Methotrexate (MTX) and 6-mercaptopurine (6MP) are the most commonly used drugs in the therapy of childhood acute lymphoblastic leukaemia (ALL). The main genotoxic effect of MTX resulting from ...inhibition of thymidylate synthase is mis-incorporation of uracil into DNA, which is considered essential for the effectiveness of the Protocol M in ALL IC BFM 2002/EURO LB 2002 regimens. In this study, we investigated the level of basal and induced DNA damage as well as the effectiveness of DNA repair in lymphocytes of children with ALL at four time-points during therapy with MTX and 6MP. To assess DNA damage and the efficacy of DNA repair we used the modified alkaline comet assay with uracil DNA glycosylase (Udg) and endonuclease III (EndoIII). In addition, we examined the induction of apoptosis in the lymphocytes of the patients during treatment. Finally, we compared the activity of base-excision repair (BER), involved in removal of both uracil and oxidized bases from DNA in lymphocytes of children with ALL and lymphocytes of healthy children. BER efficiency was estimated in an
in vitro assay with cellular extracts and plasmid substrates of heteroduplex DNA with an AP-site. Our results indicate that there is a significant decrease in the efficacy of DNA repair associated with an increased level of uracil in DNA and induction of apoptosis during therapy. Moreover, it was found that the BER capacity was decreased in the lymphocytes of ALL patients in contrast to that in lymphocytes of healthy children. Thus, we suggest that an impairment of the BER pathway may play a role in the pathogenesis and therapy of childhood ALL.
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The significance of genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Polymorphisms of genes encoding for xenobiotics and drug transporters are potential ...factors, which can influence the risk of developing ALL and its clinical outcome. P‐glycoprotein (P‐gp) is an adenosine triphosphate‐binding cassette (ABC)‐family transporter involved in protection against xenobiotics and multi‐drug resistance. Recently, the single‐nucleotide polymorphism C3435T of MDR1 gene has been found to be associated with altered tissue expression and function of P‐gp. To evaluate whether C3435T MDR1 polymorphism is associated with the occurrence and outcome of ALL, 113 children with ALL (median age 5.1 yr) and 175 healthy individuals of Polish Caucasian origin were studied by polymerase chain reaction‐restriction fragment‐length polymorhism (PCR‐RFLP) assay. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (OR, 95% CI; 1.8, 1.1–3.1; P = 0.037). Besides, the analysis of factors influencing clinical outcome of our ALL patient cohort showed that CC genotype carriers had significantly lower event‐free survival probability (pEFS) (0.62 vs. 0.87; P = 0.007) and overall survival probability (pOS) (0.72 vs. 0.91; P = 0.006). The Cox proportional hazards model‐based analysis revealed that the hazard ratios for lower pEFS and lower pOS among CC homozygous subjects were 3.9 (P = 0.008) and 3.3 (P = 0.02), respectively. In conclusion, the results of the present study provide evidence that C3435T MDR1 polymorphism may involve both the susceptibility to and the clinical outcome of childhood ALL. Carriers of the TT genotype are more at risk of developing ALL than other individuals, whereas CC genotype carriers are supposed to have worse prognosis.
Maximal intensification of antineoplastic therapy is currently a predominant trend in the treatment regimens for acute leukemias and lymphomas. However, by such approach myelosuppression and ...counteracting its sequelae become paramount problems. Hematopoietic growth factors G-CSF/GM-CSF play a great role in this aspect of the therapy. Effects of 35 courses of G-CSF/GM-CSF were evaluated in 19 children with ALL and NHL and compared with 21 episodes of neutropenia in 15 historical controls. In the treatment group time of neutropenia was approx. 3 times shorter as compared with a control group. Fever accompanying neutropenia occurred less frequently and lasted shorter in the treatment group. Also, symptoms of infection subsided faster. Subjective life quality was better in children receiving growth factors.
The purpose of this study was to determine the frequent of serum aminotransferase elevation in children with leukemias and non-Hodgkin's lymphomas and define the cause of this pathology. In the serum ...of 43 children the bilirubin concentration, activities of aspartic aminotransferase (AspAT), alanine aminotransferase (AlAT) and gammaglutamylotranspeptidase (GGTP) were measured before treatment, during and after intensive chemotherapy. 43 patients 8 (65%) had bilirubin concentration above 1.2 mg/dl and/or aminotransferase activities above 100 U/l. The most possible causes of the liver damage in the patients were: hepatotoxicity of chemotherapy, virus or bacterial infections and leukemic or lymphomatous involvement of the liver.
