Impact of CYP3A5*3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer

Abstract

Abstract:The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently the genetic variants CYP2C8*3, CYP2C8-HapC, and CYP3A5*3 were associated with paclitaxel-induced neurotoxicity. We therefore investigated the impact of CYP2C8-HapC and CYP3A5*3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than wild type patients. CYP3A5*3/*1 patients were shown to have borderline significantly lower nadir values of leukocytes (p = 0.07) than *3/*3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on the neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.

Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy

“…We applied the same criterion to assess neuropathy in the three participating hospitals, and half of the patients went through a thorough neurologic examination 7 10. However, the limited number of samples included in our study implies reduced statistical power, making it possible that additional true associations went undetected.…”

“…Blood or saliva samples were collected from 144 cancer patients treated with paclitaxel in one Spanish and two Swedish centres: 48 patients (33%) from Hospital Universitario Fundación Alcorcón,7 63 (44%) from Karolinska University Hospital, and 33 (23%) from Linköping University Hospital 10. Eligible patients were over 18 years of age and had: received a chemotherapy regimen with paclitaxel 175 mg/m 2 and carboplatin area under the time–concentration curve (AUC) 5–6 every 21 days to treat a histologically documented solid neoplasia; life expectancy of ≥12 weeks; Eastern Cooperative Oncology Group performance status of ≤2; no chemotherapy, hormonal therapy nor radiotherapy in the 4 weeks before treatment; taken contraception (fertile women only); adequate bone marrow, renal and hepatic function; and no previous history of neuropathy.…”

Pharmacogenetics, Enzyme Probes and Therapeutic drug Monitoring as Potential Tools for Individualizing Taxane Therapy

“…There is a strong linkage between the functional CYP3A5*1 allele and CYP3A4*1B allele, and presence of these alleles together has been related to increased docetaxel clearance [30,31]. A few studies have reported associations between the low-activity CYP3A5*3 (6986A>G, rs776746) SNP and a lower risk of hematological toxicity in patients treated with docetaxel [39] or paclitaxel [40], however, the opposite finding has also been reported [41]. …”

“…Secondary analyses of three small studies [32,40,44] suggested an increase in neurotoxicity risk of patients carrying the low-activity CYP2C8*3 variant, which consists of two polymorphisms that occur in almost complete linkage disequilibrium (416G>A, R139K, rs11572080; and 1196A>G, K399R, rs10509681). This has recently been replicated in analyses of independent patient cohorts [42,45].…”

Insights on Cancer Preventive Approaches Using Plant Based Extracts

“…Extensive investigations are still in pursuit in search of more effective camptothecin derivative. Certain compounds such as Topotecan-developed by SmithKline Beecham (now known as Glaxo SmithKline) and Irinotecan-developed by Yakult Honsha (Japanese company); are now in therapeutic use [45,46]. Topotecan has shown effectiveness and it is extensively used for the smallcell lung cancers, while Irinotecan for the colorectal cancer treatments.…”