Antitumor antibiotics

Mechanism and Class Overview

• Class mechanism: Mechanisms vary by drug: anthracyclines intercalate DNA and inhibit topo II (cell-cycle independent); bleomycin causes free-radical DNA breaks (G2-specific); mitomycin cross-links DNA; dactinomycin blocks transcription.
• Resistance: ↑ P170 (MDR) glycoprotein and ↑ P190 (MRP) drug efflux, altered topoisomerase II, and ↑ sulfhydryl proteins.

Anthracyclines

• Class mechanism: Form iron-dependent free radicals causing DNA strand breaks, inhibit topoisomerase II, and intercalate directly into DNA. Metabolized ~50% in the liver, so dose reduce with hepatic dysfunction. Phenobarbital and phenytoin ↑ doxorubicin clearance; cyclophosphamide, mitomycin C, trastuzumab, taxanes, and bevacizumab ↑ toxicity.
• Cardiotoxicity mechanism: The heart is iron-rich and poor in free-radical detoxification. Risk is low below a total dose of 350 mg/m2 and rises to ~10% at a cumulative 450 to 500 mg/m2. Obtain a baseline TTE in all patients.
  • Acute: within 2 to 3 days, dose-independent, arrhythmias, pericarditis, myocarditis.
  • Chronic: dose-dependent dilated cardiomyopathy. Risk ↑ with older age, CAD, HTN, and prior mediastinal radiotherapy.
• Dexrazoxane: An iron chelator that reduces anthracycline cardiotoxicity, added once cumulative dose thresholds are reached (typically dosed at a 10:1 ratio to the anthracycline). It is also the antidote for anthracycline extravasation.

Doxorubicin (Adriamycin)

• Indications: Breast, lymphoma, sarcoma, AML, and other solid tumors.
• Toxicities: Myelosuppression, GI toxicity, vesicant (treat extravasation with dexrazoxane started within 6 h, removing cold packs at least 15 min before the infusion; do not combine with topical DMSO), radiation-recall skin reaction, alopecia, red/orange urine discoloration on days 1 to 2, infertility, and cumulative cardiotoxicity. Highly emetogenic at doses ≥60 mg/m2 (anthracycline plus cyclophosphamide combos always high-risk).
• Liposomal doxorubicin: ↓ nausea/vomiting, ↓ cardiotoxicity, and ↓ myelosuppression, but causes hand-foot syndrome and acute infusion reactions.

Daunorubicin (Cerubidine)

• Indications: AML, ALL.
• Toxicities: Cumulative cardiotoxicity, myelosuppression, alopecia, GI toxicity.

Idarubicin (Idamycin)

• Indications: AML, ALL (enhanced intracellular uptake).
• Toxicities: Cardiotoxicity, myelosuppression, GI toxicity, alopecia.

Epirubicin (Ellence)

• Indications: Breast cancer (higher cumulative dose ceiling than doxorubicin). Highly emetogenic at doses > 90 mg/m2.
• Toxicities: Cardiotoxicity, myelosuppression, alopecia.

Other Intercalators

Mitoxantrone (Novantrone)

• Mechanism: Anthracenedione that intercalates DNA and inhibits topoisomerase II; structurally distinct from the anthracyclines.
• Indications: AML, lymphoma, multiple sclerosis.
• Toxicities: Cardiotoxicity: cumulative, dose-related cardiac dysfunction/CHF (anthracycline-like); monitor LVEF, myelosuppression, blue-green discoloration of urine and sclera, GI toxicity.

Others

Dactinomycin (Actinomycin D)

• Mechanism: Intercalates into DNA (G-C pairs) and blocks DNA-dependent RNA polymerase (↓ RNA synthesis); also inhibits topoisomerase II, causing DNA breaks.
• Indications: Wilms tumor, rhabdomyosarcoma, germ cell tumors, choriocarcinoma.
• Toxicities: Myelosuppression, nausea/vomiting, alopecia, radiation recall, and hepatic veno-occlusive disease (↑ mortality in children). Vesicant.

Bleomycin (Blenoxane)

• Mechanism: Binds DNA and generates single- and double-strand breaks, ↓ DNA synthesis.
• Indications: Testicular cancer (BEP), Hodgkin lymphoma (ABVD), head and neck and ovarian cancers.
• Pulmonary toxicity: dose-limiting; presents as pneumonitis (cough, dyspnea, interstitial changes), can progress to fibrosis. Risk ↑ with concurrent growth-factor use, prior lung disease, prior chest radiotherapy, age > 65, and a cumulative dose > 400 units. Follow PFTs (DLCO).
• Other toxicities: Hyperpigmentation, skin peeling, mucositis, and hypersensitivity/fever reactions.

Mitomycin C

• Mechanism: Alkylates DNA to produce cross-links, ↓ DNA synthesis.
• Indications: Anal, gastric, and bladder cancers (intravesical).
• Toxicities: Delayed myelosuppression with very late count recovery (~2 months), mucositis, hemolytic-uremic syndrome (a classic dose-related cause, along with gemcitabine and cyclosporine), and pneumonitis.