UNIVERSITAS AIRLANGGA



Detail Article

Folia Medica Indonesiana

ISSN 0303-7932

Vol. 41 / No. 4 / Published : 2005-10

Order : 7, and page :281 - 290

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Original Article :

Thymidilate synthase polymorphisms in indonesian childhood acute lymphoblastic leukemia

Author :

  1. IDG Ugrasena *1
  2. Bambang Permono*2
  3. Edy Supriadi *3
  4. Laura Vroling *4
  5. Jacqueline Cloos *5
  1. Hematology-Oncology Division, Department of Child Health Dr. Soetomo Teaching Hospital – Airlangga University School of Medicine
  2. Hematology-Oncology Division, Department of Child Health Dr. Soetomo Teaching Hospital – Airlangga University School of Medicine
  3. Hematology-Oncology Division, Department of Child Health Dr. Sardjito Hospital – Gadjah Mada University School of Medicine
  4. Pediatric Oncology of Vrije Universiteit Medical Center Amsterdam, the Netherlands
  5. Pediatric Oncology of Vrije Universiteit Medical Center Amsterdam, the Netherlands

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.

Keyword :

thymidylate synthase, acute lymphoblastic leukaemia, polymorphism, ethnic variations, childhood, Indonesia,


References :

Bagley PJ & Selhub J,(1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells - : Proc Natl Acad Sci USA

Etienne MC et al,(2002) Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses - : J Clin Oncol





Archive Article

Cover Media Content

Volume : 41 / No. : 4 / Pub. : 2005-10
  1. Editorial Vol 41 No 4 2005
  2. Opinion: Trend Of Indonesian Nurse’s Role In The Future
  3. Eosinophilia In Physical Exercise Stressor: Pathobiology Or Physiobiology?
  4. The Detection Of Staphylococcus Aureus In Swiftlets' Nest Using Immunohistochemistry (streptavidin Biotin)
  5. The Role Of Intravenous N-acetylcysteine Reduces Pulse Pressure In Patients With Chronic Kidney Disease Stage 5 During Hemodialysis. A Randomized Blinded Trial
  6. Low Fat Milk V/s Low Lactose Milk For Patients With Different Nutritional Status Who Suffered From Acute Diarrhea
  7. Thymidilate Synthase Polymorphisms In Indonesian Childhood Acute Lymphoblastic Leukemia
  8. Modulation Of Immune Response In Long-term Use Of Inhaled Corticosteroid In Childhood Asthma Receiving Specific Immunotherapy
  9. Systemic Lupus Erythematosus Associated With Cholestatic Hepatitis In A Child. A Case Report
  10. Review Article And Clinical Experience: Preventive And Therapeutic Strategies For Osteoporosis (a Highly Efficacious Risedronate-35 Mg Once Weekly)
  11. Immunological Aspect On Bone Cells
  12. Three Dimension Decision For Statistical Testing. The Significance Of Traditional Medicine Holistic Approach (a Preliminary Idea)
  13. Total Quality Management (tqm), The Best Method To Eliminate Narcotics And Psychotropics Abuse And Illegal Distribution

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