Platinum-Based Chemotherapy
Platinum compounds form DNA adducts that crosslink DNA strands, causing apoptosis in a broad range of solid tumors.
## Overview
Platinum-based drugs are among the most widely used anticancer agents. After aquation (replacement of chloride by water), they form highly reactive electrophilic species that bind to DNA purine bases, forming intrastrand and interstrand crosslinks that block DNA replication and transcription, triggering apoptosis.
## Cisplatin
Cisplatin (cis-diamminedichloroplatinum II) forms primarily intrastrand d(GpG) crosslinks. It is used in testicular, ovarian, bladder, cervical, head and neck, and NSCLC cancers.
**Toxicities**:
- **Nephrotoxicity**: Dose-limiting; prevented by aggressive IV hydration and amifostine. Cumulative tubular damage occurs. Monitor creatinine.
- **Ototoxicity**: High-frequency hearing loss; irreversible. Audiometry monitoring required.
- **Emesis**: Highly emetogenic (HEC); requires a 3-drug antiemetic regimen (NK1 antagonist + 5-HT3 antagonist + dexamethasone).
- **Peripheral neuropathy**: Cumulative sensory neuropathy.
- **Myelosuppression**: Moderate; less severe than most cytotoxics.
## Carboplatin
Carboplatin has the same mechanism as cisplatin but a different toxicity profile. It is far less nephrotoxic and emetogenic but causes more myelosuppression (thrombocytopenia is dose-limiting). Dosing uses the Calvert formula: dose (mg) = AUC × (GFR + 25), where AUC targets of 5-7 are standard for most regimens. Widely used in ovarian, lung, and head/neck cancers.
## Oxaliplatin
Oxaliplatin contains a diaminocyclohexane (DACH) carrier ligand, which forms bulkier adducts not recognized by mismatch repair proteins. This makes it active in colorectal cancer even where cisplatin resistance might exist. Unique toxicity: **cold-triggered peripheral neuropathy** (patients must avoid cold drinks and surfaces during treatment). Cumulative sensory neuropathy also occurs with higher doses.
## Resistance Mechanisms
Resistance involves reduced cellular uptake (CTR1 copper transporter downregulation), increased detoxification by glutathione/metallothionein, enhanced DNA repair (nucleotide excision repair), and tolerance of platinum-DNA adducts.
## Key Takeaways
- Platinum drugs form intrastrand DNA crosslinks; oxaliplatin adducts evade mismatch repair
- Cisplatin: nephrotoxicity + ototoxicity; hydration and audiometry monitoring are mandatory
- Carboplatin: dose by AUC (Calvert formula); thrombocytopenia is dose-limiting
- Oxaliplatin: cold-triggered neuropathy is pathognomonic; active in colorectal cancer