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| Cisplatin | |
|---|---|
| Name | Cisplatin |
| IUPAC | cis-diamminedichloroplatinum(II) |
| Formula | PtCl2(NH3)2 |
| Molar mass | 300.05 g·mol−1 |
| CAS | 15663-27-1 |
Cisplatin is a platinum-based chemotherapeutic agent used widely in oncology for solid tumors. Introduced during the 1970s, it remains a cornerstone in regimens for testicular, ovarian, bladder, and lung cancers and is included in many combination protocols alongside other cytotoxic and targeted agents. Clinical adoption followed landmark trials and approvals by regulatory agencies, and its profile influenced later development of platinum analogs and combination therapies.
Cisplatin is indicated for treatment of testicular cancer, ovarian cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, head and neck cancer, esophageal cancer, cervical cancer, and certain sarcoma subtypes, often as part of multi-agent regimens with agents such as bleomycin, etoposide, vincristine, paclitaxel, docetaxel, cyclophosphamide, doxorubicin, and ifosfamide. It is central to curative-intent protocols for metastatic and localized disease in trials conducted by groups like the National Cancer Institute and cooperative groups including the European Organisation for Research and Treatment of Cancer and the Cancer and Leukemia Group B. Neoadjuvant, adjuvant, and palliative strategies have integrated cisplatin in guidelines from organizations such as the National Comprehensive Cancer Network and the European Society for Medical Oncology. Treatment selection commonly accounts for performance status measures from scales like the Eastern Cooperative Oncology Group and comorbidity indices developed at institutions such as Mayo Clinic.
Cisplatin exerts cytotoxicity primarily via formation of platinum–DNA adducts, producing intra- and interstrand crosslinks that disrupt DNA replication and transcription, activate damage-sensing pathways including those mediated by p53, and trigger apoptosis via mitochondrial and death receptor cascades. Cellular response involves repair systems such as nucleotide excision repair, mismatch repair, and proteins including ERCC1, XPA, and MSH2, with downstream engagement of cell cycle checkpoints regulated by ATM and ATR. Signaling through kinases like CHK1 and CHK2, and interactions with proteins such as BAX, BCL2, and Caspase-3 determine cell fate. Tumor microenvironmental factors studied at centers like Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center influence sensitivity via hypoxia-inducible pathways including HIF1A.
After intravenous administration, cisplatin displays complex pharmacokinetics with rapid plasma protein binding and distribution to tissues, including renal cortex, liver, and peripheral nerves, profiles characterized in studies at Johns Hopkins Hospital and pharmacology groups at Harvard Medical School. Renal excretion via glomerular filtration and tubular secretion accounts for elimination, with dosing adjustments guided by creatinine clearance estimations such as the Cockcroft–Gault equation and measurement protocols endorsed by the World Health Organization. Plasma half-life comprises rapid initial distribution and prolonged terminal phases; therapeutic drug monitoring and pharmacokinetic modeling have been refined in pharmacology units at University of California, San Francisco.
Dose-limiting toxicities include nephrotoxicity, neurotoxicity (peripheral neuropathy), ototoxicity, and myelosuppression. Nephrotoxicity led to hydration and diuresis protocols developed following research at institutions like Roswell Park Comprehensive Cancer Center and St. Jude Children's Research Hospital, integrating agents such as mannitol and strategies adapted during trials at MD Anderson Cancer Center. Ototoxicity, especially in pediatric populations treated per protocols from the Children's Oncology Group, has prompted audiometric monitoring recommended by organizations including American Academy of Pediatrics. Nausea and vomiting are managed with antiemetics like ondansetron, aprepitant, and corticosteroids as per guidelines from the American Society of Clinical Oncology and Multinational Association of Supportive Care in Cancer.
Tumor resistance arises via reduced drug uptake, increased efflux mediated by transporters like ATP7A and ATP7B, elevated intracellular thiols including glutathione and enzymes such as glutathione S-transferase, enhanced DNA repair via ERCC1 and homologous recombination proteins like BRCA1 and BRCA2, and defects in apoptotic signaling involving p53 mutations. Research into overcoming resistance has involved combining cisplatin with targeted agents against pathways including EGFR, VEGF, PARP, and cell cycle regulators explored in trials sponsored by entities such as GlaxoSmithKline and Roche.
Cisplatin is a square-planar platinum(II) coordination complex with two ammine ligands and two chloride ligands in a cis configuration; stereochemistry contrasts with the inactive trans isomer characterized in early structural chemistry research by groups associated with University of Oxford and University of Cambridge. Formulations for intravenous use require careful handling to prevent precipitation and inactivation by chloride-poor media; solutions often follow compendial standards from pharmacopeias including the United States Pharmacopeia and European Pharmacopoeia. Structural elucidation techniques such as X-ray crystallography and NMR spectroscopy developed at laboratories like Bell Labs and Max Planck Society informed mechanistic and synthetic work that led to second-generation analogs like carboplatin and oxaliplatin.
Cisplatin's antineoplastic properties were discovered in the 1960s during investigations into metal complexes at institutions including Stanford University and subsequent preclinical and clinical development at Michigan Cancer Foundation and the National Cancer Institute. Key clinical milestones included randomized trials and regulatory approvals in the 1970s and 1980s, with influential publications in journals such as The Lancet, New England Journal of Medicine, and Journal of Clinical Oncology. Translational work bridging chemistry, pharmacology, and clinical oncology involved collaborations among investigators at Vincent T. DeVita Jr.'s teams, academic centers like Yale University School of Medicine, and pharmaceutical partners, shaping modern platinum-based chemotherapy and inspiring awards and recognition across oncology and chemistry communities.
Category:Antineoplastic agents