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: Ronald A Fleming, Jeffrey Drees, Brian W Loggie, Gregory B Russell, Kim R Geisinger, Reba T Morris, Debbie Sachs, Richard P McQuellon
• Journal: Pharmacogenetics (Pharmacogenetics) Vol. 12 Issue 1 Pg. 31-7 (Jan 2002) ISSN: 0960-314X [Print] England
• PMID: 11773862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• DNA Primers
• Mitomycin
• NAD(P)H Dehydrogenase (Quinone)

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibiotics, Antineoplastic (therapeutic use)
• Chemotherapy, Cancer, Regional Perfusion
• DNA Primers (chemistry)
• Female
• Genotype
• Humans
• Hyperthermia, Induced
• Male
• Middle Aged
• Mitomycin (therapeutic use)
• NAD(P)H Dehydrogenase (Quinone) (genetics)
• Peritoneal Neoplasms (drug therapy, enzymology, genetics)
• Polymerase Chain Reaction
• Polymorphism, Genetic
• Polymorphism, Restriction Fragment Length
• Survival Rate