topoisomerase inhibitor

**Mechanism/Background** - Topoisomerases cut and reseal DNA to relieve torsional strain (supercoils) ahead of the replication fork and during transcription. - Topo I: makes a single-strand break, passes the other strand through, then reseals. It needs no ATP. - Topo II (in bacteria, DNA gyrase): makes a double-strand break, passes another duplex through, then reseals. It needs ATP. - Most clinically used inhibitors are "topoisomerase poisons." They stabilize the covalent enzyme-DNA cleavage complex and prevent religation. This leaves persistent DNA breaks, and collision with replication forks triggers apoptosis. The drugs are S/G2-phase specific.

**Topoisomerase I inhibitors (camptothecin analogs)** - Irinotecan: - Prodrug converted to the active metabolite SN-38 (by carboxylesterase). - SN-38 is inactivated by UGT1A1 glucuronidation. Polymorphisms (UGT1A1*28, as in Gilbert syndrome) increase toxicity. - Toxicity: severe diarrhea (early cholinergic type treated with atropine; late type treated with loperamide) and myelosuppression. - Use: colorectal cancer (FOLFIRI), small cell lung cancer. - Topotecan: - Use: ovarian cancer, small cell lung cancer, cervical cancer. - Toxicity: myelosuppression (dose-limiting).

**Topoisomerase II inhibitors** - Etoposide, teniposide (epipodophyllotoxins): - Uses: small cell lung cancer, testicular cancer (BEP regimen), lymphomas, Ewing sarcoma. - Toxicity: myelosuppression, alopecia, and secondary leukemia (AML, often with 11q23/KMT2A rearrangements). - Anthracyclines (doxorubicin, daunorubicin) also inhibit topo II, in addition to intercalating into DNA and generating free radicals. - Toxicity: dilated cardiomyopathy (prevented with dexrazoxane, an iron chelator), plus secondary malignancy. - Mitoxantrone is also a topo II inhibitor and is cardiotoxic.

**Antibacterial topoisomerase inhibitors: fluoroquinolones** - Examples: ciprofloxacin, levofloxacin, moxifloxacin. - They inhibit bacterial DNA gyrase (topo II), which is the main target in gram-negative organisms. They also inhibit topo IV, which is the main target in gram-positive organisms. This blocks replication and segregation of DNA. - Adverse effects: - Tendinopathy/tendon rupture (higher risk with corticosteroids and in older patients). - Cartilage damage (avoid in children and pregnancy). - QT prolongation. - CNS effects and seizures. - Peripheral neuropathy. - Aortic aneurysm/dissection. - Dysglycemia. - Myasthenia gravis exacerbation. - C. difficile infection. - Absorption is reduced by divalent cations (antacids, Fe, Ca, Mg). - Resistance arises from gyrase/topo IV mutations and efflux pumps.

**Other** - Novobiocin and the newer "novel bacterial topoisomerase inhibitors" (NBTIs) act on the ATPase/other sites. - Quinolones are not related to the topoisomerase inhibitors used as antineoplastics, but both classes work by trapping the DNA-enzyme cleavage complex.

**High-yield pearls** - Irinotecan → diarrhea. Etoposide → secondary AML. Doxorubicin → cardiotoxicity. Fluoroquinolones → tendon rupture. - Distinguish from other DNA-targeting drugs: antimetabolites inhibit nucleotide synthesis, alkylators cross-link DNA, and bleomycin causes strand breaks via free radicals.