Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction.
Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic/vasculature targeting agents enhances the therapeutic ratio of ionizing radiation alone. Because radiotherapy is one of the most widely used treatments for cancer, it is important to understand how best to use these two modalities to aid in the design of rational patient protocols. The mechanisms of interaction between antiangiogenic/vasculature targeting agents and ionizing radiation are complex and involve interactions between the tumor stroma and vasculature and the tumor cells themselves. Vascular targeting agents are aimed specifically at the existing tumor vasculature. Antiangiogenic agents target angiogenesis or the new growth of tumor vessels. These agents can decrease overall tumor resistance to radiation by affecting both tumor cells and tumor vasculature, thereby breaking the codependent cycle of tumor growth and angiogenesis. The hypoxic microenvironment of the tumor also contributes to the mechanisms of interactions between antiangiogenic/vasculature targeting agents and ionizing radiation. Hypoxia stimulates up-regulation of angiogenic and tumor cell survival factors, giving rise to tumor proliferation, radioresistance, and angiogenesis. Preclinical evidence suggests that antiangiogenic agents reduce tumor hypoxia and provides a rationale for combining these agents with ionizing radiation. Optimal scheduling of combined treatment with these agents and ionizing radiation will ultimately depend on understanding how tumor oxygenation changes as tumors regress and regrow during exposure to these agents. This review article explores the complex interactions between antiangiogenic/vasculature targeting agents and radiation and offers insight into the mechanisms of interaction that may be responsible for improved tumor response to radiation.
Wachsberger
Phyllis
P
Division of Experimental Radiation Oncology, Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. phyllis.wachsberger@mail.tju.edu
Burd
Randy
R
Dicker
Adam P
AP
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D008565:Membrane Proteins; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000532:radiotherapy*; D011451:Prostaglandin-Endoperoxide Synthases; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D040262:Receptors, Vascular Endothelial Growth Factor