Role of base-excision repair in the treatment of childhood acute lymphoblastic leukaemia with 6-mercaptopurine and high doses of methotrexate.

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.

[The assessment of hepatic enzymes' levels in children treated for leukemia and non-Hodgkin's lymphomas]. / Ocena poziomów enzymów watrobowych u dzieci leczonych z powodu bialaczek i chloniaków nieziarniczych.

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.

[The use of hematopoietic growth factors G-CSF/GM-CSF in the treatment of neutropenia in children with acute lymphoblastic leukemia and non-Hodgkin's lymphomas]. / Zastosowanie krwiotwórczych czynników wzrostu granulocytów i makrofagów w leczeniu neutropenii u dzieci z ostra bialaczka limfoblastyczna i nieziarniczymi chloniakami zlosliwymi.

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.