Recognition and processing of cisplatin- and oxaliplatin-DNA adducts

doi:10.1016/j.critrevonc.2004.08.008

Critical Reviews in Oncology/Hematology

Volume 53, Issue 1, January 2005, Pages 3-11

https://doi.org/10.1016/j.critrevonc.2004.08.008 Get rights and content

Abstract

The cytotoxicity of platinum compounds is thought to be determined primarily by their DNA adducts. Cisplatin and oxaliplatin are structurally distinct, but form the same types of adducts at the same sites on DNA. However, the DNA adducts are differentially recognized by a number of cellular proteins. For example, mismatch repair proteins and some damage-recognition proteins bind to cisplatin–GG adducts with higher affinity than to oxaliplatin–GG adducts, and this differential recognition of cisplatin- and oxaliplatin–GG adducts is thought to contribute to the differences in cytotoxicity and tumor range of cisplatin and oxaliplatin. A detailed kinetic analysis of the insertion and extension steps of dNTP incorporation in the vicinity of the adduct shows that both DNA polymerase β (pol β) and DNA polymerase η (pol η) catalyze translesion synthesis past oxaliplatin–GG adducts with greater efficiency than past cisplatin–GG adducts. In the case of pol η, the efficiency and fidelity of translesion synthesis in vitro is very similar to that previously observed with cyclobutane TT dimers, suggesting that pol η is likely to be involved in error-free bypass of Pt adducts in vivo. This has been confirmed for cisplatin by comparing the cisplatin-induced mutation frequency in human fibroblast cell lines with and without pol η. Thus, the greater efficiency of bypass of oxaliplatin–GG adducts by pol η may explain the lower mutagenicity of oxaliplatin compared to cisplatin. The ability of these cellular proteins to discriminate between cisplatin and oxaliplatin adducts suggest that there exist significant conformational differences between the adducts, yet the crystal structures of the cisplatin- and oxaliplatin–GG adducts were very similar. We have recently solved the solution structure of the oxaliplatin–GG adduct and have shown that it is significantly different from the previously published solution structures of the cisplatin–GG adducts. Furthermore, the observed differences in conformation provide a logical explanation for the differential recognition of cisplatin and oxaliplatin adducts by mismatch repair and damage-recognition proteins.

Section snippets

Cisplatin and oxaliplatin DNA adducts

cis-Diamminedichloroplatinum(II) (cisplatin) and cis-diammine-1,1-cyclobutane dicarboxylate (carboplatin) are widely used in chemotherapy, and are particularly effective in the treatment of testicular, ovarian, head, neck and non-small cell lung cancer. However, cisplatin and carboplatin have significant toxicity and are mutagenic in cell culture and animal model systems [1], [2]. Resistance is also a major limitation of cisplatin and carboplatin chemotherapy, with many tumors displaying

Discrimination between cisplatin and oxaliplatin adducts by cellular proteins

Studies in yeast [14], [15], [16], [17] and mammalian cell lines [17] have shown that Pt–DNA adducts are processed by components of nucleotide excision repair, recombination repair and translesion DNA synthesis. Defects in any of these pathways result in increased sensitivity to cisplatin. Nucleotide excision repair is required for the repair of Pt–DNA intrastrand cross-links, while repair of Pt–DNA interstrand cross-links is thought to require components of both the nucleotide excision repair

The NMR solution structure of the oxaliplatin–GG adduct

X-ray crystallographic structures have been reported for both the cisplatin–GG [99] and oxaliplatin–GG [100] adducts in the same dodecamer DNA sequence. The two structures were virtually identical [100]. However, all of the mismatch repair proteins, DNA polymerases, and damage-recognition proteins that discriminate between cisplatin and oxaliplatin adducts and for which structural information is available appear to bind DNA primarily in the minor groove and bend DNA in the direction of the

Discussion

The average solution structure of the oxaliplatin–GG adduct is relatively similar to the crystal structure of the oxaliplatin–GG adduct, but very different from all previous solution structures of the cisplatin–GG adducts. However, the crystal structure of the cisplatin–GG adduct [99] is also less bent than the solution structures of the cisplatin–GG adduct [106], [107]. This has been interpreted as suggesting that the crystal structure of the cisplatin–GG adduct may be influenced by crystal

Reviewers

Turchi J., Ph.D., Department of Biochemistry and Molecular Biology, Wright State Universtiy, 3640 colonel Glenn Highway, Dayton, OH 45435, USA.

Dr. Siddik Z., Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center, Box 104, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Dr. Meijer C., Department of Medical Oncology (lab), University Hospital Groningen, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands.

Acknowledgements

The authors would like to thank Sanofi-Synthelabo for providing oxaliplatin and Pt(dach)PtCl₂; Dr. Sam Wilson for providing DNA polymerase β; Dr. Fumio Hanaoka for providing DNA polymerase η; and Jody Havener for preparing the cisplatin- and oxaliplatin-DNA templates used in these studies. Support for this work was provided by USPHS grant CA84480.

Stephen G. Chaney received his B.S. in Chemistry from Duke University and his Ph.D. in Biochemistry from UCLA. He is currently Professor of Biochemistry and Biophysics at the University of North Carolina. He is also affiliated with the Lineberger Cancer Center and the Curriculum in Toxicology at UNC.

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Recognition and processing of cisplatin- and oxaliplatin-DNA adducts

Abstract

Section snippets

Cisplatin and oxaliplatin DNA adducts

Discrimination between cisplatin and oxaliplatin adducts by cellular proteins

The NMR solution structure of the oxaliplatin–GG adduct

Discussion

Reviewers

Acknowledgements

Mutat Res

J Inorgan Biochem

Biochem Pharmacol

Chem-Biol Interact

Pharmacol Ther

J Biol Chem

J Biol Chem

J Biol Chem

J Inorgan Biochem

Eur J Cancer

J Biol Chem

J Biol Chem

Mutat Res-DNA Repair

J Biol Chem

Biochim et Biophys Acta-Gene Struct Express

Mutat Res-Fundam Mol Mech Mut

J Biol Chem

J Biol Chem

J Mol Biol

J Inorg Biochem

J Biol Chem

J Biol Chem

DNA Repair (Amst)

J Biol Chem

J Biol Chem

Is cisplatin a human carcinogen

J Nat Cancer Inst

Mutagenic and carcinogenic properties of platinum-based anticancer drugs

Mutat Res-Fundam Mol Mech Mut

Mechanisms of drug resistance in ovarian cancer

Cancer

Drug resistance: an overview of the current state of the art

Int J Oncol

Oxaliplatin

Drugs Future

Mutagenicity, tumorigenicity, and electrophilic reactivity of the stereoisomeric platinum(II) complexes of 1,2-diaminocyclohexane

Cancer Res

Effect of the diaminocyclohexane carrier ligand on platinum adduct formation, repair, and lethality

Biochemistry

Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA

Mol Pharmacol

Differential toxicities of anticancer agents among DNA repair and chaeckpoint mutants of Saccharomyces cerevisiae

Cancer Res

DNA damage-processing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs

Mol Pharmacol

Genome-wide identification of genes conferring resistance to the anticancer agents cisplatin, oxaliplatin, and mitomycin C

Cancer Res

Homologous recombination is a highly conserved determinant of the synergistic cytotoxicity between cisplatin and DNA topoisomerase I poisons

Mol Cancer Ther

HIV-1 Tat increases cell survival in response to cisplatin by stimulating Rad51 gene expression

Oncogene

Loss of DNA mismatch repair in acquired resistance to cisplatin

Cancer Res

The role of mismatch repair in platinum drug resistance

Cancer Res

In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair

Cancer Res

Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin

Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis-aceto-amine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts

Cancer Res

Role of carrier ligand in platinum resistance in L1210 cells

Cancer Res

Role of carrier ligand in platinum resistance of human carcinoma cell lines

Cancer Res

Increased gene specific repair of cisplatin induced interstrand crosslinks in cisplatin resistant cell lines, and studies on carrier ligand specificity

Carcinogenesis

Differential induction of c-Jun NH2-terminal kinase and c-Abl kinase in DNA mismatch repair-proficient and deficient cells exposed to cisplatin

Cancer Res

Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells

Br J Cancer

The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlation with replicative bypass of platinum-DNA adducts