[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
European Journal of Clinical Pharmacology 10/2011; 68(4):389-95. DOI:10.1007/s00228-011-1134-0 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polymorphic genes of drug metabolizing enzymes and transporters may influence drug response. With some exemptions, single nucleotide polymorphisms in such genes, however, are not known to be susceptibility factors for breast cancer. This study explored genotype profiles for the breast cancer patients on fluorouracil, doxorubicin and cyclophosphamide (FAC) in a Pakistani set of population and their comparison with HapMap data. Sixty-eight female breast cancer patients were included. All received FAC chemotherapy. Relevant genotyping was done either through restriction fragment length polymorphism or pyrosequencing. The variant allele frequencies were: 5.1% for CYP2C9*2 (430C>T), 15.4% for CYP2C9*3 (1075A>C), 27.2% for CYP2C19*2 (681G>A), 33.1% for GSTA1*B (-69C>T, -52G>A), 62.5% for ALDH3A1*2 (985C>G), 58.8% and 4.4% for ABCB1 (2677 G>T/A), 64.7% for ABCB1 3435 C>T, and 15.4%, 33.1% and 39.7% for ABCC2 (-24 C>T, 1249 G>A and 3972 C>T). In comparison with HapMap, this first exploration in Pakistani samples shows higher frequency of (i) CYP2C9*3 carriers (p < 0.05) than in Hispanic, Chinese, Japanese and African samples, (ii) ALDH3A1*2 carriers (p < 0.01) than Caucasian, Hispanic, Chinese, Japanese and African samples. For ABC transporters, a higher frequency of variant allele was observed in (iii) ABCB1 2677 G>T/A (p < 0.01) than Caucasian, Hispanic and African, (iv) ABCB1 3435 C>T (p < 0.05) than Chinese, Japanese and African, (v) ABCC2 1249 G>A (p < 0.01) than Hispanic, Chinese and Japanese samples. In conclusion, cyclophosphamide activation and detoxification of reactive intermediates may be altered in the Pakistani. Though carriers of CYP2C19*2 were higher than in Caucasian and Hispanics, they did not reach statistical significance (p = 0.05).
[Show abstract][Hide abstract] ABSTRACT: This study was planned to audit female breast cancers and their chemotherapy in a busy public sector institution. As a case-study, Pakistan provides an opportunity to explore the issue in a low-GDP, low-literacy, populous developing country.
Retrospective analysis of the records at Karachi Institute of Radiotherapy and Nuclear Medicine.
A total of 3,431 female breast cancer patients presented during 2001-2008, half being <45 years, mostly suffering from infiltrating ductal carcinoma of breast. Further analyzing a subgroup of 183 consecutive patients over six months revealed that only 1.6% were at stage-I, whereas 75% had node-positive disease, including 19.1% with distant metastases. Some 41.6% were either high grade or poorly differentiated. The low grade tumors showed a two-fold likelihood of ER and PR positivity as compared to high grade lesions. 5-Flourouracil, doxorubicin and cyclophosphamide (FAC) constituted the most common chemotherapy. Earlier diagnosis was associated with complete remission. Overall, 33% developed myelotoxicity, more often if age ≥ 45 years (p=0.012), out of which 60% needed active correction. All those patients who did not experience a drop in total leukocyte count (TLC) below 4 x 10⁹/L did not show complete remission.
Infiltrating ductal carcinoma of the breast is the most common type. FAC is the most common chemotherapy. Tendency for late diagnosis, metastatic disease, treatment failure as well as leukopenia especially in ≥ 45 years is present. Failure to show leukopenia is suggestive of poor therapeutic outcome.
Asian Pacific journal of cancer prevention: APJCP 01/2010; 11(3):825-30. · 2.51 Impact Factor