Alkylating Agents
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Direct answer
Alkylating agents transfer alkyl groups to DNA bases, forming cross-links that block replication and transcription, and they kill cells throughout the cell cycle. Nitrogen mustards (cyclophosphamide, ifosfamide, chlorambucil, melphalan), nitrosoureas (carmustine, lomustine), alkyl sulphonates (busulfan) and the platinum compounds (cisplatin, carboplatin, oxaliplatin) constitute the class, with temozolomide as an oral imidazotetrazine alkylator for gliomas. Signature toxicities dominate exams: haemorrhagic cystitis with cyclophosphamide (acrolein; prevented by mesna), pulmonary fibrosis with busulfan and bleomycin-class nitrosoureas, and nephrotoxicity, ototoxicity and emetogenicity with cisplatin.
What you must remember
- Mechanism: alkylation of N7 of guanine with cross-linking of DNA strands — cell-cycle non-specific, so effective in both dividing and resting tumours; myelosuppression and secondary leukaemia are class consequences.
- Cyclophosphamide: the most used alkylator (lymphomas, breast cancer, vasculitis, nephrotic syndrome); haemorrhagic cystitis from the metabolite acrolein — prevented by mesna, hydration and frequent voiding; bladder cancer is a late risk; SIADH occurs at very high doses.
- Ifosfamide: the analogue whose signature is encephalopathy (confusion, hallucinations) from chloroacetaldehyde, treated with methylene blue; also causes cystitis, so mesna accompanies it.
- Nitrosoureas (carmustine, lomustine, semustine): lipophilic, crossing the blood-brain barrier for brain tumours; delayed cumulative myelosuppression and pulmonary fibrosis; streptozotocin targets pancreatic islet tumours with diabetes and nephrotoxicity.
- Busulfan: pulmonary fibrosis ("busulfan lung"), skin pigmentation, adrenal insufficiency and gynaecomastia; used in chronic myeloid leukaemia historically and conditioning regimens.
- Platinum drugs: cisplatin — emetogenic, nephrotoxic (aggressive saline hydration and magnesium replacement), ototoxic (high-frequency loss, tinnitus) and neuropathic; carboplatin — mainly thrombocytopenia, dosed by the Calvert formula; oxaliplatin — acute cold-triggered and chronic sensory neuropathy.
- Temozolomide: oral, crosses the blood-brain barrier, standard with radiotherapy in glioblastoma; resistance relates to MGMT repair enzyme expression.
Common confusion
Cisplatin and carboplatin are not interchangeable in toxicity: cisplatin injures kidney, ear and nerve but spares platelets relatively, while carboplatin is gentle on the kidney but thrombocytopenic — a direct exam discrimination. Cyclophosphamide versus ifosfamide confusions mirror their metabolites: acrolein causes bladder toxicity, chloroacetaldehyde the brain toxicity, and only the latter responds to methylene blue.
Exam-focused takeaway
Stems pair each alkylator with its hallmark: the lymphoma patient with pink urine on cyclophosphamide (mesna answer), the confused ifosfamide patient (methylene blue), the glioma on an oral capsule crossing the blood-brain barrier (temozolomide), the transplanted lung with busulfan, and the colon cancer patient whose hands cramp in cold weather (oxaliplatin). Nausea grading and hydration questions test cisplatin protocols. Learn mechanism once — DNA cross-linking — then hang one unique toxicity per drug.
Frequently asked questions
Why does cyclophosphamide cause haemorrhagic cystitis?
Its metabolite acrolein is excreted in urine and irritates the bladder mucosa; mesna binds acrolein and, with hydration, prevents cystitis and late bladder cancer.
How do the toxicities of cisplatin and carboplatin differ?
Cisplatin is nephrotoxic, ototoxic, neurotoxic and highly emetogenic; carboplatin mainly causes thrombocytopenia, with dosing calculated from renal function.
Which alkylators cross the blood-brain barrier?
The lipophilic nitrosoureas carmustine and lomustine, and the oral agent temozolomide used in gliomas.
What causes ifosfamide encephalopathy and its treatment?
Chloroacetaldehyde accumulation produces confusion and hallucinations; methylene blue, with thiamine, is the standard treatment.
Why is oxaliplatin neuropathy unusual?
It triggers acute pharyngeal and hand cramps provoked by cold exposure within days, distinct from the cumulative chronic sensory neuropathy of other platinum drugs.
What is the role of MGMT in temozolomide therapy?
MGMT repair enzyme removes the methyl adducts temozolomide creates; high tumour MGMT predicts resistance and poorer response.