Genotyping of NAD(P)H : quinone oxidoreductase (NQO1) in a panel of human tumor xenografts: relationship between genotype status, NQO1 activity and the response of xenografts to Mitomycin C chemotherapy in vivo

Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is c urrently generating considerable interest as a means of individualizing pat ient therapy. Recent studies have suggested that patients that are homozygo us for a polymorphic variant (a C to T transition at position 609 of the cD NA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be res istant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenogr afts by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), classified tumors as wild type (40/54), heterozygotes (11/54), and homozygous mutants (3/54). Previously, 37 of these tumors had been char acterized in terms of their response to MMC in vivo, and in this study, a f urther nine tumor xenografts have been characterized in terms of their resp onse to MMC. No correlation could be found between the NQO1 polymorphic sta tus of xenografts and their response to MMC in vivo. In terms of genotype/p henotype relationships, NQO1 activity in tumors genotyped as wild type, het erozygotes, and homozygous mutants were 311.1 +/- 421.9 (N = 40), 76.9 +/- 109.5 (N = 11), and 0.2 +/- 0.17 (N = 3) nmol/min/mg, respectively. Genotyp ing of patients may provide a useful initial step in identifying patients w ho are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of indiv iduals with respect to NQO1 is unlikely to be beneficial in terms of predic ting tumor responses to MMC. (C) 2001 Elsevier Science Inc. All rights rese rved.