Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Gamma and delta tocotrienols are isomers of Vitamin E with established potency in pre-clinical anti-cancer research. This single-dose, randomized, crossover study aimed to compare the safety and bioavailability of a new formulation of Gamma Delta Tocotrienol (GDT) in comparison with the existing Tocotrienol-rich Fraction (TRF) in terms of gamma and delta isomers in healthy volunteers. Subjects were given either two 300 mg GDT (450 mg γ-T3 and 150 mg δ-T3) capsules or four 200 mg TRF (451.2 mg γ-T3 & 102.72 mg δ-T3) capsules and blood samples were taken at several time points over 24 hours. Plasma tocotrienol concentrations were determined using HPLC method. The 90% CI for gamma and delta tocotrienols for the ratio of log-transformation of GDT/TRF for Cmax and AUC0–∞ (values were anti-logged and expressed as a percentage) were beyond the bioequivalence limits (106.21–195.46, 154.11–195.93 and 52.35–99.66, 74.82–89.44 respectively). The Wilcoxon Signed Rank Test for Tmax did not show any significant difference between GDT and TRF for both isomers (p > 0.05). No adverse events were reported during the entire period of study. GDT was found not bioequivalent to TRF, in terms of AUC and Cmax. Gamma tocotrienol in GDT showed superior bioavailability whilst delta tocotrienol showed less bioavailability compared to TRF.

No abstract

This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.

Mucositis is one of the major non-hematological adverse effects (AEs) of docetaxel, besides fatigue, nausea, vomiting, diarrhea and rash which limit its use in cancer patients. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel demonstrates extensive binding to plasma proteins (>98%) including AAG, lipoproteins and albumin. However, there is a remarkable inter-individual variation of AAG level among cancer patients. Low plasma AAG levels will result in excessive free drug in the circulation, which in turn causes more AEs. Consequently, either the dose is reduced or treatment modality is diverted. In addition, single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in the transport of docetaxel (SLCO1B3) could lead to reduced clearance and accumulation in the circulation and subsequent AEs. Hence, we investigated 91 Malaysian breast cancer patients receiving docetaxel as a single agent chemotherapy at 90-100 mg/m2 and 75 mg/m2 in the adjuvant and metastatic settings respectively, to determine the association between the SNP (SLCO1B3 334TG), plasma AAG level and docetaxel AEs. The plasma AAG level was determined using Enzyme Linked Immunosorbent assay (ELISA) technique, while the SNPs were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. The patients consisted of 49 Chinese (54%), 34 Malays (37%) and 8 Indians (9%). We found a significant difference in plasma AAG level between patients with mucositis and those without (178±74 mg/dl vs 225±97 mg/dl,P<0.05). Moreover, patients with mutant SLCO1B3 334GG who developed diarrhea also had mucositis (p<0.05). In conclusion, patients with lower plasma AAG level are more susceptible to develop mucositis. In addition, patients carrying mutant SLCO1B3 334GG who have diarrhea tend to develop mucositis concurrently. Plasma AAG level and SNPs could serve as potential predictive biomarkers of docetaxel-induced mucositis.We would like to thank Malaysian Ministry of Higher Education (MOHE) and University Malaya for funding this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants. Citation Format: Rafid S. Jabir, Gwo F. HO, Muhammad Azrif A. Anuar, Johnson Stanslas. Docetaxel-induced mucositis in breast cancer patients: Association with plasma alpha-1-acid glycoprotein level and SLCO1B3 genotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5563. doi:10.1158/1538-7445.AM2014-5563