Platinum-DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes.
Platinum-based compounds are widely used as chemotherapeutics for the treatment of a variety of cancers. The anticancer activity of cisplatin and other platinum drugs is believed to arise from their interaction with DNA. Several cellular pathways are activated in response to this interaction, which include recognition by high-mobility group and repair proteins, translesion synthesis by polymerases, and induction of apoptosis. The apoptotic process is regulated by activation of caspases, p53 gene, and several proapoptotic and antiapoptotic proteins. Such cellular processing eventually leads to an inhibition of the replication or transcription machinery of the cell. Deactivation of platinum drugs by thiols, increased nucleotide excision repair of Pt-DNA adducts, decreased mismatch repair, and defective apoptosis result in resistance to platinum therapy. The differences in cytotoxicity of various platinum complexes are attributed to the differential recognition of their adducts by cellular proteins. Cisplatin and oxaliplatin both produce mainly 1,2-GG intrastrand cross-links as major adducts, but oxaliplatin is found to be more active particularly against cisplatin-resistant tumor cells. Mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these two agents. This review describes the formation of Pt-DNA adducts, their interaction with cellular components, and biological effects of this interaction.
Ahmad
Saeed
S
Department of Chemistry, University of Engineering and Technology, Lahore 54890, Pakistan. saeed_a786@hotmail.com
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D053843:DNA Mismatch Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D010984:Platinum / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D018736:DNA Adducts; D024002:HMGB Proteins; D016159:Tumor Suppressor Protein p53; D010984:Platinum; D004247:DNA; D004259:DNA-Directed DNA Polymerase