Bleomycin belongs to a subfamily of glycopeptide antibiotics and is utilized primarily as an antineoplastic agent. Bleomycin is part of combination cytotoxic chemotherapy regimens, including ABVD ([adriamycin], doxorubicin, bleomycin, vinblastine, dacarbazine). It first received approval from the FDA in 1975 for the treatment of squamous cell carcinomas, malignant lymphomas, and testicular cancers. Bleomycin has since received a wide array of FDA-approved therapeutic indications, including germinal cell tumors, gestational trophoblastic disease, Hodgkin lymphoma, and non-Hodgkin lymphoma. Non-FDA approved indications include AIDS-associated Kaposi sarcoma, osteosarcoma, malignant melanoma, and advanced stages of mycosis fungoides. Another non-FDA approved indication for bleomycin is pleural effusion in patients requiring chemical pleurodesis due to metastatic disease. In pleurodesis, bleomycin can be injected into the pleural space, causing the lung to adhere to the chest wall, thus preventing the collection of fluid or air. Due to factors discussed below, including the high risk of adverse effects with this drug, chemotherapy regimens, including less dangerous alternatives to bleomycin, are increasingly preferred in many cases.[1][2][3][4]

The primary mechanism of action of bleomycin involves the drug's ability to oxidatively damage DNA by binding to metal ions, including iron, forming metallobleomycin complexes. The reactive oxygen species generated by these complexes cause DNA single-strand and double-strand breaks between 3'-4' bonds in deoxyribose. These strand breaks produce free base propenals, particularly of thymine, causing cell cycle arrest at the G2 phase. Chromosomal aberrations, fragments, chromatid breaks, and translocations can be observed cytologically after bleomycin exposure. Resistance to bleomycin in normal tissues correlates with the presence of bleomycin hydrolase enzyme, a member of the cysteine proteinase family. This enzyme substitutes a terminal amine with a hydroxyl group, thereby inhibiting cytotoxic activity by reducing the binding of iron. The low concentration of hydrolase in the skin and lung tissue has contributed to the hypothesis for the unique bleomycin sensitivity found in these sites.[5][6][7]

Bleomycin administration is via the parenteral route, as the GI tract does not significantly absorb it. Bleomycin is quickly absorbed following intramuscular, subcutaneous, intraperitoneal, or intrapleural administration, and reaches peak plasma concentrations in approximately 60 minutes. The half-life of bleomycin varies between patients and depends on a variety of factors, including the route of administration. Less than 1% of the drug given intravenously binds to plasma proteins, leading to high bioavailability. Although the metabolic fate of bleomycin remains poorly understood, the elimination of bleomycin has been described in several studies by first-order rate kinetics with a mean plasma drug clearance approaching 70 mL/min/m2. These pharmacokinetics demonstrate that bleomycin possesses a high plasma elimination rate and high urinary excretion rate.[8][9]

The most common serious adverse effect of bleomycin is pulmonary toxicity, often referred to as bleomycin pulmonary toxicity or BPT. This adverse effect sometimes leads to pulmonary fibrosis, a chronic and irreversible disease with a poor prognosis. Administration of bleomycin is likely to induce functional changes in endothelial cells of the lung, although the exact mechanism of these changes not entirely understood. Other adverse reactions include fever, chills, faintness, chest pain, and shortness of breath. Less serious reactions include skin pigmentation changes, itching, hypogeusia, rash, nausea, vomiting, and weight loss. Some of these symptoms appear to correlate with a hypersensitivity type reaction.[10]

Although absolute contraindications for bleomycin have not been established, it is crucial to assess lung disease history and renal function before administration. Patients with a history of smoking are at elevated risk for pulmonary complications due to bleomycin. Additionally, elderly patients and patients with stage IV disease have demonstrated to be more likely to experience lung toxicity with bleomycin exposure; this is also true of patients who receive bolus drug delivery as opposed to continuous infusion, and those who require supplemental oxygen delivery. Although studies regarding teratogenic effects of bleomycin exposure in humans are limited, some sources consider antineoplastic therapy during gestation to be generally harmful to fetal development, especially during the first trimester.[11]