Bleomycin lung toxicity: who are the patients with increased risk?

Abstract

Bleomycin is an antibiotic drug with anticancer properties produced by Streptomyces verticillus [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459]. It was isolated in 1966 by Umezawa et al. and its mechanism of action is breaking the DNA double helix by the production of free radicals, which is oxygen and iron dependent [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin may be inactivated by bleomycin hidrolase presents in normal and tumoral cells [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94; Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clinics Chest Med 1990;11:1-20]. The complex bleomycin-Fe has been the most studied because bleomycin joins the DNA and Fe at the same time, and release of free radicals happens in the presence of molecular oxygen [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin has a renal metabolism with 50% of dose eliminated in 4h after its administration and 70% in the next 24h. Its half-life (T 1/2) is not altered, although the creatinine clearance drops to 25-35 ml/min [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. This drug has been used as cytostatic treatment of many malignant tumors, such as germ cell tumors, lymphomas, head and neck, and Kaposi's sarcomas [Chen XL, Li WB, Zhou AM et al. Role of endogenous peroxynitrite in pulmonary injury and fibrosis induced by bleomycin A5 in rats. Acta Pharmacol Sin 2003;24:697-702]. Minor important adverse effects are myelossupression, nauseas, vomiting, allergic reactions, mucositis, alopecia, erythema, hyperkeratosis, hypopigmentation, skin ulceration, and acute arthritis [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Fever is reported in 20-50% of patients and some of them present hyperthermia [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94].