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Biochemical mechanisms of resistance to tiazofurin
Abstract:
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)
Insights
Tiazofurin resistance in tumors involves reduced NAD pyrophosphorylase activity and altered guanylate synthesis. These factors, along with TAD accumulation and TADase activity, predict tumor sensitivity or resistance to tiazofurin therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Tiazofurin is an anticancer agent whose efficacy can be limited by tumor resistance.
- Understanding the mechanisms of tiazofurin resistance is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To investigate the biochemical and genetic factors regulating gene expression in tumors that confer resistance to tiazofurin.
- To compare these resistance mechanisms across different tumor types, including hepatoma, leukemia, murine tumors, and human lung cancer cell lines.
Main Methods:
- Drug-induced resistant tumor lines (hepatoma 3924A, leukemias L1210, P388) were established and analyzed for biochemical alterations.
- Murine tumors were examined for correlation between metabolic profiles and tiazofurin sensitivity/resistance.
- Human lung cancer cell lines (small cell lung cancer and adenocarcinoma) were tested for tiazofurin cytotoxicity and metabolic responses.
Main Results:
- Tiazofurin resistance in hepatoma and leukemia lines was associated with reduced NAD pyrophosphorylase activity, decreased NAD content, and altered guanylate synthesis.
- Hepatoma lines showed additional alterations including increased IMP dehydrogenase activity and reduced tiazofurin uptake.
- TAD accumulation and TADase activity correlated with tiazofurin sensitivity in human lung cancer cells, while NAD pyrophosphorylase activity did not.
Conclusions:
- Key factors regulating tiazofurin resistance include reduced NAD pyrophosphorylase activity, altered guanylate metabolism, and TAD accumulation.
- TADase activity is a significant predictor of tiazofurin resistance in human lung cancer.
- These findings provide insights into tiazofurin resistance mechanisms applicable to various cancer types.