Overview
Platinum compounds are DNA-damaging agents that form intrastrand and interstrand DNA crosslinks, leading to replication arrest, transcription inhibition, and apoptosis. They are classified as alkylating-like agents (though they do not have a true alkyl group) because they covalently bind DNA.
Core agents in clinical use:
- Cisplatin
- Carboplatin
- Oxaliplatin
- (Less common: Nedaplatin, Lobaplatin, Heptaplatin – used mainly in Asia)
Mechanism of Action
- Aquation step: In aqueous media, the chloride (cisplatin) or leaving group (oxaliplatin: oxalate) is replaced by water, producing a positively charged, highly reactive complex.
- DNA binding: Prefers N7 of guanine (and to a lesser extent adenine) → primarily 1,2-intrastrand crosslinks between adjacent guanines or G–A bases.
- Cell cycle effects: Although not cell-cycle–specific, maximal effect occurs in S-phase when DNA is replicating.
- Cytotoxicity: Crosslinked DNA triggers mismatch repair, apoptosis via p53 activation, and mitochondrial pathway involvement.
Toxicity Profiles
| Toxicity | Cisplatin | Carboplatin | Oxaliplatin |
|---|---|---|---|
| Nephrotoxicity | ++ | +/– | Rare |
| Ototoxicity | ++ | + | Rare |
| Neurotoxicity | + | + | ++ (cold-induced, acute + chronic sensory) |
| Myelosuppression | +/– (mild) | ++ (DLT) | + |
| Nausea/Vomiting | +++ (highly emetogenic) | ++ | ++ |
| Hypersensitivity | + (late, cumulative) | ++ (often >6 cycles) | ++ (can be severe) |
| Electrolyte wasting | Mg²⁺, K⁺, Ca²⁺ loss | Mild | Rare |
Quick Indication Summary Table
| Drug | Main Approved Indications | Frequent Off-label/Guideline Uses |
|---|---|---|
| Cisplatin | Testicular, ovarian, bladder | NSCLC, SCLC, HNSCC, cervical, esophageal, gastric, osteosarcoma, pediatric solid tumors |
| Carboplatin | Ovarian, SCLC | NSCLC, HNSCC, bladder, breast, pediatric CNS & germ cell tumors |
| Oxaliplatin | Colorectal | Gastric, pancreatic, biliary, GEJ, esophageal, neuroendocrine |