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Agents designed to attack blood vessels that feed a growing tumor are effective against tumor growth in laboratory experiments. However, results of early clinical trials with these inhibitors have not yet exhibited the same success observed in animal models. Now, a new study published in the December issue of Cancer Cell demonstrates that a unique time period exists during which combined radiation and antiangiogenic therapy can exert a remarkable synergistic effect that significantly slows tumor growth.
Recent clinical studies have suggested that antiangiogenic therapy is most effective when delivered in combination with radiation or chemotherapy. However, evidence supporting combined therapies has been inconsistent. Dr. Rakesh K. Jain from the Steele Laboratory for Tumor Biology at Massachusetts General Hospital and Harvard Medical School led a study to investigate whether the timing of combined therapy impacts treatment effectiveness.
Mice implanted with gliomas were treated with radiation, with the antiangiogenic agent DC101, or with combinations of the two. DC101 blocks the action of VEGF, a protein that stimulates blood vessel formation and is found at very high levels in gliomas. Blood vessels in gliomas and many other tumors are abnormal and do not deliver oxygen to tumor cells as efficiently as normal blood vessels do in normal tissues. This is clinically significant because lack of oxygen, or hypoxia, can make a tumor resistant to radiation therapy.
The researchers found that antiangiogenic therapy passively pruned some of the immature blood vessels of tumors and actively recruited pericytes, cells that support a blood vessel, to temporarily stabilize the tumor vasculature. During this period of vascular normalization, tumor hypoxia was substantially decreased and the effect of radiation treatment was enhanced. These results demonstrate that antiangiogenic therapy not only reduces the density of blood vessels in a tumor but, for a short time, makes the existing tumor vasculature more like that of normal tissues, thereby facilitating oxygen delivery to the tumor and enhancing the effects of radiation treatment.
"The time course of this vascular normalization should be taken into account when radiation and antiangiogenic therapy are combined," suggests Dr. Jain. He further speculates that, "If the time course of vascular changes induced by VEGF blockade is taken into account, one might achieve a survival advantage greater than the five months seen in the recent landmark clinical trial of combination therapy."
Frank Winkler, Sergey V. Kozin, Ricky T. Tong, Sung-Suk Chae, Michael F. Booth, Igor Garkavtsev, Lei Xu, Daniel J. Hicklin, Dai Fukumura, Emmanuelle di Tomaso, Lance L. Munn, and Rakesh K. Jain: "Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases"
Publishing in Cancer Cell, Volume 6, Number 6, December 2004, pages 553-563. http://www.cancercell.org
The other members of the research team include Frank Winkler, Sergey V. Kozin, Ricky T. Tong, Sung-Suk Chae, Michael F. Booth, Igor Garkavtsev, Lei Xu, Dai Fukumura, Emmanuelle di Tomaso, and Lance L. Munn of Massachusetts General Hospital and Harvard Medical School; and Daniel J. Hicklin of ImClone Systems Incorporated.
This work was supported by the Goldhirsh Foundation and the National Cancer Institute. F.W. is a fellow of the Deutsche Forschungsgemeinschaft, Emmy-Noether Programm. The monoclonal antibody DC101 was generated by ImClone Systems, of which D.J.H. is an employee. The remaining authors have no financial interest related to this work.
The context and implications of this work are discussed in a Preview by Michelle I. Lin and William C. Sessa of Yale University School of Medicine.
Journal
Cancer Cell