2-Deoxyglucose (2-DG), a glycolytic inhibitor analog of glucose, is widely investigated in experimental and clinical oncology for targeting glucose metabolism. Inhibition of the glycolytic pathway with 2-deoxyglucose leads to sensitization of tumor cells to other apoptotic stimuli(Maschek, G., et al Cancer Res. 64: 31-34, 2004). A phase I/II clinical trial of 2-DG for the treatment of advanced solid tumors and hormone refractory prostrate cancer has been initiated. One of the objectives of this dose escalation trial was to evaluate PK of 2-DG. The drug was administered orally on a daily schedule for 2 weeks of every 3 week cycle. The standard dose escalation format was followed with a starting dose 30mg/kg, escalated to 45mg/kg and 60mg/kg. So far twelve patients have been accrued for this trial (mean age, 65.4± 9.9 yrs), and all completed the study. Repeated oral administration of 2-DG was well tolerated, with a maximum tolerated dose (MTD) not exceeding 60mg/kg consecutive-day dosing. For the PK analyses, blood samples were collected immediately before drug administration, hourly up to 6hr, and predose at 24hr and 48hr after administration on cycle 1 day 1 and cycle 2 day 1. For the quantitiation of 2-DG in plasma, the sample extracts were derivatized to 2-aminobenzoic acid derivatives, and determined using a highly sensitive high performance liquid chromatography fluorometric method (HPLC-FL). The HPLC-FL assay showed excellent linearity ranging from 125ng/ml to 10 μg/ml (r2=0.9992±0.0009, n=4). The limit of detection was 62.5ng/ml. The assay precision for 125ng/ml (LOQ) and 10µg/ml were 12.5% and 4.9% and the accuracy ranged from 105.9% to 101.8%. Pharmacokinetic parameters were determined and utilized to assess dose-dependency across the dose range studied. Consecutive-day dose of 2-DG showed no effect on plasma glucose levels. The mean steady state concentration at dose level 1, was 0.33± 0.09 μg/ml, and at dose levels 2 and 3, were 1.06± 0.25, and 1.08± 0.41 μg/ml respectively. Mean plasma concentrations and area under concentration-time curve (AUC) values were dose dependent in cohort 1 (30mg/kg) and 2 (45mg/kg). Tmax occurred at 1 hr after dosing. The elimination t1/2 ranged between 3.3 −8.9 hr (5.8±1.8hr) and 1.2 − 10.6 hr (6.6±2.8 hr), among three cohorts in cycle 1 and 2. PK parameters AUC, and clearance (CL), showed no significant difference between two cycles in cohort 1 and 2. However, AUC in cohort 3 (60mg/kg) decreased significantly (p<0.05), from cycle 1 (342.47±121.99 µg/ml*h) to cycle 2 (201.41±93.77µg/ml*h), and the CL in cycle 1 (184±52.6 ml/kg) was significantly less than Cycle 2 (314.9±108.7 ml/kg, p<0.05). This is the first report to examine plasma 2-DG level using a HPLC-FL method. The HPLC-FL assay is suitable and reproducible for clinical trials.

Acknowledgement: The study is supported by the grants from The Department of Defense.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2756.