Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients.
OBJECTIVE
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).


CONCLUSIONS
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.
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. drnasirpk@yahoo.com
Nasir Ali
NA
Afsar
Mike
M
Ufer
Sierk
S
Haenisch
Cornelia
C
Remmler
Ahmed
A
Mateen
Ahmed
A
Usman
Khwaja Zafar
KZ
Ahmed
Hakimuddin Razi
HR
Ahmad
Ingolf
I
Cascorbi
D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged
D018906:Antineoplastic Agents, Alkylating; C012358:4-hydroxycyclophosphamide; D004317:Doxorubicin; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D005472:Fluorouracil