title: Effect of interaction of glutathione S-transferases (T1 and M1) on the hematologic and cytogenetic responses in chronic myeloid leukemia patients treated with imatinib.
abstract: The glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes known to be involved in the detoxification of carcinogens and anticancer drugs. Individual genetic variation linked to inherited polymorphisms of GSTT1 and GSTM1 leading to a complete loss of enzyme activity could expose subjects to develop cancer or to induce drug resistance. Indeed, despite the impressive results obtained with the imatinib, some patients with chronic myeloid leukemia (CML) fail to achieve the expected results or develop resistance. The present study aimed to examine the impact of GSTT1 and GSTM1 polymorphisms on the response to imatinib in patients with CML. Multiplex polymerase chain reaction was used to detect the genotypes of GSTT1 and GSTM1 in 60 CML patients. We found that side effects were more frequent in patients carrying GSTT1 null when compared to GSTT1 present carriers (31 vs. 16.6 %; χ (2) = 6.2; p = 0.013). The loss of hematologic response was statistically greater in patients carrying the combined genotype GSTT1 present/GSTM1 present (26.3 %) when compared to GSTT1 null/GSTM1 present (12.8 %), GSTT1 present/GSTM1 null (8.3 %) and GSTT1 null/GSTM1 null (0 %), (χ (2) = 18.85; p < 0.001). The complete cytogenetic response was higher in patients harboring the GSTT1 null/GSTM1 null (75 %) compared with GSTT1 null/GSTM1 present (55.6 %), GSTT1 present/GSTM1 null (50 %) and GSTT1 present/GSTM1 present (47.8). On the other hand, the frequency of none cytogenetic responders was more common in patients carrying GSTT1 present/GSTM1 present (34.8 %) when compared to other genotype combinations (χ (2) = 20.99; p = 0.05). Moreover, the GSTT1 present/GSTM1 present appeared to be associated with a final dose of 600 or 800 mg of imatinib, but not significantly. Based on these findings, we find that the interaction between GSTT1 and GSTM1 seems to influence treatment outcome in patients with CML. Therefore, further investigations are required to confirm these results, for better genotype-phenotype correlation.
authors.affiliation: Genetics and Molecular Pathology Laboratory, Medical School of Casablanca, University Hassan II, 19 Rue Tarik Ibnou Ziad, BP. 9154, Casablanca, Morocco, kassoy2@yahoo.fr.
authors.forename: Y
authors.initials: Y
authors.lastname: Kassogue
authors.forename: M
authors.initials: M
authors.lastname: Quachouh
authors.forename: H
authors.initials: H
authors.lastname: Dehbi
authors.forename: A
authors.initials: A
authors.lastname: Quessar
authors.forename: S
authors.initials: S
authors.lastname: Benchekroun
authors.forename: S
authors.initials: S
authors.lastname: Nadifi
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001549:Benzamides; D005982:Glutathione Transferase; D000068877:Imatinib Mesylate; D010879:Piperazines; D011743:Pyrimidines; C413545:glutathione S-transferase T1