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

Hiremagalur N. Jayaram, Weining Zhen, Kamran Gharehbaghi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase l/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 μM 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.

Original languageEnglish
Pages (from-to)2344-2348
Number of pages5
JournalCancer Research
Volume53
Issue number10
StatePublished - May 15 1993

Fingerprint

tiazofurin
K562 Cells
Nicotinamide-Nucleotide Adenylyltransferase
IMP Dehydrogenase
Cell Proliferation
Pharmaceutical Preparations
Myeloid Leukemia
Guanine
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jayaram, H. N., Zhen, W., & Gharehbaghi, K. (1993). Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells. Cancer Research, 53(10), 2344-2348.

Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells. / Jayaram, Hiremagalur N.; Zhen, Weining; Gharehbaghi, Kamran.

In: Cancer Research, Vol. 53, No. 10, 15.05.1993, p. 2344-2348.

Research output: Contribution to journalArticle

Jayaram, HN, Zhen, W & Gharehbaghi, K 1993, 'Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells', Cancer Research, vol. 53, no. 10, pp. 2344-2348.
Jayaram, Hiremagalur N. ; Zhen, Weining ; Gharehbaghi, Kamran. / Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells. In: Cancer Research. 1993 ; Vol. 53, No. 10. pp. 2344-2348.
@article{51f2f25313d0426bbd129d30aa8c0df2,
title = "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 l/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 μM 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.",
author = "Jayaram, {Hiremagalur N.} and Weining Zhen and Kamran Gharehbaghi",
year = "1993",
month = "5",
day = "15",
language = "English",
volume = "53",
pages = "2344--2348",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells

AU - Jayaram, Hiremagalur N.

AU - Zhen, Weining

AU - Gharehbaghi, Kamran

PY - 1993/5/15

Y1 - 1993/5/15

N2 - Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase l/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 μM 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.

AB - Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase l/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 μM 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.

UR - http://www.scopus.com/inward/record.url?scp=0027245461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027245461&partnerID=8YFLogxK

M3 - Article

C2 - 8097964

AN - SCOPUS:0027245461

VL - 53

SP - 2344

EP - 2348

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 10

ER -