ONCOLOGY Vol 19 No 4_Suppl_3

Although the idea of utilizing antiangiogenic agents to hinder tumor growthis not new,[1] and the discovery of angiogenesis in tumors is evenolder,[2] this field of research is still in its infancy. Much has been learnedabout angiogenesis in tumor growth and development, yet the process is exceedinglycomplex and tightly regulated by a sophisticated interplay between pro- andantiangiogenic factors. Decades will pass before these regulatory mechanisms arewell elucidated and understood.

There is substantial preclinical and clinical evidence that angiogenesisplays a role in the development of tumors and the progression ofmalignancies. Inhibiting angiogenesis has been shown to suppress tumorgrowth and metastasis in many preclinical models. These benefitshave translated to the clinic with both marketed and investigationalantiangiogenesis agents. The most prominent target of these compoundsis vascular endothelial growth factor (VEGF) and its receptors. However,several other factors are of interest as well. These include integrins,matrix metalloproteinases, and endogenous antiangiogenic factors. Datafrom late-stage clinical trials support the role of antiangiogenic agents incancer therapy and the significant role that VEGF plays in angiogenesis.Future research will focus on determining the tumor types and stages thatwill benefit most from antiangiogenic therapy and combining therapiesthat target different factors in the angiogenesis pathway.

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.

Angiogenesis is an essential step in the growth and spread of solidtumors-the cause of more than 85% of cancer mortality. Inhibitingangiogenesis would therefore seem to be a reasonable approach to preventor treat cancer. However, tumor angiogenesis differs from normalangiogenesis in that the resulting vessels are tortuous, irregularlyshaped, and hyperpermeable. These abnormalities result in irregularblood flow and high interstitial fluid pressure within the tumor, whichcan impair the delivery of oxygen (a known radiation sensitizer) anddrugs to the tumor. Emerging evidence suggests that antiangiogenictherapy can prune some tumor vessels and normalize the structure andfunction of the rest, thereby improving drug delivery and normalizingthe tumor microenvironment. This normalization effect may underliethe therapeutic benefit of combined antiangiogenic and cytotoxic therapies.This paper reviews current and emerging concepts of the mechanismof action of antiangiogenic therapies and discusses the implicationsof these mechanisms for their optimal clinical use.