Role of differentiation induction in action of purine antimetabolites

Abstract

In cancer cells, particularly in leukaemic cells, guanylate biosynthesis is up-regulated as shown by the increased activities of IMP dehydrogenase, the rate-limiting enzyme of de novo GTP biosynthesis, and of the salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity. A triad of responses was observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras and c-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and gemcitabine [corrected]. Induced differentiation plays an important role in the overall impact of antipurine agents.

Synthesis and Modeling Studies with Monocyclic Analogues of Mycophenolic Acid

“…Neat 3f (0.70 g, 2.73 mmol) was heated to 210 ( 5 °C for 4 h while under a flow of nitrogen. The reaction mixture was allowed to cool to room temperature, and the resulting brown oil was subjected to flash chromatography (dichloromethane-hexanes, 1:1) to give 6c (0.358 g, 51%) as a white oily solid: mp 38-39.5 °C; 1 H NMR δ 3.44 (d,2 H),3.84 (s,3 H),3.90 (s,3 H),5.00 (m, 2 H), 6.00 (m, 1 H), 7.78 (s, 1 H), 11.0 (s, 1 H); IR (CHCl3) 908, 1213, 1269, 1338, 1476, 1670 cm -1 . Anal.…”

“…Inhibitors of IMPD reduce GTP and deoxyGTP pool levels and have been shown to possess antineoplastic, antiparasitic, antiviral (including anti-HIV), and immunosuppressive activity. Inhibitors of IMPD have also been shown to induce differentiation in certain cell lines. The utility of the IMPD inhibitor tiazofurin in the treatment of human leukemia is a result of cytotoxicity and differentiation−induction (maturation−induction).…”