Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells.

Abstract

Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to tiazofurin were developed by drug-selection pressure. Compared to a concentration producing 50% cell proliferation reduction that was 9.1 microM in sensitive cells, the resistant variants displayed concentrations producing 50% cell proliferation reductions of 12 and 16 mM. The activity of the target enzyme, IMP dehydrogenase, was not altered in the resistant cells. Studies on tiazofurin metabolism revealed that resistant variants formed < 10% of the active metabolite, thiazole-4-carboxamide adenine dinucleotide. This correlated with the activity of NAD pyrophosphorylase, the enzyme that synthesizes thiazole-4-carboxamide adenine dinucleotide, which was reduced to 10% in the resistant lines. Concurrently, the activity of thiazole-4-carboxamide adenine dinucleotide phosphodiesterase was elevated in the refractory cells. Compared to the sensitive counterpart, the levels of GMP and NAD were lower in the resistant lines. Guanine salvage activity was decreased in the resistant cells. Basal dGTP and dATP concentrations were elevated in the resistant line; nevertheless, tiazofurin incubation decreased dGTP levels in only the sensitive cells. Although there was no difference in the Km of tiazofurin transport or efflux, the Vmax of uptake of the drug was reduced in the resistant lines. Sensitive and resistant cells exhibit similar cytotoxicity to agents which do not share the mechanism of action of tiazofurin, suggesting that refractory cells are still sensitive to other standard antileukemic drugs.

• Authors: H N Jayaram, W Zhen, K Gharehbaghi
• Journal: Cancer research (Cancer Res) Vol. 53 Issue 10 Suppl Pg. 2344-8 (May 15 1993) ISSN: 0008-5472 [Print] United States
• PMID: 8097964 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenine Nucleotides
• Antineoplastic Agents
• Carbon Radioisotopes
• Deoxyribonucleotides
• Nucleic Acids
• Purine Nucleotides
• Ribavirin
• Guanine
• thiazole-4-carboxamide adenine dinucleotide
• IMP Dehydrogenase
• Nicotinamide-Nucleotide Adenylyltransferase
• Phosphoric Diester Hydrolases
• tiazofurin

Topics

• Adenine Nucleotides (metabolism)
• Antineoplastic Agents (metabolism, pharmacokinetics, pharmacology)
• Biological Transport
• Carbon Radioisotopes
• Deoxyribonucleotides (metabolism)
• Drug Resistance
• Drug Screening Assays, Antitumor
• Guanine (metabolism, pharmacokinetics)
• Humans
• IMP Dehydrogenase (metabolism)
• Leukemia, Myeloid (drug therapy, enzymology, metabolism)
• Nicotinamide-Nucleotide Adenylyltransferase (metabolism)
• Nucleic Acids (metabolism)
• Phosphoric Diester Hydrolases (metabolism)
• Phosphorylation
• Purine Nucleotides (metabolism)
• Ribavirin (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Tumor Cells, Cultured