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(1)

R M Phillips, Angelika M Burger, Heinz-Herbert Fiebig, J A Double

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Abstract

Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is currently generating considerable interest as a means of individualizing patient therapy. Recent studies have suggested that patients that are homozygous for a polymorphic variant (a C to T transition at position 609 of the cDNA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be resistant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenografts 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 characterized in terms of their response to MMC in vivo, and in this study, a further nine tumor xenografts have been characterized in terms of their response to MMC. No correlation could be found between the NQO1 polymorphic status of xenografts and their response to MMC in vivo. In terms of genotype/phenotype relationships, NQO1 activity in tumors genotyped as wild type, heterozygotes, 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. Genotyping of patients may provide a useful initial step in identifying patients who are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of individuals with respect to NQO1 is unlikely to be beneficial in terms of predicting tumor responses to MMC.

Original languageEnglish
Pages (from-to)1371-7
Number of pages7
JournalBiochemical Pharmacology
Volume62
Issue number10
DOIs
Publication statusPublished - 15 Dec 2001
Externally publishedYes

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Chemotherapy
Mitomycin
Heterografts
NAD
Tumors
Oxidoreductases
Genotype
Drug Therapy
Neoplasms
Heterozygote
Polymorphism
Polymerase chain reaction
Enzymes
Restriction Fragment Length Polymorphisms
benzoquinone
Complementary DNA
Phenotype
Polymerase Chain Reaction
Pharmaceutical Preparations

Cite this

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title = "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(1)",
abstract = "Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is currently generating considerable interest as a means of individualizing patient therapy. Recent studies have suggested that patients that are homozygous for a polymorphic variant (a C to T transition at position 609 of the cDNA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be resistant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenografts 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 characterized in terms of their response to MMC in vivo, and in this study, a further nine tumor xenografts have been characterized in terms of their response to MMC. No correlation could be found between the NQO1 polymorphic status of xenografts and their response to MMC in vivo. In terms of genotype/phenotype relationships, NQO1 activity in tumors genotyped as wild type, heterozygotes, 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. Genotyping of patients may provide a useful initial step in identifying patients who are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of individuals with respect to NQO1 is unlikely to be beneficial in terms of predicting tumor responses to MMC.",
keywords = "Animals, Antibiotics, Antineoplastic/therapeutic use, Disease Models, Animal, FMN Reductase, Genotype, Humans, Mice, Mice, Nude, Mitomycin/therapeutic use, NADH, NADPH Oxidoreductases/genetics, Neoplasm Transplantation, Neoplasms, Experimental/drug therapy, Polymorphism, Genetic, Transplantation, Heterologous, Tumor Cells, Cultured, Xenograft Model Antitumor Assays",
author = "Phillips, {R M} and Burger, {Angelika M} and Heinz-Herbert Fiebig and Double, {J A}",
year = "2001",
month = "12",
day = "15",
doi = "10.1016/S0006-2952(01)00769-9",
language = "English",
volume = "62",
pages = "1371--7",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "10",

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TY - JOUR

T1 - Genotyping of NAD(P)H:quinone oxidoreductase (NQO1) in a panel of human tumor xenografts

T2 - relationship between genotype status, NQO1 activity and the response of xenografts to Mitomycin C chemotherapy in vivo(1)

AU - Phillips, R M

AU - Burger, Angelika M

AU - Fiebig, Heinz-Herbert

AU - Double, J A

PY - 2001/12/15

Y1 - 2001/12/15

N2 - Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is currently generating considerable interest as a means of individualizing patient therapy. Recent studies have suggested that patients that are homozygous for a polymorphic variant (a C to T transition at position 609 of the cDNA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be resistant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenografts 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 characterized in terms of their response to MMC in vivo, and in this study, a further nine tumor xenografts have been characterized in terms of their response to MMC. No correlation could be found between the NQO1 polymorphic status of xenografts and their response to MMC in vivo. In terms of genotype/phenotype relationships, NQO1 activity in tumors genotyped as wild type, heterozygotes, 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. Genotyping of patients may provide a useful initial step in identifying patients who are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of individuals with respect to NQO1 is unlikely to be beneficial in terms of predicting tumor responses to MMC.

AB - Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is currently generating considerable interest as a means of individualizing patient therapy. Recent studies have suggested that patients that are homozygous for a polymorphic variant (a C to T transition at position 609 of the cDNA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be resistant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenografts 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 characterized in terms of their response to MMC in vivo, and in this study, a further nine tumor xenografts have been characterized in terms of their response to MMC. No correlation could be found between the NQO1 polymorphic status of xenografts and their response to MMC in vivo. In terms of genotype/phenotype relationships, NQO1 activity in tumors genotyped as wild type, heterozygotes, 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. Genotyping of patients may provide a useful initial step in identifying patients who are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of individuals with respect to NQO1 is unlikely to be beneficial in terms of predicting tumor responses to MMC.

KW - Animals

KW - Antibiotics, Antineoplastic/therapeutic use

KW - Disease Models, Animal

KW - FMN Reductase

KW - Genotype

KW - Humans

KW - Mice

KW - Mice, Nude

KW - Mitomycin/therapeutic use

KW - NADH, NADPH Oxidoreductases/genetics

KW - Neoplasm Transplantation

KW - Neoplasms, Experimental/drug therapy

KW - Polymorphism, Genetic

KW - Transplantation, Heterologous

KW - Tumor Cells, Cultured

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/S0006-2952(01)00769-9

DO - 10.1016/S0006-2952(01)00769-9

M3 - Article

VL - 62

SP - 1371

EP - 1377

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 10

ER -