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[Cancer Research 60, 4066-4069, August 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Antiangiogenic Treatment Enhances Photodynamic Therapy Responsiveness in a Mouse Mammary Carcinoma1

Angela Ferrario, Karl F. von Tiehl, Natalie Rucker, Margaret A. Schwarz, Parkash S. Gill and Charles J. Gomer2

Clayton Center for Ocular Oncology, Childrens Hospital Los Angeles, Los Angeles, California 90027 [A. F., K. F. v. T., N. R., C. J. G.], and Departments of Pediatrics [C. J. G., M. A. S.], Radiation Oncology [C. J. G.], Medicine [P. S. G.], Pathology [P. S. G.], and Surgery [M. A. S.], Keck School of Medicine, University of Southern California, Los Angeles, California 90033

Photodynamic therapy (PDT) is a promising cancer treatment that induces localized tumor destruction via the photochemical generation of cytotoxic singlet oxygen. PDT-mediated oxidative stress elicits direct tumor cell damage as well as microvascular injury within exposed tumors. Reduction in vascular perfusion associated with PDT-mediated microvascular injury produces tumor tissue hypoxia. Using a transplantable BA mouse mammary carcinoma, we show that Photofrin-mediated PDT induced expression of the hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) subunit of the heterodimeric HIF-1 transcription factor and also increased protein levels of the HIF-1 target gene, vascular endothelial growth factor (VEGF), within treated tumors. HIF-1{alpha} and VEGF expression were also observed following tumor clamping, which was used as a positive control for inducing tissue hypoxia. PDT treatment of BA tumor cells grown in culture resulted in a small increase in VEGF expression above basal levels, indicating that PDT-mediated hypoxia and oxidative stress could both be involved in the overexpression of VEGF. Tumor-bearing mice treated with combined antiangiogenic therapy (IM862 or EMAP-II) and PDT had improved tumoricidal responses compared with individual treatments. We also demonstrated that PDT-induced VEGF expression in tumors decreased when either IM862 or EMAP-II was included in the PDT treatment protocol. Our results indicate that combination procedures using antiangiogenic treatments can improve the therapeutic effectiveness of PDT.




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