Topoisomerase inhibitors
Topoisomerase inhibitors are cytotoxic chemotherapy agents that trap DNA in a broken, unresealed state: camptothecins (irinotecan, topotecan) poison topoisomerase I, while epipodophyllotoxins (etoposide, teniposide) poison topoisomerase II. Irinotecan anchors first-line combination chemotherapy for metastatic colorectal cancer, and etoposide with a platinum agent is standard therapy for small cell lung cancer, germ cell tumors, and lymphoma. Myelosuppression, and for irinotecan severe diarrhea, are dose-limiting.
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What this article covers
- Overview
Definition: Topoisomerase inhibitors are cytotoxic drugs that convert a normally transient, resealed DNA nick made by a topoisomerase enzyme into a persistent break, driving the cell into arrest and apoptosis.
- Epidemiology
Irinotecan use: A core component of first- and second-line chemotherapy for metastatic colorectal cancer, paired with fluorouracil and leucovorin.
- Risk factors
Marrow reserve: Prior chemotherapy or radiation, older age, baseline cytopenias, and any concurrent myelosuppressive drug predispose to severe or prolonged myelosuppression.
- Pathophysiology
Topoisomerase I mechanism: Topoisomerase I relaxes supercoiled DNA ahead of the replication fork by nicking one strand, allowing rotation, then resealing; camptothecins stabilize the topoisomerase I-DNA complex so the nick is not resealed.
- Clinical features
Irinotecan, acute cholinergic syndrome: During or within 24 hours of infusion, diaphoresis, cramping, salivation, and early diarrhea from acetylcholinesterase inhibition, treated with atropine.
- Differential diagnosis
Anthracyclines: Also poison topoisomerase II, but through DNA intercalation with a class-defining, cumulative cardiomyopathy; chosen over etoposide when the benefit outweighs lifetime cardiac dose tracking, as in CHOP for lymphoma.
- Diagnosis
What establishes the indication: Use of a topoisomerase inhibitor is established by a tissue-confirmed diagnosis and stage of a chemosensitive malignancy, most often colorectal adenocarcinoma, small…
- Management
First, choose the topoisomerase target by tumor type, then dose the chosen agent as below.
- Complications
Neutropenia and infection: Neutrophil nadir at day 8 to 14, recovery by around day 21; febrile neutropenia during the nadir requires prompt antibiotics.
- Prognosis
Germ cell tumors: One of the most curable solid tumors because of sensitivity to cisplatin-etoposide chemotherapy; even recurrent disease may be cured with further or high-dose chemotherapy.
- Prevention
Pharmacogenomic screening: Obtain UGT1A1 genotyping before irinotecan when feasible and lower the starting dose in UGT1A128 homozygotes.
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