Premium
Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells
Author(s) -
Pillwein Konrad,
Schuchter Katharina,
Ressmann Gabi,
Gharehbaghi Kamran,
Knoflach Andreas,
Cermak Benedikt,
Jayaram Hiremagalur N.,
Szalay Stefan M.,
Szekeres Thomas,
Chiba Peter
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910550117
Subject(s) - imp dehydrogenase , neuroblastoma , hypoxanthine , retinoic acid , biochemistry , metabolite , cytotoxic t cell , biology , chemistry , microbiology and biotechnology , pharmacology , medicine , cell culture , transplantation , in vitro , enzyme , mycophenolic acid , gene , genetics
The IMP dehydrogenase inhibitor, tiazofurin (TR)‐2‐β‐D‐ribofuranosylthiazole‐4‐carboxamide, which exhibited oncolytic activity in patients with chronic myelogenous leukaemia (CML) in blast crisis was found to inhibit the growth of human neuroblastoma SK‐N‐SH cells with an IC 50 of 4.2 μM. TR treatment of cells perturbed nucleic acid and catecholamine pathways. As biochemical markers of TR action decreased cellular GTP pools, increased inosine and hypoxanthine concentrations and depleted dopamine content were found. Incubation of tumour specimens obtained from paediatric patients with grade‐IV neuroblastoma with TR resulted in the formation of the active metabolite, thiazole‐4‐carboxamide adenine dinucleotide, in concentrations sufficient to inhibit tumour growth. Cytotoxic and biochemical effects of TR were enhanced by combining it with allopurinol (an inhibitor of xanthine dehydrogenase), and hypoxanthine (an alternate substrate for hypoxanthine‐guanine phosphoribosyltransferase). 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. Transdifferentiating treatment with TR resulted in a 2‐fold‐enhanced sensitivity towards adriamycin. However, differentiation with all‐trans‐retinoic acid rendered the cells more resistant to adriamycin. Our results suggest that TR might be a promising agent for the treatment of children suffering from neuroblastoma. © 1993 Wiley‐Liss, Inc.