Biochemical mechanisms of resistance to tiazofurin

Hiremagalur N. Jayaram

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The purpose of this investigation was to examine factos which regulate the reprogramming of gene expression in tumors responsible for resistance to tiazofurin. To study the resistance phenomenon drug-induced tumor lines were selected and examined for the mechanism of resistance. A comparison of the biochemical expression of resistance to tiazofurin in drug-induced resistant lines of hepatoma 3924A, leukemia L1210 and P388 revealed that the 3 lines expressed similar genetic alterations related to reduced TAD content, decreased NAD pyrophosphorylase activity and increased synthesis of guanylates from salvaging preformed guanine indicating that these 3 factors play an important role in the resistance to tiazofurin. Resistance was stable in the leukemia lines and did not require drug to maintain resistance. Hepatoma 3924A resistant line reverted to sensitive state in the absence of drug selection pressure. NAD pyrophosphorylase activity was substantially deleted in the tiazofurin resistant leukemia lines, but was only signficantly decreased in the hepatoma resistant line, Extensive biochemical alterations including enhanced activity of IMP dehydrogenase, increased inosinate and guanylate pools, and reduced uptake of tiazofurin were ound in the hepatoma line resistant to tiazofurin. To examine the applicability of these results to naturally sensitive and spontaneously resistant tumors, murine tumors were examined. In murine tumors, TAD accumulation, ratios of enzyme activities responsible for the synthesis and degradation of TAD, and the ratios of perturbation of inosinate and guanylate pools following tiazofurin challenge demonstrated significant correlation with the sensitive or resistant nature of the tumors. To extrapolate these observations to human tumor systems, cytotoxicity of tiazofurin and its metabolic effects were compared in 6 human lung cancer cell lines derived from cancer patients with small cell lung cancer (4 lines) and lung adenocarcinoma (2 lines). Cell lines exhibiting greater sensitivity to tiazofurin accumulated significantly larger amounts of TAD and showed signficant reduction of guanylate pools following tiazofurin incubation. The activity of the enzyme responsible for the formation of TAD, NAD prophosphorylase, did not correlate with responsiveness to tiazofurin but the enzyme which hydrolzes TAD, TADase, correlated positively with the status of resistance. These studies demonstrate the adaptability of the factors responsible for the sensitivity of resistance to tiazofurin from experimental animal tumors to human tumor systems, indicating the need to monitor important biochemical parameters such as TAD content and levels of IMP, GTP and dGTP during clinical trials.

Original languageEnglish (US)
Pages (from-to)67-89
Number of pages23
JournalAdvances in Enzyme Regulation
Volume24
Issue numberC
DOIs
StatePublished - 1985

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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