The use of tyrosine kinase inhibitors in modifying the response of tumor microvasculature to radiotherapy.
The response of the tumor microvasculature to ionizing radiation can be modified to improve tumor control in preclinical mouse models of cancer. Recent studies have shown that a variety of cancer drugs can improve the response of cancers to radiotherapy. Protein tyrosine kinase inhibitors (TKIs) have been shown to enhance radiation-induced destruction of tumor blood vessels. Among these compounds are inhibitors of a broad spectrum of receptor tyrosine kinases (RTKs). Inhibition of RTKs attenuates downstream signaling from various angiogenic growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). RTK inhibitors with various specificities against the receptors for VEGF, PDGF, and FGF manifest significant antiangiogenic activities as well. We have shown using tumor vascular window model and tumor growth delay assays that these compounds can enhance tumor radiation response by attacking tumor microvasculature. Furthermore, we have shown that radiation and RTK inhibitors exert their antiangiogenic effect through inhibition of the PI3K/Akt signaling pathway, which results in induction of apoptosis. Our studies have provided a basis for future clinical investigations of combining radiotherapy and RTK inhibitors.
Lu
Bo
B
Department of Radiation Oncology, Vanderbilt School of Medicine, Vanderbilt University, Nashville, Tennessee 37232-5671, USA.
Shinohara
Eric T
ET
Edwards
Eric
E
Geng
Ling
L
Tan
Jiahuai
J
Hallahan
Dennis E
DE
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D011838:Radiation-Sensitizing Agents; D020794:Receptor Protein-Tyrosine Kinases