Clinical significance of a NAD(P)H

Quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C

Ronald A. Fleming, Jeffrey Drees, Brian W. Loggie, Gregory B. Russell, Kim R. Geisinger, Reba T. Morris, Debbie Sachs, Richard P. McQuellon

Research output: Contribution to journalArticle

31 Citations (Scopus)

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°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.

Original languageEnglish
Pages (from-to)31-37
Number of pages7
JournalPharmacogenetics
Volume12
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Mitomycin
NAD
Oxidoreductases
Drug Therapy
Neoplasms
Survival
benzoquinone
Gastrointestinal Neoplasms
Perfusion
Genotype
Carcinoma
Polymerase Chain Reaction
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Clinical significance of a NAD(P)H : Quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C. / Fleming, Ronald A.; Drees, Jeffrey; Loggie, Brian W.; Russell, Gregory B.; Geisinger, Kim R.; Morris, Reba T.; Sachs, Debbie; McQuellon, Richard P.

In: Pharmacogenetics, Vol. 12, No. 1, 2002, p. 31-37.

Research output: Contribution to journalArticle

Fleming, Ronald A. ; Drees, Jeffrey ; Loggie, Brian W. ; Russell, Gregory B. ; Geisinger, Kim R. ; Morris, Reba T. ; Sachs, Debbie ; McQuellon, Richard P. / Clinical significance of a NAD(P)H : Quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C. In: Pharmacogenetics. 2002 ; Vol. 12, No. 1. pp. 31-37.
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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°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.",
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AB - 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°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.

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