hiamine (OT) was observed in several in vitro and in vivo tumor models. Her e, we demonstrate that pentose cycle (PC) inhibitors, OT rand dehydroepiand rosterone (DHEA), efficiently regulate the cell cycle and tumor proliferati on processes. Increasing doses of OT or DHEA were administered by daily int raperitoneal injections to Ehrlich's ascites tumor hosting mice for 4 days. The tumor cell number and their cycle phase distribution profile were dete rmined by DNA flow histograms, Tumors showed a dose dependent increase in t heir G(0)-G(1) cell populations after both OT and DHEA treatment and a simu ltaneous decrease in cells advancing to the S and G(2)-M cell cycle phases, This effect of PC inhibitors was significant, OT was more effective than D HEA, both drugs acted synergistically in combination and no signs of direct cell or host toxicity were observed, Direct inhibition of PC reactions cau ses a G(1) cell cycle arrest similar to that of 2-deoxyglucose treatment. H owever, no interference with cell energy production and cell toxicity is ob served, PC inhibitors, specifically ones targeting TK, introduce a new targ et site for the development of future cancer therapies to inhibit glucose u tilizing pathways selectively for nucleic acid production. (C) 1999 Federat ion of European Biochemical Societies.