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.
Nuver
Janine
J
Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.
Lutke Holzik
Martijn F
MF
van Zweeden
Martine
M
Hoekstra
Harald J
HJ
Meijer
Coby
C
Suurmeijer
Albert J H
AJ
Groen
Harry J M
HJ
Hofstra
Robert M
RM
Sluiter
Wim J
WJ
Groen
Henk
H
Sleijfer
Dirk T
DT
Gietema
Jourik A
JA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001483:Base Sequence; D001761:Bleomycin / Q000009:adverse effects*; D015331:Cohort Studies; D003546:Cysteine Endopeptidases / Q000235:genetics*; D017931:DNA Primers; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000201:enzymology; D011014:Pneumonia / Q000139:chemically induced*
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D001761:Bleomycin; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase