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Updated: Aug 7, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Phenotypic evolution of cells resistant to bromodeoxyuridine

M Harris, K Collier

    Proceedings of the National Academy of Sciences of the United States of America
    |July 1, 1980
    PubMed

    Insights

    Bromodeoxyuridine (BrdUrd) resistance and thymidine kinase deficiency develop in V79 cells through a gradual, drug-induced transition. BrdUrd acts as both an inducer and selector, leading to complex cellular phenotypes over time.

    Area of Science:

    • Cell biology
    • Genetics
    • Biochemistry

    Background:

    • Bromodeoxyuridine (BrdUrd) is a thymidine analog used to study DNA synthesis and cell proliferation.
    • Thymidine kinase (TK) is a crucial enzyme in DNA precursor metabolism, phosphorylating thymidine and BrdUrd.
    • Drug resistance mechanisms in mammalian cells are complex and can involve multiple genetic and epigenetic alterations.

    Purpose of the Study:

    • To investigate the mechanisms of bromodeoxyuridine (BrdUrd) resistance and thymidine kinase (TK) deficiency development in V79 Chinese hamster cells.
    • To characterize the phenotypic changes associated with prolonged BrdUrd exposure.
    • To explore the role of BrdUrd as both a selective and inductive agent in cellular evolution.

    Main Methods:

    • Induction of drug resistance using spontaneous and drug-induced mutations in V79 cells.
    • Isolation of partially resistant clones via one-step selection in BrdUrd.
    • Long-term culture of tolerant populations in BrdUrd-containing medium.
    • Measurement of thymidine kinase activity and relative plating efficiency in hypoxanthine/aminopterin/thymidine (HAT) medium.
    • Clonal analysis to assess phenotypic modifications.

    Main Results:

    • Prolonged BrdUrd exposure induced a gradual phenotypic transition, leading to complete BrdUrd resistance and thymidine kinase deficiency.
    • Thymidine kinase activity declined logarithmically over 8-10 weeks, correlating with increased growth rate.
    • Colony formation in HAT medium decreased exponentially for at least 18 weeks post-TK deficiency.
    • Phenotypic modifications were continuous or multistep, occurring in most cells maintained in BrdUrd.

    Conclusions:

    • Bromodeoxyuridine (BrdUrd) can act as both an inductive and selective agent, driving the evolution of drug-resistant cell populations.
    • The development of BrdUrd resistance and thymidine kinase deficiency is a complex, multistep process.
    • New models are required to explain the progressive evolution of these cellular phenotypes.

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