Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients

Objective Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). Methods From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. Results BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. Conclusions The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.