CYTOTOXICITY, DIFFERENTIATING ACTIVITY AND METABOLISM OF TIAZOFURIN IN HUMAN NEUROBLASTOMA-CELLS

The IMP dehydrogenase inhibitor, tiazofurin (TR)-2-beta-D-ribofuranosy lthiazole-4-carboxamide, which exhibited oncolytic activity in patient s with chronic myelogenous leukaemia (CML) in blast crisis was found t o inhibit the growth of human neuroblastoma SK-N-SH cells with an IC50 of 4.2 muM. TR treatment of cells perturbed nucleic acid and catechol amine pathways. As biochemical markers of TR action decreased cellular GTP pools, increased inosine and hypoxanthine concentrations and depl eted dopamine content were found. Incubation of tumour specimens obtai ned from paediatric patients with grade-IV neuroblastoma with TR resul ted in the formation of the active metabolite, thiazole-4-carboxamide adenine dinucleotide, in concentrations sufficient to inhibit tumour g rowth. Cytotoxic and biochemical effects of TR were enhanced by combin ing it with allopurinol (an inhibitor of xanthine dehydrogenase), and hypoxanthine (an alternate substrate for hypoxanthine-guanine phosphor ibosyltransferase). Induction of transdifferentiation of SK-N-SH cells from a neuroblast to an epitheloid, substrate-adherent phenotype was more pronounced with TR than with all-trans-retinoic acid. Transdiffer entiating treatment with TR resulted in a 2-fold-enhanced sensitivity towards adriamycin. However, differentiation with all-trans-retinoic a cid rendered the cells more resistant to adriamycin. Our results sugge st that TR might be a promising agent for the treatment of children su ffering from neuroblastoma. (C) 1993 Wiley-Liss, Inc.