Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition.

The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P<0.0001). Similar observations were made in the Colo-26 colorectal carcinoma, where light exposure of the sunitinib-treated mice inhibited tumor growth by 50% as compared with the control and by 25% as compared with sunitinib-only-treated tumors (N≥4; P=0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications.

Recent developments in tumor angiogenesis.

Angiogenesis is a developmental process that also plays the central role in adults during the female menstruation cycle, wound healing and neoplastic growth and metastasis. Ideally, blocking neovessel growth starves the developing tumor and induces tumor regression. Restricting the vascular ingrowth into the tumor might have adverse effect on drugs targeting the tumor. Nevertheless, anti-VEGF treatment of the neoplastic diseases when combined with chemotherapy significantly increases median survival in treated patients. This suggests alternative mechanisms of anti-angiogenesis therapy. A number of molecules that are in current clinical trials have been identified using angiogenesis models. However, current angiogenesis models have advantages and inconvenience and conclusion drawn upon their use should be interpreted with caution. Thus, it is necessary to optimize existing models and to develop new ones that take into account the complexity of the angiogenic process as it happens in many angiogenesis-related diseases and in particular in cancer.