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Related Experiment Videos

Protein interactions with platinum-DNA adducts: from structure to function.

Stephen G Chaney1, Sharon L Campbell, Brenda Temple

  • 1Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center and Curriculum in Toxicology, CB #7260 Mary Ellen Jones Building, University of North Carolina, Chapel Hill, NC 27599-7260, USA. Stephen_Chaney@med.unc.edu

Journal of Inorganic Biochemistry
|October 2, 2004
PubMed
Summary

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Oxaliplatin is less mutagenic than cisplatin due to differences in how DNA polymerase eta bypasses platinum-DNA adducts. Structural variations in these adducts explain differential cellular recognition and repair, impacting drug efficacy and range.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Cisplatin and carboplatin are effective platinum-based anticancer drugs, but only oxaliplatin, a third-generation platinum compound, is approved in the US.
  • Understanding the mechanistic differences between cisplatin and oxaliplatin is crucial for explaining variations in their efficacy, mutagenicity, and tumor range.
  • Both drugs form similar Pt-GG intrastrand diadducts on DNA, the most abundant adduct type.

Purpose of the Study:

  • To elucidate the mechanistic basis for the differential efficacy, mutagenicity, and tumor range between cisplatin and oxaliplatin.
  • To investigate the role of DNA repair proteins and DNA polymerases in recognizing and bypassing cisplatin- and oxaliplatin-DNA adducts.

Main Methods:

  • Kinetic analysis of deoxynucleotide triphosphate (dNTP) incorporation near platinum-DNA adducts.

Related Experiment Videos

  • In vitro translesion synthesis assays using purified DNA polymerases (pol beta and pol eta).
  • Comparison of cisplatin-induced mutation frequencies in human fibroblast cell lines with and without pol eta.
  • Solution structure determination of the oxaliplatin-GG adduct and comparison with cisplatin-GG adduct structures.
  • Molecular modeling studies of DNA polymerase bypass mechanisms.

    • Main Results:

    • DNA polymerases, particularly pol eta, bypass oxaliplatin-GG adducts more efficiently and with similar fidelity as cyclobutane thymine dimers.
    • Pol eta's involvement in error-free bypass of platinum adducts in vivo was confirmed for cisplatin.
    • The solution structure of the oxaliplatin-GG adduct differs significantly from cisplatin-GG adducts, explaining differential recognition by repair proteins.
    • Mismatch repair and damage-recognition proteins discriminate between cisplatin- and oxaliplatin-GG adducts.

    Conclusions:

    • The greater bypass efficiency of oxaliplatin-GG adducts by pol eta likely contributes to oxaliplatin's lower mutagenicity compared to cisplatin.
    • Conformational differences between cisplatin- and oxaliplatin-GG adducts explain differential recognition by cellular proteins.
    • These findings provide a mechanistic basis for the distinct clinical profiles of cisplatin and oxaliplatin.