title: Clinical significance of a NAD(P)H: quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C.
abstract: Recent data indicate that NAD(P)H: quinone oxidoreductase 1 (NQO1) is important in the activation of mitomycin C. A polymorphism in human NQO1 (609C>T) is associated with diminished NQO1 activity. The purpose of our study was to determine the effect of the 609C>T polymorphism on tumor NQO1 activity and overall survival in patients with disseminated peritoneal cancer receiving intraperitoneal mitomycin C therapy. Patients with disseminated peritoneal cancer of gastrointestinal or other origin were eligible. Following aggressive surgical debulking, patients were administered a 2-h heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. NQO1 activity was determined in tumor tissue obtained during surgery and patients were genotyped for the NQO1 C609T polymorphism using a polymerase chain reaction-based method. The major response variable monitored during the trial was overall survival. Of the 117 patients genotyped for the NQO1 609C>T polymorphism, 67% were wild-type (WT), 31% were heterozygous (HE), and 2% were homozygous mutant (HM). In tumor tissue, the mean NQO1 activities from WT (n = 14) and HE (n = 5) patients were 794 +/- 603 and 70 +/- 133.1 nmol/min/mg protein respectively (P = 0.006). Significant differences in survival between WT versus HE/HM genotypes were noted in optimally debulked patients (R0/R1) (43.6+ months, median not yet reached versus 23 months respectively, P = 0.037) and in patients with peritoneal carcinomatosis of colonic origin (18.2 versus 11.5 months respectively, P = 0.050). These data indicate that the NQO1 609C>T polymorphism results in significantly reduced tumor NQO1 activity and reduced survival in subsets of patients receiving intraperitoneal hyperthermic mitomycin C therapy.
authors.affiliation: Section on Hematology/Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Fleming
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Drees
authors.forename: Brian W
authors.initials: BW
authors.lastname: Loggie
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Russell
authors.forename: Kim R
authors.initials: KR
authors.lastname: Geisinger
authors.forename: Reba T
authors.initials: RT
authors.lastname: Morris
authors.forename: Debbie
authors.initials: D
authors.lastname: Sachs
authors.forename: Richard P
authors.initials: RP
authors.lastname: McQuellon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005838:Genotype; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000627:therapeutic use*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D015996:Survival Rate
chemical_list: D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone)