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-CP:CP 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-CP:CP ratio was negatively affected by
CYP2C19*2
genotype (
p
= 0.039) showing a gene-dose effect. Moreover
ALDH3A1*2
genotype increased 4-OH-CP:CP 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.