The purpose of this investigation was to examine factors 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,
leukemias 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 significantly 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 found 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 significant reduction of guanylate pools following
tiazofurin incubation. The activity of the
enzyme responsible for the formation of TAD,
NAD pyrophosphorylase, did not correlate with responsiveness to
tiazofurin but the
enzyme which hydrolyzes TAD, TADase, correlated positively with the status of resistance.(ABSTRACT TRUNCATED AT 400 WORDS)