The relationship among tumor architecture, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in mouse xenograft models

Abstract

Understanding a compound's preclinical pharmacokinetic, pharmacodynamic, and efficacy relationship can greatly facilitate its clinical development. Bortezomib is a first-in-class proteasome inhibitor whose pharmacokinetic/pharmacodynamic parameters are poorly understood in terms of their relationship with efficacy. Here we characterized the bortezomib pharmacokinetic/pharmacodynamic/efficacy relationship in the CWR22 and H460 xenograft models. These studies allowed us to specifically address the question of whether the lack of broad bortezomib activity in solid tumor xenografts was due to insufficient tumor penetration. In vivo studies showed that bortezomib treatment resulted in tumor growth inhibition in CWR22 xenografts, but not in H460 xenografts. Using 20S proteasome inhibition as a pharmacodynamic marker and analyzing bortezomib tumor exposures, we show that efficacy was achieved only when suitable drug exposures drove proteasome inhibition that was sustained over time. This suggested that both the magnitude and duration of proteasome inhibition were important drivers of efficacy. Using dynamic contrast-enhanced magnetic resonance imaging and high-resolution computed tomographic imaging of vascular casts, we characterized the vasculature of CWR22 and H460 xenograft tumors and identified prominent differences in vessel perfusion, permeability, and architecture that ultimately resulted in variations in bortezomib tumor exposure. Comparing and contrasting the differences between a bortezomib-responsive and a bortezomib-resistant model with these techniques allowed us to establish a relationship among tumor perfusion, drug exposure, pharmacodynamic response and efficacy, and provided an explanation for why some solid tumor models do not respond to bortezomib treatment. [Mol Cancer Ther 2009;8(12):3234-43]

Magnetic fluid hyperthermia enhances cytotoxicity of bortezomib in sensitive and resistant cancer cell lines

“…8 Additionally, several studies have suggested that BZ is not affected by the efflux pumps involved in multidrug resistance. [36][37][38][39] However, it is possible that the membrane fluidity induced by MFH can enhance intracellular accumulation of BZ, and we will explore this possibility in future research.…”

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancerA phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer

“…Prior xenograft models have identified prominent differences in vessel perfusion, permeability, and architecture that ultimately resulted in variations in bortezomib tumour exposure. Comparing and contrasting the differences between a bortezomib-responsive and a bortezomib-resistant model with these techniques allowed the authors to establish a relationship among tumour perfusion, drug exposure, pharmacodynamic response and efficacy, and provided a hypothesis for why some solid tumour models did not respond to bortezomib treatment (45). We provide data that there was a significant proteasome inhibition and that the lack of an objective antitumour response in these two patients could not be attributed to insufficient target inhibition in the tumour.…”

Impairment of the Ubiquitin-Proteasome Pathway by Methyl N-(6-Phenylsulfanyl-1H-benzimidazol-2-yl)carbamate Leads to a Potent Cytotoxic Effect in Tumor Cells

“…24 h later, cells were exposed to the specified doses of FZ for 24 h or 10 M MG132 for 12 h, following which they were incubated with 5 M JC-1 dye for 30 min in the CO 2 incubator. After several washes with prewarmed PBS, mitochondrial membrane 3 The abbreviations used are: FZ, fenbendazole (methyl N- (6- potential was evaluated qualitatively under a fluorescence microscope using a 568-nm filter. The localization of cytochrome c was examined using immunofluorescent staining.…”

“…In the present study, we report that treatment of human lung cancer cell lines with fenbendazole (FZ) 3 induces apoptotic cell death, whereas primary normal cells in culture remain widely unaffected. FZ exerts its cytotoxicity possibly through interference with proteasome function and induction of unfolded protein response, ultimately resulting in cancer cell death via the intrinsic pathway of apoptosis.…”

“…Unfortunately, the efficacy of the treatment has been restricted to a narrow therapeutic window. Bortezomib as a single agent has limited activity in non-small cell lung cancer, and it has been reported earlier to have no anti-tumor activity in H460 xenografts (3,4). Therefore, the search for new proteasomal inhibitors that can preferentially eradicate cancer cells is of high priority for effective treatment of the disease.…”