SN5 SHORT NOTE 5M ★ High-yield

Describe cisplatin and the platinum compounds with their uses and toxicity.

Pharmacology · 2nd Professional — Para-Clinical

Mechanism and the Platinum Compounds

Cisplatin is a platinum coordination complex that forms intrastrand and interstrand DNA cross-links, chiefly between adjacent guanines. It behaves like an alkylating agent and is cell cycle non-specific.

Drug	Distinctive features	Dose-limiting toxicity
Cisplatin	The most potent; requires vigorous hydration	Nephrotoxicity
Carboplatin	Much less nephrotoxic, ototoxic and emetogenic; dosed by renal function using the Calvert formula rather than by surface area	Myelosuppression, particularly thrombocytopenia
Oxaliplatin	Active in colorectal cancer, where the others are not; a component of FOLFOX	Peripheral neuropathy, characteristically triggered and worsened by cold

Uses

Testicular cancer — cisplatin-based combination therapy (BEP) transformed a usually fatal disease into one cured in the great majority, and remains among the outstanding achievements of medical oncology
Ovarian cancer — carboplatin with paclitaxel
Lung cancer, both small cell and non-small cell
Head and neck cancer, often with radiotherapy as a radiosensitiser
Bladder, cervical, oesophageal and gastric cancer
Colorectal cancer — oxaliplatin specifically

Toxicity of Cisplatin

Toxicity	Features	Prevention
Nephrotoxicity — dose-limiting	Proximal tubular damage, reduced glomerular filtration, and marked renal wasting of magnesium and potassium; may be cumulative and irreversible	Vigorous pre- and post-hydration with saline, forced diuresis, magnesium supplementation, and avoiding other nephrotoxins
Severe vomiting	Among the most emetogenic drugs known; both acute and delayed	5-HT3 antagonist + dexamethasone + NK1 antagonist, given prophylactically
Ototoxicity	Irreversible high-frequency sensorineural hearing loss and tinnitus, from hair cell damage; particularly serious in children	Baseline and serial audiometry; sodium thiosulphate is protective in children
Peripheral neuropathy	Sensory, glove-and-stocking, cumulative; often incompletely reversible	Dose reduction; no effective prophylaxis
Electrolyte disturbance	Hypomagnesaemia (almost universal), hypokalaemia, hypocalcaemia	Routine magnesium replacement
Myelosuppression	Moderate	Monitoring
Others	Hypersensitivity; rarely optic neuritis and haemolytic-uraemic syndrome	—

CLINICAL PEARL

Cisplatin is nephrotoxic and its major toxicities are all cumulative and largely irreversible — which changes how the drug is given. Hearing loss, neuropathy and renal damage do not recover meaningfully when the drug is stopped, so the emphasis falls entirely on prevention: hydration before the damage, audiometry before the deafness, and a decision to reduce or switch to carboplatin before the neuropathy is disabling.

Resistance

Increased DNA repair of platinum adducts — the principal mechanism, which is why tumours with defective repair (BRCA-mutated) are unusually platinum-sensitive
Inactivation by glutathione and metallothioneins, which bind the platinum
Reduced uptake through loss of the copper transporter CTR1
Failure of apoptosis, often through p53 mutation
"Platinum-sensitive" relapse — in ovarian cancer, relapse more than 6 months after treatment usually responds to platinum again, whereas earlier relapse does not; this distinction guides second-line treatment

Applied Aspects

Never give cisplatin without adequate hydration and a check of renal function and magnesium before each cycle
Check magnesium routinely and replace it; hypomagnesaemia is almost universal, causes tetany, arrhythmia and weakness, and prevents correction of potassium and calcium until it is treated
Arrange audiometry in children before and during treatment; hearing loss in a child has lifelong consequences for language and schooling, and switching to carboplatin may be preferable
Substitute carboplatin where renal function, hearing or neuropathy are a concern, accepting greater myelosuppression in exchange
Warn oxaliplatin patients to avoid cold drinks, cold air and touching cold objects in the days after infusion, since cold precipitates distressing pharyngolaryngeal dysaesthesia
Discuss fertility and sperm banking before treatment, particularly in testicular cancer where the patients are young and the cure rate is high — they will live with the consequences for decades

All questions in Blood, Haematinics & Anticancer Drugs

Every Pharmacology chapter →