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Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate and 5-fluorouracil in mice

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  1. Tez No: 542353
  2. Yazar: BAŞAK ÇELTİKÇİ
  3. Danışmanlar: Dr. RIMA ROZEN
  4. Tez Türü: Doktora
  5. Konular: Genetik, Genetics
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2008
  8. Dil: İngilizce
  9. Üniversite: Mcgıll Unıversıty
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

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Özet (Çeviri)

Folates are essential cofactors that are required for the synthesis of nucleotides, the precursors of DNA and RNA. Two widely used anti-metabolite chemotherapeutic drugs, anti-folate methotrexate (MTX) and the pyrimidine antagonist 5-fluorouracil (5-FU), inhibit DNA and RNA synthesis and induce apoptosis, through their effects on the folate pathway. A common polymorphism (677C→T) in methylenetetrahydrofolate reductase (MTHFR), a critical folate-metabolizing enzyme in nucleotide synthesis, may modify the chemosensitivity of MTX and 5-FU. In this thesis, two mouse models (a well-characterized mouse model deficient in MTHFR (Mthfr/ and Mthfr/) and a new mouse model that overexpresses MTHFR (MTHFR-Tg)) were used to investigate the effect of MTHFR expression on response to MTX and 5-FU. The latter mouse model, MTHFR-Tg, was generated and characterized in this thesis. MTHFR-Tg mice had an increase in methionine in brain, a decrease in cysteine in duodenum, an increase in glutathione in liver and decreases in 10-formyltetrahydrofolate levels in liver and duodenum. Mthfr-deficient and MTHFR-Tg mice and their wild-type littermates were injected with MTX or 5-FU (with saline as a control) and assessed for hematological parameters (hematocrit, hemoglobin, red and white blood cell numbers), plasma homocysteine levels, serum nephrotoxicity and hepatotoxicity markers, splenic dUTP/dTTP ratios and apoptosis. MTHFR overexpression increased the effect of MTX on hematopoietic cells, through reduced DNA synthesis and deoxyribonucleotide imbalance (higher dUTP/dTTP ratios)-induced splenic apoptosis, with a protection against MTX-induced hyperhomocysteinemia. MTHFR deficiency had similar effects on MTX-treated hematopoietic cells, through hyperhomocysteinemia-induced splenic apoptosis, with enhanced MTX-induced hyperhomocysteinemia and nephrotoxicity. Furthermore, in transformed mouse embryonic fibroblasts, MTHFR overexpression was protective against MTX-induced apoptosis, possibly through its protective effect against hyperhomocysteinemia. Lastly, MTHFR overexpression enhanced 5-FU-induced leucopoenia and splenic apoptosis while reducing plasma Hcy levels. The major problem with MTX and 5-FU therapies is the variability in therapeutic outcome and toxicity which is the primary reason for discontinuation of therapy. Our studies illustrate the critical effect of MTHFR expression on the chemosensitivity to MTX and 5-FU, and the importance of pharmacogenetic testing for the MTHFR polymorphism and possibly polymorphisms in other folate-metabolizing enzymes to maximize efficacy and minimize toxicity.

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