Lung toxicity bleomycin

Newer bleomycins such as peplomycin and especially liblomycin, are more resistant to bleomycin hydrolase. This results in less lung toxicity but more bone marrow toxicity, and allows for a different spectmm of antitumor action. Bleomycin is inactive orally it is given intravenously, intramuscularly, subcutaneously, or directiy into a cavity such as the pleural cavity. The majority of dmg is excreted unchanged in the urine. 

A potentially fatal lung toxicity occurs in 10 to 20% of patients receiving bleomycin. Patients particularly at risk are those who are over 70 years of age and have had radiation therapy to the chest. Rarely, bleomycin also may cause allergic pneumonitis. Bleomycin skin toxicity is manifested by hyperpigmentation, erythematosus rashes, and thickening of the skin over the dorsum of the hands and at dermal pressure points, such as the elbows. Many patients develop a low-grade transient fever within 24 hours of receiving bleomycin. Less common adverse effects include mucositis, alopecia, headache, nausea, and arteritis of the distal extremities. 

Ward HE, Nicholson A, Berend N. 1987. Failure of systemic N-acetyl cysteine to protect the rat lung against bleomycin toxicity. Pathology 19 358-60... 

The oxidants are products of normal cellular respiration that are normally counterbalanced by an antioxidant defense system that prevents tissue destruction. The antioxidants include superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, and a-tocopherol (vitamin E). Antioxidants are ubiquitous in the body. Hy-peroxia produces toxicity by overwhelming the antioxidant system. There is experimental evidence that a number of drugs and chemicals produce lung toxicity through increasing production of oxidants (e.g., bleomycin, cyclophosphamide, nitrofurantoin, and paraquat) and/or by inhibiting the antioxidant system (e.g., carmustine, cyclophosphamide, and nitrofurantoin). ... 

Excessive irradiation produces a pneumonitis and fibrosis thought to be caused by oxygen free-radical formation. Evidence for synergistic toxicity with radiation exists for bleomycin, busulfan, and mitomycin. Hyperoxia has shown synergistic toxicity with bleomycin, cyclophosphamide, and mitomycin. Carmustine, mitomycin, cyclophosphamide, bleomycin, and methotrexate all appear to show increased lung toxicity when they are part of multiple-drug regimens. 

Azambuja, E., Fleck, J. F., Batista, R. G., Menna Barreto, S. S. (2005). Bleomycin lung toxicity Who are the patients with increased risk Pulmonary Pharmacology Therapeutics, 15(5), 363-366. 

Gilson AJ, Sahn SA. Reactivation of bleomycin lung toxicity followii oxygen administration. A second re nse to corticosteroids. Chest (1985) 88, 304-6. 

Morphometric methods showed that low temperature (4°C for 7 days) inhibited bleomycin lung toxicity in the rat (Berend 1983). 

Importantly, the toxicity of bleomycin is cumulative. Total doses in excess of 450 units are associated with a significantly increased incidence of adverse lung reactions and death. The incidence of bleomycin-induced lung toxicity has been reported between 0% and 46% with a mortality rate of 3% (5,7). As mentioned above, high cumulative dose, extreme of age, uremia, the use of supplemental oxygen, and radiation therapy are well-documented risk factors for bleomycin toxicity. Other chemotherapeutic agents (cyclophosphamide and vincristine) may also have a synergistic effect with bleomycin. Finally, bleomycin may occasionally reactivate a prior radiation-induced pneumonitis, a phenomenon known as radiation-recall. ... 

The pulmonary toxicity of busulfan was first reported in 1961. No clear risk factors for the development of lung toxicity have been consistently identified. The reported incidence of lung toxicity is 6% (4). The onset is typically subacute with fever and dry cough. Bleomycin is histologically characterized by NSIP or UIP. Pulmonary veno-occlusive disease and DIP have also been reported (1). Occasionally, busulfan may lead to alveolar proteinosis secondary to massive deposition of intracellular debris. This form of alveolar proteinosis is poorly responsive to whole lung lavage, and the role of steroids is not clearly estabhshed (9). 

Bleomycin hydrolase, which inactivates bleomycin, is an enzyme that is abundant in liver and kidney but virtually absent in lungs and skin the latter two organs are the major targets of bleomycin toxicity. It is thought that bleomycin-induced dermal and pulmonary toxici-ties are related to the persistence of relatively high local concentrations of active drug. 

BLEOMYCIN ANTICANCER AND IMMUNOMODULATING DRUGS-CISPLATIN t bleomycin levels, with risk of pulmonary toxicity Elimination of bleomycin is delayed by cisplatin due to 1 glomerular filtration. This is most likely with accumulated doses of cisplatin in excess of 300 mg/m2 Monitor renal function and adjust dose of bleomycin as per creatinine clearance. Monitor clinically, radiologically and with lung function tests for pulmonaiy toxicity... 

Severe morbidity has been reported after the use of regimens containing bleomycin 10% of patients developed adult respiratory distress syndrome and a further 9% needed prolonged ventilation (11). The authors thought that these rates were higher than expected and attributed this to a combination of the toxic effects of bleomycin on the lung and a large retroperitoneal and/or pulmonary tumor burden. 

Bleomycin is inactivated within cells by the enzyme aminohy-drolase. This enzyme is widely distributed, but is present in only low concentrations in the skin and the lungs, explaining the predominant toxicities of bleomycin to those sites. The presence of hydrolase enzymes in tumor cells is the primary mechanism of resistance to bleomycin. Cells can also become resistant by repairing the DNA breaks produced by bleomycin. ... 

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