(Principal Investigator's) Diarylsulfonylureas (DSU) have been identified as a new class of antitumor agents. DSU exhibit a broad spectrum of activity against solid tumors and lack the toxicity to proliferating normal tissues, which is often associated with other conventional antitumor agents. Moreover, DSU do not show cross- resistance with other antitumor agents, and are not part of the P- glycoprotein-mediated multidrug resistance (MDR) phenotype, showing great potential in treating tumors which are resistant to current antitumor agents. In spite of numerous efforts, the antitumor mechanism of DSU remains undefined. But it is clear that, unlike other conventional antitumor agents, DSU do not inhibit the synthesis of DNA, RNA or proteins and show no cell cycle dependency suggesting that they act through a potentially unique and novel mechanism. We propose that the antitumor activity of DSU is contributed (or partially contributed) by inhibition of glutathione reductase (GR) in tumor cells by glutathione conjugates-potential metabolites of DSU. GR is an important enzyme to cell viability. Our preliminary results demonstrated that a GR inhibitor related to the glutathione conjugates inhibited DSU-sensitive tumor cell growth 10 times as potent as the parent drug. The proposed research is designed to test this hypothesis and sulofenur, a representative compound of DSU, will be employed to test the hypothesis. The study will involve synthesis of the glutathione conjugates, identification and quantification of the conjugates as metabolites of DSU, as well as evaluation of the conjugates effects against GR and DSU-sensitive tumor cells. The long term objective is, based on the information obtained from this study, to conduct rational structural modification to search for more potent and less toxic antitumor agents, and also to explore the potential of inhibiting GR as a novel approach for cancer therapy, as well as for reversal of tumor resistance to radiation therapy and chemotherapy.
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