The angiogenic phenotype is associated with increased
tumor neovascularization and a state of vascular hyperpermeability to macromolecules.
Angiogenesis inhibitors could reverse these processes, resulting in
tumor capillaries that have normal membrane permeability. It was proposed that the switch from a hyperpermeable to a normal permeable state could have the untoward effect of decreasing
tumor concentrations of anticancer drugs coadministered with
angiogenesis inhibitors. The current investigation evaluated a potential drug interaction between the
angiogenesis inhibitor O-(N-chloroacetyl-carbamoyl)-
fumagillol (TNP-470) and the
alkylating agent temozolomide (TMZ), in xenograft models that differentially expressed
vascular endothelial growth factor (
VEGF), a driving force for angiogenesis. Nude rats bearing either s.c. low
VEGF (V-) or high
VEGF (V+) or intracerebral V+
gliomas were administered either a multiple-dose regimen of
TNP-470 or vehicle control. One day after the last dose of vehicle or
TNP-470, a steady-state dosing regimen of TMZ was administered with subsequent collection and high-performance liquid chromatography analysis of plasma and either
tumor homogenate or
tumor microdialysis steady-state TMZ concentrations, and in some cases [5-(3-methyltriazen-1-yl)
imidazole-4-carboximide]
MTIC, its active metabolite. Microvessel density (MVD) was quantitated by image analysis using an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end points in the control and
TNP-470 treatment groups were completed by nonparametric tests. In both the s.c. and intracerebral V+ models,
TNP-470 treatment produced significant reductions in TMZ
tumor concentrations and
tumor:plasma concentration ratios compared with control, being reduced an average of 25% and 50% in the s.c. and intracerebral
tumors, respectively.
MTIC concentrations in V+ s.c.
tumors also were reduced by 50% in the presence of
TNP-470. Consistent with the lower extent of neovascularization in the V-
tumors, TMZ and
MTIC tumor concentrations were not different in
TNP-470 and control treatment groups in s.c.
tumors. MVD was reduced by
TNP-470 compared with vehicle control in the V+
tumors, but was unaltered in V-
tumors, attesting to the use of MVD as a pharmacodynamic end point and the effectiveness of
TNP-470 as an
angiogenesis inhibitor.
Angiogenesis inhibitor's pharmacodynamic actions on
tumor angiogenesis can produce a reduction in
tumor concentrations of coadministered
anticancer agents. It is increasingly important to understand the pharmacokinetic and pharmacodynamic behavior of each class of
drug so that optimal dosing regimens can be designed.