title: Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma.
abstract: 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-1alpha (HIF-1alpha) 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-1alpha 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.
authors.affiliation: Clayton Center for Ocular Oncology, Childrens Hospital Los Angeles, California 90027, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ferrario
authors.forename: K F
authors.initials: KF
authors.lastname: von Tiehl
authors.forename: N
authors.initials: N
authors.lastname: Rucker
authors.forename: M A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: P S
authors.initials: PS
authors.lastname: Gill
authors.forename: C J
authors.initials: CJ
authors.lastname: Gomer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia; D003131:Combined Modality Therapy; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D017323:Dihematoporphyrin Ether / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000494:pharmacology; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D004268:DNA-Binding Proteins; D004151:Dipeptides; D016228:Endothelial Growth Factors; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D017319:Photosensitizing Agents; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C077219:small inducible cytokine subfamily E, member 1; C060736:thymogen; D017323:Dihematoporphyrin Ether