RT Journal Article
SR Electronic
T1 Pharmacodynamic-Mediated Effects of the Angiogenesis Inhibitor SU5416 on the Tumor Disposition of Temozolomide in Subcutaneous and Intracerebral Glioma Xenograft Models
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 833
OP 839
DO 10.1124/jpet.102.048587
VO 305
IS 3
A1 Jianguo Ma
A1 Shaolan Li
A1 Karin Reed
A1 Ping Guo
A1 James M. Gallo
YR 2003
UL http://jpet.aspetjournals.org/content/305/3/833.abstract
AB The objective of this study was to determine the tumor distribution of temozolomide, an alkylating agent, in the absence and presence of the angiogenesis inhibitor 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]indolin-2-one (SU5416), a specific vascular endothelial cell growth factor receptor 2 inhibitor. The study was conducted in nude rats bearing either subcutaneous or intracerebral tumors that overexpressed vascular endothelial cell growth factor. For both tumor locations, animals were assigned to either of two treatment groups, SU5416 (25 mg/kg, dissolved in dimethyl sulfoxide) or vehicle control, dimethyl sulfoxide (710 μl/kg) administered i.p. every day for a total of nine doses. Twenty-four hours after the last dose of SU5416 or dimethyl sulfoxide, temozolomide was administrated as a steady-state infusion regimen designed to achieve target plasma concentrations (Cp) of 20 μg/ml. In addition to the measurement of temozolomide Cp, tumor interstitial fluid unbound concentrations of temozolomide were evaluated by microdialysis. In subcutaneous tumors, SU5416 treatment produced a 24% reduction in steady-state temozolomide Ct values (p < 0.05) as well as 21% reductions in tumor/plasma concentration ratios (Ct/Cp; p = 0.11) compared with controls. In intracerebral tumors, steady-state temozolomide Ct and Ct/Cp ratios were significantly increased by 2-fold in the SU5416 treatment group compared with control. The apparent paradoxical effect of SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral tumors is discussed in the context of physiological changes (for example, interstitial fluid pressure and microvessel density) and the sampling region in the tumor. It is proposed that the net balance of antiangiogenic drug-mediated pharmacodynamic actions will determine how drug disposition in tumors may be affected. The American Society for Pharmacology and Experimental Therapeutics