[Frontiers in Bioscience E3, 541-548, January 1, 2011]

Therapeutic approaches targeting tumor vasculature in gastrointestinal cancers

Yutaka Takahashi1, and Kenji Nishioka2

1Department of Cancer Chemotherapy, KAKEN Hospital, International University of Health and Welfare. 6-1-14 Kounodai, Ichikawa 272-0827, Japan, 2Nishioka Consulting, P.O. Box 720367, Houston, TX 77272-0367, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Discussion
3.1. Clinical trials of bevacizumab in gastrointestinal cancers
3.1.1. Esophageal and gastric cancers
3.1.2. Pancreatic cancer
3.1.3. Colon cancer
3.2. Resistance to anti-VEGF antibody
3.2.1. Mechanism
3.2.2. How to conquer the resistance
3.2.2.1. Metronomic chemotherapy
3.2.2.2. Non-VEGF-targeted antiangiogenic drug
3.3. Angiogenic switch in gastrointestinal cancers
3.3.1. Colorectal cancer
3.3.2. Other cancers
4. Perspective
5. References

1. ABSTRACT

Antiangiogenic therapy, especially anti-vascular endothelial growth factor (VEGF) antibody therapy, has become an important treatment option for the management of a number of human malignancies including some gastrointestinal tumors. However, there have been many cases of resistance observed against anti-VEGF antibody treatment. As to the first reason, some types of advanced colon cancers do not upregulate VEGF. As to the second reason, not a few malignancies will acquire phenotypic resistance to VEGF or its receptors after anti-VEGF antibody therapy. The molecular and cellular mechanisms associated with the resistance to VEGF-targeted agents are not fully understood. Better understanding of the mechanisms and improvement of antiangiogenic regimens to overcome drug resistance would help in the selection of those patients who are more likely to benefit from VEGF-targeted therapy. Other possible applications of anti-VEGF antibody include chemoprevention of cancer progression. It is well known that angiogenic switch and upregulation of angiogenic cascades are essential for cancer development. Therefore, prophylatic application of anti-VEGF antibody before angiogenic switch may inhibit aggressive growth of these malignancies at an initial phase.