THYMIDILATE SYNTHASE POLYMORPHISMS IN INDONESIAN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA
ABSTRACT: The enzyme
thymidylate synthase (TS) converts dUMP into dTMP and requires folates as
co-factors. Since dTMP is necessary for DNA synthesis, TS is an important
target of cancer chemotherapy. Ethnic variations of the polymorphic tandem
repeat sequence in the enhancer region of the TS promoter, has previously been
described to influence the outcome of acute lymphoblastic leukaemia (ALL). A
triple repeat is associated with a higher TS gene expression than a double
repeat, resulting in poorer outcome of ALL patients treated with the
anti-folate methotrexate (MTX). In addition, the association of TS expression
and MTX resistance appears to be even more pronounced in combination with an accumulation
of folates. This latter event can occur when methylenetetrahydrofolate
reductase (MTHFR) has impaired enzyme activity due to a C667T mutation. In this
study, we determined the ethnic variations of the TS and MTHFR genotype between
Caucasian an Indonesian in ALL cells obtained at diagnosis from 157 Caucasian
and 101 Indonesian children with MTX-treatment in prospective. Furthermore, we
determined the involvement of TS polymorphisms in MTX sensitivity, by using a
TS inhibition assay (TSIA). Homozygous TS triple repeats were more than twice
as common in Indonesian samples (76.3%) than in Caucasian samples (33.1%).
Heterozygotes of the MTHFR mutations were seen in 15% of the screened
Indonesian samples. These results demonstrate significant ethnic variation in a
TS gene regulatory element in leukemic cells. A difference was found between
the MTX sensitivity and the presence of a double or triple repeat in the
Caucasian ALL group. Interestingly, according to these data it seems that the
samples with a triple repeat show a shift in their distribution towards
hypersensitivity to MTX, in contrast to previously described results. However four
of the samples (16.0%) did show resistance to MTX, which may suggest an additional
role for other enzymes, such as MTHFR. Further investigation in the Indonesian
samples may give insight in the role of the polymorphisms in MTX sensitivity.
Keywords: thymidylate
synthase, acute lymphoblastic leukaemia, polymorphism, ethnic variations,
childhood, Indonesia
Author: IDG Ugrasena, Bambang
Permono, Edy Supriadi, Laura Vroling
Journal Code: jpkedokterangg050051

Artikel Terkait :
Jp Kedokteran gg 2005
- Treatment of taeniasis and cysticercosis with praziquantel and albendazole
- The benefits of progesterone therapy in imminent abortion
- PM10 as Predictor of Ventilation Efficiency of Houses in Relation to Health Effect
- Fatty acids intake among diverse ethnic groups in Indonesia
- The effects of balanced low calorie diet on body composition and serum leptin of obese women
- QT dispersion, a simple tool to predict ventricular tachyarrhythmias and/or sudden cardiac death after myocardial infarction
- Endoscopical appearances of nonsteroidal anti inflammatory drug (NSAID)- enteropathy
- Role of general practitioner in the management of acute myocardial infarction
- Genotyping of hepatitis B virus from dried and stored serum on filter paper
- Development of bioassay for pathogenecity testing of Ureaplasma urealyticum as part of host-pathogen communication
- Detection of GAD65 autoantibodies of type-1 diabetes using anti-GAD65-abs reagent produced from bovine brain tissue
- The use of ceftriaxone impregnated beads in the management of chronic osteomyelitis
- The correlation between total lymphocyte count and the number of candida colony from the oral cavity in HIV/AIDS patients
- Survival rate and prognostic factors in advanced cervical cancer patients accompanied by renal impairment
- Left ventricular diastolic dysfunction in type 2 diabetes mellitus patient without cardiovascular disease: the association with microalbuminuria
- Hormonal contraception as a risk factor for obesity
- Effect of irrigating fluid temperature on core body temperature during transurethral resection of the prostate
- T-lineage blast crisis of chronic myelogenous leukemia: simple record of 4 cases
- Intracranial germ cell tumour with extra cranial extension in a four month old infant – a case report
- Drospirinone: new generation of progestogen
- Implementation of 25-well culture plates for M. tuberculosis drug susceptibility testing in Indonesia
- Cytosolic estrogen and progesterone receptor content in the endometriotic tissues and endometrium in women with and without endometriosis
- Nutritional status of hyperlipidemics elderly in Indonesia according to body mass lndex (study in four Indonesian big cities)
- Age, duration of work, noise and vibration in inducing hearing and balance impairments
- Presurgical cytologic diagnostic test of uterine cavity in ovarian malignant tumor