“The Impact of ABCG2 polymorphism on the high dose of Methotrexate in childhood with acute lymphoblastic leukemia”

Abstract

Childhood ALL is the most common childhood malignancy as it accounts for the 25% of all childhood cancer and 75% of all childhood leukemia. High Dose MTX therapy is the corner stone in most contemporary multimodal childhood ALL protocols. As a matter of concern, HD-MTX is not only costly but also more toxic than low dose MTX. The incidence of fatal toxicity from HD-MTX administration is 5%, ascompared to nearly no fatal toxicity observed with low dose MTX. Genetic variability of ALL patients is the one of the importantrisk factors that induces MTXtoxicity. Among outward transporters of MTX is the adenosine triphosphate (ATP)–binding cassette class G2 transporter (ABCG2), also known as breast cancer resistant protein (BCRP). The most extensively studied among those SNPs with potential clinical relevance is 421 C>A resulting in a glutamine to lysine substitution (Q141K) in the ABCG2 protein, and as both lysine and glutamine are different in their electronic charges so this substitution results in the tertiary structure of the glutamine leading to greater susceptibility to degradation, therefore up to 70% low protein expression of ABCG2 and hypersensitivity of normal cells to anticancer drugs. It has a major role in MTX elimination. Thus, we aimedto correlate the variability of ABCG2 polymorphism [421 C >A] on the plasma level of HD-MTX of the consolidation phase at both 42h and 68h after its administration. Additionally, to correlate the variability of ABCG2 polymorphism [421 C >A] on the Cpss of HD-MTX at hour 23 of its administration. In order to fulfil our aim, this study was conducted on 200 subjects divided into the following two groups: a) 85 patients of LR group. b) 115 patients of SR/HR groups. Blood specimen was withdrawn from subjects to determine the genetic polymorphism of ABCG2 (C421A) gene by PCR-RFLP using the specific primers. Also, the plasma levels of MTX were determined routinely at the specified time intervals (23h, 42h and 68 h after HD-MTX administration. Results of the current study can be summarized as follows: (1) No statistical significance between the plasma toxic levels of MTX at 42h and 68h after the I.V infusionand treatment outcome, ABCG2 C421A polymorphism and clinical characteristics e.g sex, age and IP. (2) No statistical significance between Cpss of HD-MTX at 23h ABCG2 C421A polymorphism andtreatment outcome, ABCG2C421A polymorphism and clinical characteristics e.g sex, age and IP. (3) There is statistical difference between patients underwent toxicity at both 42h and 68h. Revision of guidelines of HD-MTX administration regarding post-hydration, urinepH, leucovorin rescueis highly recommended. (4) There is no prognostic significance of ABCG2 C421A polymorphism on ALL treatment.