Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

• Published in: Radiology and oncology Vol. 53; no. 2; pp. 148 - 158
• Main Author: Makovec, Tomaz
• Format: Journal Article
• Language: English
• Published: Poland Sciendo 28.03.2019; De Gruyter Poland
• Subjects: Adducts; Anticancer properties; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor activity; Antitumor agents; Cancer; Chemical properties; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - chemistry; Cisplatin - pharmacokinetics; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA adducts; DNA Adducts - chemistry; DNA Repair; DNA, Neoplasm - drug effects; Drug development; Drug Hypersensitivity - etiology; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - physiology; Drugs; Gene expression; Genomics; Gold Compounds - pharmacology; Humans; Metabolic pathways; Metal compounds; molecular mechanisms; Molecular modelling; Neoplasms; Neoplasms - blood; Neoplasms - drug therapy; Organic chemistry; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Palladium - pharmacology; Platinum; Platinum Compounds - adverse effects; Platinum Compounds - pharmacokinetics; Platinum Compounds - pharmacology; Polymorphism, Genetic; resistance; Review; Ribonucleic acid; RNA; Ruthenium - pharmacology; Toxicity; molecular mechanisms; cisplatin; chemotherapy; resistance
• ISSN: 1581-3207; 1318-2099; 1581-3207; 0485-893X
• DOI: 10.2478/raon-2019-0018

Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients' responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.