Oncology-Anti-Tumor Antibiotics

Oncology-Anti-Tumor Antibiotics

I. Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin, Idarubicin)

A. Mechanism of Action:

• Multiple Effects: Anthracyclines affect cell surfaces, signal transduction (activating protein kinase C), and, most importantly, DNA topoisomerase II (topo II). The exact contribution of each effect to cytotoxicity remains unclear.
• Free Radical Generation: Reduction to highly reactive compounds and free radical production contribute to their anti-cancer activity, but also cause cardiotoxicity (due to lower antioxidant defenses in the heart).
• Topoisomerase II Inhibition: Anthracyclines bind to the DNA-topo II complex, preventing DNA strand rejoining after temporary breaks, leading to DNA damage and cell death.

B. Drug Resistance:

• MDR1 Gene/P-glycoprotein (Pgp): This efflux pump, encoded by the MDR1 gene, actively removes anthracyclines from cells, limiting their effectiveness. Manipulating Pgp expression has had limited clinical success.
• MRP (Multidrug Resistance-associated Protein): Another efflux pump contributing to anthracycline resistance.

C. Pharmacokinetics & Metabolism:

• Rapid Initial Decline: After IV administration, plasma levels fall rapidly due to tissue distribution and DNA binding.
• Slow Elimination: Subsequent metabolism and elimination result in slow plasma concentration decline over several days.
• Liver Function: Dose reduction is recommended for patients with abnormal liver function to minimize toxicity.

D. Clinical Use:

• Doxorubicin & Epirubicin: IV administration for breast cancer, sarcoma, and hematological malignancies.
• Daunorubicin & Idarubicin: Primarily used in acute leukemia (idarubicin can be oral).

E. Toxicity:

• Acute Toxicities (5-10 days post-treatment): Myelosuppression (bone marrow suppression), mucositis (mouth sores), and alopecia (hair loss - reversible). Extravasation (leakage from IV site) is severe and lacks effective treatment.
• Cumulative Cardiotoxicity: Dose-dependent heart failure due to free radical accumulation. Risk is <5% below 450mg/m² doxorubicin, significantly increasing at higher doses. Pre-existing heart disease and radiation therapy increase risk. Liposomal doxorubicin reduces cardiotoxicity. Epirubicin, daunorubicin, and idarubicin are less cardiotoxic than doxorubicin.

II. Other Anti-Tumor Antibiotics

A. Mitoxantrone:

• Mechanism: Binds to DNA, interacts with topo II, but produces fewer free radicals than anthracyclines. Also a Pgp substrate.
• Clinical Use: Less cardiotoxic alternative to doxorubicin in advanced breast cancer, NHL, and non-lymphocytic leukemia, but less effective.

B. Dactinomycin (Actinomycin-D):

• Mechanism: Strong DNA intercalator, inhibiting RNA and protein synthesis. Pgp substrate.
• Clinical Use: Highly active against childhood cancers.

C. Mitomycin (MMC):

• Mechanism: Active against various solid tumors; also used as a radiosensitizer.
• Clinical Use: Used in combination chemotherapy for breast cancer, NSCLC, GI cancer, and as a radiosensitizer in anal cancer.
• Toxicity: Delayed and cumulative myelosuppression (especially thrombocytopenia). Administered every 6 weeks due to this toxicity. Uncommon side effects include hemolytic-uremic syndrome, pulmonary fibrosis, and cardiac complications.

III. Key Differences & Summary Table

Drug Class	Example Drugs	Mechanism of Action	Major Toxicity	Clinical Use
Anthracyclines	Doxorubicin, Daunorubicin, Epirubicin, Idarubicin	Topoisomerase II inhibition, free radical generation	Cardiotoxicity, myelosuppression, mucositis	Various cancers, especially breast and leukemia
Mitoxantrone	Mitoxantrone	Topoisomerase II inhibition	Less cardiotoxic than anthracyclines	Breast cancer, NHL, non-lymphocytic leukemia
Dactinomycin	Dactinomycin (Actinomycin-D)	DNA intercalation, inhibits RNA/protein synthesis	Varies	Childhood cancers
Mitomycin (MMC)	Mitomycin	DNA alkylation, radiosensitizer	Delayed, cumulative myelosuppression	Solid tumors, radiosensitization