Cyclophosphamide lung toxicity

Patel JM, Block ER, Hood Cl. 1984. Biochemical indexes of cyclophosphamide- induced lung toxicity. Toxicol Appl Pharmacol 767 128-138. 

Bhagat R, Sporn TA, Long GD, Folz RJ. Amiodarone and cyclophosphamide potential for enhanced lung toxicity. Bone Marrow Transplant 2001 27(10) 1109-11. 

Malik SW, Myers JL, DeRemee RA, Specks U. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 1996 154(6 Pt l) 1851-6. 

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. 

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 efficacy of doxorubicin can be increased by verapamil and nicardipine in doxorubicin-resistant tissue culture systems, while nifedipine has only minimal activity. A study in five patients with small cell lung cancer given doxorubicin, vincristine, etoposide and cyclophosphamide showed that when they were given verapamil 240 to 480 mg daily the AUC of doxorubicin was doubled, its peak serum levels were raised and its clearance was reduced. No increased toxicity was seen in this study. However, although another study found no increase in non-cardiac toxic-ities, verapamil caused an unacceptable degree of cardiac toxicity. Be alert for this possibility if both drugs are used. 

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