Association of CYP3A4 genotype with detection of Vgamma/Jbeta trans-rearrangements in the peripheral blood leukocytes of pediatric cancer patients undergoing chemotherapy for ALL.
Cancer patients receiving chemotherapy are exposed to high doses of cytotoxic and genotoxic drugs which, in some cases, can lead to treatment related leukemia. Since this only occurs in a minority of patients, however, it is possible some individuals are predisposed due to genetic polymorphisms in genes for enzymes that mediate drug metabolism. To address this possibility we measured the genotoxicity of chemotherapeutic agents in patients receiving treatment for ALL by the frequency of the Vgamma/Jbeta trans-rearrangement in their peripheral blood leukocytes and compared this with CYP3A4 genotype. CYP3A4 is the most abundant of the cytochrome P450 (CYP) enzyme in the liver and intestine which contains a common -392A>G substitution in the promoter region (CYP3A4*1B allele). We found a significant increase in the frequency of rearrangements during chemotherapy only in patients homozygous for the wild type CYP3A4*1A allele. This provides a direct link between CYP3A4 genotype and susceptibility to drug genotoxicity thus strengthening the possibility that predisposition to treatment related leukemia may be measurable by simple genetic testing.
Lopes
Luiz Fernando
LF
Pediatric Department, Centro de Tratamento e Pesquisa Hospital do Cancer Rua Prof. Antônio Prudente, 211 CEP 04038-002 São Paulo, SP, Brazil. lf.lopes@sti.com.br
Piccoli
Fábio De Simone
Fde S
Paixão
Valéria A
VA
Latorre
Maria do Rosário D O
Mdo R
Camargo
Beatriz de
Bd
Simpson
Andrew J G
AJ
Caballero
Otávia L
OL
D000970:Antineoplastic Agents / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D015321:Gene Rearrangement; D005838:Genotype; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007962:Leukocytes; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000209:etiology / Q000235:genetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy / Q000235:genetics*
D000970:Antineoplastic Agents; D007135:Immunoglobulin Variable Region; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human