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Related Experiment Videos

Unbalanced deoxyribonucleotide synthesis caused by methotrexate.

A V Hoffbrand, E Tripp

    British Medical Journal
    |April 15, 1972
    PubMed
    Summary

    Methotrexate significantly alters nucleotide pools in lymphocytes, decreasing thymidylate triphosphate (dTTP) and increasing deoxyadenosine triphosphate (dATP). This imbalance may impair DNA synthesis and repair, potentially explaining methotrexate

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    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Background:

    • Methotrexate is a chemotherapy agent that inhibits dihydrofolate reductase, impacting DNA synthesis.
    • Understanding its effects on intracellular nucleotide pools is crucial for explaining its toxicity and efficacy.
    • Phytohaemagglutinin-transformed lymphocytes are a model system for studying drug effects on rapidly dividing cells.

    Purpose of the Study:

    • To investigate the impact of methotrexate on the intracellular pools of thymidylate triphosphate (dTTP) and deoxyadenosine triphosphate (dATP) in human lymphocytes.
    • To explore the potential mechanisms by which methotrexate-induced nucleotide pool alterations may affect DNA synthesis and repair.

    Main Methods:

    • Normal human lymphocytes were transformed using phytohaemagglutinin.
    • The cells were treated with methotrexate.
    • Free intracellular pools of dTTP and dATP were measured.

    Main Results:

    • Methotrexate treatment led to a significant decrease in the dTTP pool (38%–88%).
    • Methotrexate treatment resulted in a significant increase in the dATP pool (24%–185%).

    Conclusions:

    • Methotrexate disrupts the balance of critical DNA precursors, dTTP and dATP, in lymphocytes.
    • Elevated dATP levels may inhibit DNA synthesis and repair enzymes, contributing to methotrexate's effects.
    • Folate deficiency, whether inherent or drug-induced, might impair DNA synthesis via altered dATP and dTTP pools, potentially causing megaloblastic changes and chromosomal abnormalities.

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