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A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
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Published on: September 25, 2017

Comparison of biochemical and biological effects of four nitrosoureas with differing carbamoylating activities

H E Kann

    Cancer Research
    |August 1, 1978
    PubMed

    Insights

    Strongly carbamoylating chloroethylnitrosoureas inhibit DNA and protein synthesis, but this is not essential for their cytotoxic effects. Recovery of synthesis depends on serum factors.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Pharmacology

    Background:

    • Chloroethylnitrosoureas (CENUs) are a class of anticancer drugs.
    • Their mechanism of action involves alkylation and carbamoylation of cellular macromolecules.
    • The relationship between carbamoylating activity and cytotoxicity is not fully understood.

    Purpose of the Study:

    • To investigate the effects of four CENUs with varying carbamoylating activities on macromolecular synthesis.
    • To determine if inhibition of DNA and protein synthesis is essential for the cytotoxic effects of CENUs.

    Main Methods:

    • Comparison of four CENUs with different carbamoylating potentials.
    • Exposure of cells to drug concentrations causing 0.5-log or 2-log reductions in cloning efficiency.
    • Measurement of radioactive precursor incorporation into nucleic acids and proteins during and after drug exposure.

    Main Results:

    • Strongly carbamoylating CENUs (BCNU and CCNU) dose-dependently inhibited DNA, RNA, and protein synthesis.
    • Inhibition was most pronounced in DNA synthesis.
    • Weakly carbamoylating CENUs (chlorozotocin and the unclassified CENU) did not inhibit synthesis.
    • Cells partially recovered DNA synthesis after BCNU/CCNU removal, dependent on serum factors.
    • Inhibition of synthesis was not essential for cytotoxicity, as two compounds lacking this effect were still cytotoxic.

    Conclusions:

    • The cytotoxic effects of CENUs are not solely dependent on the inhibition of macromolecular synthesis.
    • Carbamoylating activity influences the immediate effects on DNA and protein synthesis.
    • Serum factors play a role in cellular recovery from CENU-induced inhibition of DNA synthesis.

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