Abstract 1447: PDE5 inhibitors increase trastuzumab transport for treatment of HER2-positive metastatic brain tumors

Abstract

Abstract Objective: Chemotherapeutic drugs and newly developed therapeutic antibodies can be adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. Our previous publication showed that phosphodiesterase type (PDE) 5 inhibitors enhance brain tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Here, we further examined the effect of PDE 5 inhibitors on drug delivery to intracranial human lung and breast tumors in nude mice as a model of brain metastasis, and the underlying mechanisms of drug transport. Methods: In the in vitro setting, a Corning transwell system seeded with mouse brain endothelial cells (MBEC) was used for cellular [14C]dextran transport study as a model of blood brain barrier (BBB). For in vitro uptake of a therapeutic monoclonal antibody to HER2/neu, trastuzumab (Herceptin®), MBEC were treated with labeled drug with or without pre-incubation with vardenafil. To study the underlying mechanisms of transport, inhibitors of caveolae and macropinocytosis endocytic pathways were used to block the effect of PDE5 inhibitors. In the in vivo study, vardenafil was given at an oral dose of 10 mg/kg for transport of [14C]dextran and labeled trastuzumab to mice with human lung tumor growing in the brain. For the survival experiments, HER2/neu-positive human lung or breast intracranial tumor-bearing mice were randomly divided into four groups treated as follows: (1) control saline; (2) vardenafil (10 mg/kg, po); (3) trastuzumab (10 mg/kg, iv); and (4) vardenafil (10 mg/kg, P.O.) + trastuzumab (10 mg/kg, I.V.). Results: In vitro assay demonstrated that PDE5 inhibitors enhanced the uptake of [14C]dextran and trastuzumab by cultured MBECs. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced trastuzumab uptake. Oral administration of PDE5 inhibitor vardenafil to mice with intracranial lung tumors led to an increased tumor permeability to high molecular weight [14C]dextran (2.6-fold increase) and to trastuzumab (2-fold increase). Survival of intracranial lung cancer-bearing mice treated with trastuzumab in combination with vardenafil significantly increased as compared to the untreated, vardenafil alone- or trastuzumab alone-treated mice (p<0.01). In mice bearing intracranial breast tumors, log-rank analysis of survival curves also showed a significant survival increase (p<0.02) in the group treated with trastuzumab plus vardenafil as compared to other groups. Conclusion: These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability and enhance drug delivery, and may increase the efficacy of therapeutic monoclonal antibodies in hard-to-treat brain metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1447.