Acute Lymphoblastic Leukemia (ALL) is the most common type of hematologic malignancy in children. Although most children with leukemia are currently diagnosed and treated, many have long-term complications. The duration of treatment is about three years. More than 80% of children diagnosed with ALL recover completely. Methotrexate has been proven as a treatment in patients with ALL, but it can cause many complications. Therefore, it is precious to study the factors that cause or exacerbate these complications. Evaluation of this drug's toxicity and recognition of the patient's genetic factors (mutant alleles) in identifying patients exposed to the hematologic and hepatic toxicity of this drug is necessary.
In our study, the prevalence of ABCB 1 gene mutation at point 3435 C->T was 70.4% and the prevalence of ABCB 1 gene mutation at point 1199G->A was 4.9%, while, the allelic frequency of Ser400Asn in the Caucasian population was 5.5% and the prevalence of ABCB 1 gene mutation at 3435 was reported to be 53.9. (23).
In CML patients, the prevalence of ABCB 1 gene mutation in 3435 points was 60% in the normal population and 87.14% in the CML population (24). Moreover, the prevalence of this mutation in the Japanese population was 72.7%, and in Italy's Tuscany population was 69.6% (25).
The results of our study showed that the frequency of gastrointestinal toxicity, leukopenia, anemia, thrombocytopenia, hepatotoxicity, neutropenia, and nephrotoxicity in patients with heterozygous and homozygous mutant mutations of ABCB 1 gene at point 1199 is less than patients with polymorphism.
To date, no study has been done on the association of ABCB 1 gene polymorphisms at point 1199 with gastrointestinal, hematologic, hepatic, and kidney toxicity. However, studies on this gene mutation have shown that the risk of recurrence in patients with 1199GA polymorphisms increased 2.9 times compared to 1199GG, suggesting that the 1199 G->A ABCB1 mutation may be a new predictor of prognosis in children (40). Woodahl et al. said that MDR1 G1199A polymorphism might play an anticancer role by modulating drug distribution and delivering tumor cells (26).
Data analysis results showed the frequency of gastrointestinal toxicity, leukopenia, anemia, thrombocytopenia, hepatotoxicity, neutropenia, and nephrotoxicity in patients with heterozygous and homozygous polymorphisms of ABCB 1 gene mutation is higher in patients with polymorphism at point 3435. However, this difference was not statistically significant. This result shows that the mutation of the ABCB 1 gene at 3435 C->T point can increase the incidence of hematologic, hepatic, gastrointestinal, and renal toxicities. In addition, due to our results, high prevalence of ABCB 1 gene mutation at point 3435 in patients with ALL this mutation can be a risk factor for ALL.
A study of 127 Lebanese ALL patients by Zgheib et al. showed a statistically significant association between neutropenia (absolute neutrophil count < 500) and alkaline carriers of type ABCB1 rs1045642 and ABCB1 rs1128503. They also stated that genotyping for ABCB1 polymorphism may be useful in identifying patients at risk for methotrexate toxicity (27).
The study of Gregers et al. showed that bone marrow toxicity in patients with TT genotype at 3435 points of the ABCB1 gene during doxorubicin, vincristine, and Prednisolone therapy is more. Hepatotoxicity was also observed in high-dose treatment with methotrexate in patients with the CC genome at 3435 points (28). Another study showed that patients with different ABCB1 C3435T alleles showed a more significant reduction in neutrophils (for CC, CT, and TT, 63%, 72%, and 80%) (29).
However, in a study by Yao et al., 78 single nucleotide polymorphisms (SNPs) in ABCB1, ABCC1, and ALDH1A1 were analyzed in 882 breast cancer patients. None of the SNPs in ABCB1 were associated with blood toxicity, and none of the 16 single nucleotide polymorphisms in ABCB1 or ALDH1A1 were associated with gastrointestinal toxicity (30).
On the other hand, the study of Samara et al. aimed to investigate the relationship between MDR1 C3435T and RFC1 G80A polymorphism with toxicity and response to methotrexate in rheumatoid arthritis patients, showing that there is a significant relationship between RFC1 G80A and MDR1 C3435T polymorphism with MTX toxicity. Patients with the RFC1 80GG genotype were at higher risk for gastrointestinal toxicity. Patients carrying at least one MDR1 3435T allele were at increased risk for MTX general toxicity, especially hepatotoxicity (31).
Suthandiram et al. illustrated that hepatic toxicity is associated with SLC19A1 G80A and ABCB1 C3435T and methotrexate plasma concentrations were significantly higher in patients with MTHFR C677T and ABCB1 C3435T polymorphisms (32).
In another study, Troels K Et al. examined the effect of paclitaxel in patients with ovarian cancer and the effect of genetic variants in CYP2C8 and ABCB1 on the toxicity and survival of the disease. They resulted that there was no statistically significant relationship between CYP2C8 and ABCB1. C1236T, G2677T / A, and C3435T with neutropenia, sensory neuropathy, and general survival (33).