Selective toxicity of the tricyclic thiophene NSC652287 in renal carcinomacell lines - Differential accumulation and metabolism

The tricyclic compound 2,5-bis(5-hydroxymethyl-2-thienyl)fura (NSC 652287) has shown a highly selective pattern of differential cytotoxic activity in the tumor cell lines comprising the National Cancer Institute (NCI) Antican cer Drug Screen. The mechanism underlying the selective cytotoxicity is unk nown. We hypothesized that differential sensitivity to the compound observe d in several renal tumor cell lines could be the result of selective accumu lation or differential metabolism of this agent. We demonstrated here that the capacity of certain renal cell lines to accumulate and retain the compo und, determined by accumulation of [C-14]NSC 652287-derived radioactivity a nd by flow cytometric determination of unlabeled compound, paralleled the s ensitivity of the renal cell lines re, growth inhibition by NSC 652287: A-4 98 > TK-10 >> ACHN similar to UO-31. The ability of the cell lines to metab olize [C-14]NSC 652287 to a reactive species capable of binding covalently to cellular macromolecules also directly correlated with sensitivity to the compound. Different patterns of metabolites were generated by relatively m ore drug-sensitive cell lines in comparison with drug-resistant cell lines. The metabolizing capacity for NSC 652287 was localized primarily to the cy tosolic (S100) fraction. The rate of metabolism in the cytosolic fraction f rom the most sensitive renal cell line, A-498, was faster than that observe d in the cytosolic fractions from the other, less sensitive cell lines. The data support the hypothesis that both selective cellular accumulation and the capacity to metabolize NSC 652287 to a reactive species by certain rena l carcinoma cell types are the basis fur the differential cytotoxicity of t his compound class. BIOCHEM PHARMACOL 57;11:1283-1295, 1999. (C) 15)99 Else vier Science Inc.