POLYMORPHISM OF BIOTRANSFORMATION GENES AND RISK OF RELAPSE IN CHILDHOOD ACUTE LEUKEMIA
Gra OA1,2, Kozhekbaeva ZhM1,2,3, Makarova OV4,Samochatova EV4, Nasedkina TV1,*
*Corresponding Author: Tatyana V. Nasedkina, Ph.D., Department of Biological Microarray, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; Tel.: +7-499-135-62-59; Fax: +7-499-135-14-05; E-mail: nased@biochip.ru, nased@eimb.ru
page: 21

INTRODUCTION

Leukemia is a hematological malignancy that involves bone marrow. This disease is socially important, as it is among the major causes of death in children. Acute lymphoblastic leukemia (ALL) is the most common form, accounting for about 80% of all acute leukemia cases. Acute myeloblastic leukemia (AML) accounts for 15% of leukemia cases in children [1,2]. The causes of the acute leukemias have not yet been identified. The current concept of their etiology and pathogenesis suggests an important role for chromosome aberrations, which may be inherited or induced by external factors [3].

Childhood acute leukemia is a clinically heterogeneous disease with highly variable response to therapy and prognosis. Almost all current prognostic factors are characteristics of leukemia cells in both primary acute leukemia and in relapse [3,4]. Individual features of drug metabolism are not presently considered during choice of anti cancer therapy. However, several studies have shown that the activities of some drug-metabolizing enzymes can modulate to a considerable extent the individual efficacy of cancer therapy [5,6].

All xenobiotics, including therapeutic agents, are degraded and eliminated from the body by a system of enzymes encoded by specific genes. Most of these genes are polymorphic, and some polymorphic forms have a changed activity. The most important are phase I biotransformation enzymes (cytochromes of the P450 family, such as CYP1A1, CYP2D6, CYP2C9, and CYP2C19), which activate xenobiotics to yield genotoxic intermediates, and phase II enzymes [glutathione S-transferases (GSTs), arylamine N-acetyltransferases (NATs), etc.], which convert the genotoxic compounds to non toxic ones [7,8]. In addition, several genes determine the response to anti cancer drugs. For instance, the products of methylene tetrahydrofolate reductase(MTHFR), methionine synthase reductase (MTRR) and thiopurine-S-methyltransferase (TPMT) genes, participate in metabolism of the anti cancer agents 5-fluorouracil, methotrexate, and thiopurine derivatives [6,9,10].

Polymorphism of phase I and II enzymes play an important role in primary childhood leukemia [8,11-14]. Moreover, polymorphisms of the biotransformation genes affect the incidence and features of acute leukemia relapse [6,10,15-20]. Since genotype frequencies vary among populations, it is useful to test the polymorphisms of the xenobiotic detoxification genes for association with the efficacy of therapy.

A biochip that assesses several polymorphisms of biotransformation genes has been designed in our laboratory [7,21,22]. It permits assessment of 24 mutations of 11 genes: CYP1A1 (4887>, 4889A>G, and 6235T>C), CYP2D6 (1934G>A and DelA2637), GSTT1 (deletion), GSTM1 (deletion), MTHFR (677C>T and 1298A>C), MTRR (66A>G), NQO1 (609C>T), CYP2C9 (430C>T and 1075A>C), CYP2C19 (681G>A), NAT2 (341T>C, 481C>, 590G>A, and 857G>A), and P (238G>C, 292G>T, 460G>A, 644G>A, 681T>G and 719A>G). The relation of 6-MP therapy to TPMT-genotype was studied previously and showed that ALL patients with a heterozygous TPMT-genotype were characterized by lower tolerance for standard doses [6,23]. In the present study, we set out to identify the markers for the prognosis and the efficacy of therapy for children with acute leukemia, in the genetic polymorphisms of key enzymes involved in the metabolism of xenobiotics and anti cancer agents. Using the biochip, we determined the frequency of the polymorphic alleles of CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19 and NAT2 in 403 children with acute leukemia. After the patients were classified by type of leukemia, the frequency of the allelic variants of the genes were compared in children diagnosed with primary leukemia or with leukemia relapse.




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