Pharmacodynamic-mediated reduction of temozolomide tumor concentrations bythe angiogenesis inhibitor TNP-470

The angiogenic phenotype is associated with increased tumor neovascularizat ion and a state of vascular hyperpermeability to macromolecules, Angiogenes is inhibitors could reverse these processes, resulting in tumor capillaries that have normal membrane permeability. It was proposed that the switch Fr om a hyperpermeable to a normal permeable state could have the untoward eff ect of decreasing tumor concentrations of anticancer drugs coadministered w ith angiogenesis inhibitors, The current investigation evaluated a potentia l drug interaction between the angiogenesis inhibitor O-(N-chloroacetyl-car bamoyl)-fumagillol (TNP-470) and the alkylating agent temozolomide (TMZ), i n xenograft models that differentially expressed vascular endothelial growt h 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 admi nistered 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 regime n of TMZ was administered with subsequent collection and high-performance l iquid chromatography analysis of plasma and either tumor homogenate or tumo r microdialysis steady-state TMZ concentrations, and in some cases [5-(3-me thyltriazen-1-yl) imidazole-4-carboximide] MTIC, its active metabolite. Mic rovessel density (MVD) was quantitated by image analysis using an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end po ints in the control and TNP-470 treatment groups were completed by nonparam etric tests. In both the s.c. and intracerebral V+ models, TNP-470 treatmen t produced significant reductions in TMZ tumor concentrations and tumor:pla sma concentration ratios compared with control, being reduced an average of 25% and 50% in the s.c. and intracerebral tumors, respectively. MTIC conce ntrations 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- tumo rs, TMZ and MTIC tumor concentrations were not different in TNP-470 and con trol treatment groups in s.c. tumors. MVD was reduced by TNP-470 compared w ith vehicle control in the V+ tumors, but was unaltered in V-tumors, attest ing to the use of MVD as a pharmacodynamic end point and the effectiveness of TNP-470 as an angiogenesis inhibitor. Angiogenesis inhibitor's pharmacod ynamic actions on tumor angiogenesis can produce a reduction in tumor conce ntrations of coadministered anticancer agents. It is increasingly important to understand the pharmacokinetic and pharmacodynamic behavior of each cla ss of drug so that optimal dosing regimens can be designed.