Gene expression profile of enzymes involved in gemcitabine (Gem) metabolism in bone marrow mononuclear cells as predictors of myelosuppression

Abstract

2007 Background: The dose-limiting toxicity of gemcitabine (Gem) is hematologic toxicity (heme tox), and there is wide intra-patient variability in the degree of heme tox. This study was done to assess the possible impact of gene expression of enzymes involved in Gem metabolism or mechanism of action on heme tox. Methods: Pre-therapy mononuclear cells were isolated from bone marrow aspirates collected from 71 consenting patients with various advanced malignancies enrolled in an IRB-approved phase I trial in which single agent Gem was given over 30 min weekly for 2 of 3 weeks during cycle 1 at doses ranging from 750–1,560 mg/m2. Gene expression of deoxycytidine kinase (DCK), an activating enzyme, cytidine deaminase (CD) and deoxycytidylate deaminase (DCD), deactivating enzymes, and ribonucleotide reductase M2 (RNR), which is inhibited by Gem diphosphate, was measured by real-time RT-PCR. Target gene expression was relative to beta-actin. Heme tox was calculated as the % decrease in white blood cells (WBC), neutrophils (ANC) and platelets (PLT) from baseline. Results: 71 patients (26 females, 35 males) with a median age of 56 years (range: 20–75) were included in the analysis. The median (25th %, 75th %) gene expression was as follows (x10e3/beta-actin): DCK, 0.34 (0.19, 0.64); CD, 1.88 (1.33, 2.92); DCD, 2.48 (1.15, 7.78); and RNR, 0.39 (0.19, 0.80). A strong linear correlation was noted only between RNR & DCD gene expression (Pearson r = 0.89). When gene expression was categorized as above or below the median value, only CD appeared to influence heme tox (mean ± std dev) ( Table ). T-test p value is shown. Conclusions: Gem is rapidly metabolized to its inactive metabolite by CD. Subjects with a higher relative gene expression of CD tended to have a lesser degree of heme tox following Gem. Correlation with Gem pharmacokinetics in these subjects is planned. [Table: see text] No significant financial relationships to disclose.