Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients.
Eur J Clin Pharmacol
; 68(4): 389-95, 2012 Apr.
Article
in En
| MEDLINE
| ID: mdl-22012257
ABSTRACT
PURPOSE:
The cytotoxic drug cyclophosphamide (CP) is bioactivated into 4-hydroxy-cyclophosphamide (4-OH-CP) through cytochrome P450 enzymes and cleared through aldehyde dehydrogenase and glutathione S-transferase. This prospective study analyzes the influence of drug metabolizing enzyme genotype on (1) plasma 4-OH-CPCP ratio and (2) myelotoxicity in breast cancer patients on 500 mg/m(2) cyclophosphamide.METHODS:
Sixty-eight female breast cancer patients on FAC (fluorouracil, adriamycin, cyclophosphamide) were included. Genotyping of cytochrome P450 enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5, aldehyde dehydrogenase (ALDH3A1), and glutathione S-transferase (GSTA1) was done either through RFLP or pyrosequencing. Plasma CP and 4-OH-CP were measured immediately and 1 and 2 h after the end of infusion through LC-MS. The leukocyte count was determined on day 10 and 20 after chemotherapy.RESULTS:
At CP dose of 500 mg/m(2), the 4-OH-CPCP ratio was negatively affected by CYP2C19*2 genotype (p = 0.039) showing a gene-dose effect. Moreover ALDH3A1*2 genotype increased 4-OH-CPCP ratio (p = 0.037). These effects did not remain significant in a univariate analysis of variance including all genotypes. GSTA1*B carriers were at increased risk of severe leucopenia (OR 6.94; 95% CI 1.75-27.6, p = 0.006).CONCLUSION:
The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.
Full text:
1
Database:
MEDLINE
Main subject:
Breast Neoplasms
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Antineoplastic Combined Chemotherapy Protocols
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Cytochrome P-450 Enzyme System
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Aldehyde Dehydrogenase
/
Glutathione Transferase
Type of study:
Clinical_trials
/
Observational_studies
/
Risk_factors_studies
Limits:
Adult
/
Aged
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Female
/
Humans
/
Middle aged
Language:
En
Year:
2012
Type:
Article