The effect of chlorambucil on in vitro antiangiogenesis of human HMVECs and ECFCs and cytotoxicity of SF767 and U87-MG human glioma cells compared to clinically-relevant concentrations derived from the in vivo pharmacokinetic profile in tumor-bearing dogs
Abstract
The objective of this study was to investigate a possible mechanism of action of metronomic chlorambucil on brain tumors by studying the in vitro cytotoxicity and antiangiogenic effect on glioma and endothelial cells, respectively. The in vitro median lethal dose (LD 50) and half maximal inhibitory concentration (IC50) of chlorambucil were determined using two human glioma cell lines (U87-MG and SF767) and two human endothelial cell lines (HMVECs and ECFCs). Results were compared with the pharmacokinetic profile achieved in dogs receiving 4 mg m-2 metronomic chlorambucil. The LD50 and IC50 of chlorambucil were 330 µM and 120 µM for SF767, and >500 µM and 95 µM for U87-MG, respectively. The IC50 chlorambucil for tube formation using the HMVECs and ECFCs was 0.53 µM and 145 µM, respectively. Pharmacokinetic data yielded a mean plasma Cmax of 0.06 µM. The results of this study suggest that any clinical improvement that might be observed in tumor-bearing dogs receiving 4 mg m-2 of metronomic chlorambucil is not likely due to direct cytotoxic or growth inhibitory effects on glioma and endothelial cells, based on our in vitro results.
Degree
M.S.
Advisors
Packer, Purdue University.
Subject Area
Veterinary services
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