Surpassing several setbacks, the clinical development of antiangiogenic agents has accelerated remarkably over the past 3–4 years. As a result, there are currently three direct blockers of the VEGF ...pathway approved for use in cancer, and two others for age-related wet macular degeneration. Other agents that block the VEGF pathway are currently in advanced stages of clinical development and have shown promising results. With these exciting developments come critical questions regarding the use of these new molecularly targeted agents, alone or in combination with standard cytotoxic or targeted agents.
As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the ...antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.
Solid tumors require blood vessels for growth, and many new cancer therapies are targeted against the tumor vasculature. The widely held view is that these antiangiogenic therapies destroy the tumor ...vasculature, thereby depriving the tumor of oxygen and nutrients. Indeed, that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis, that judicious application of agents that block angiogenesis directly (e.g., bevacizumab, AZD2171) and indirectly (e.g., trastuzumab) can also transiently “normalize” the abnormal structure and function of tumor vasculature. In addition to being more efficient for oxygen and drug delivery, the normalized vessels are fortified with pericytes, which can hinder intravasation of cancer cells, a necessary step in hematogenous metastasis. Drugs that induce vascular normalization can also normalize the tumor microenvironment—reduce hypoxia and interstitial fluid pressure—and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumor-associated edema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the “vascular normalization window” can potentially sensitize tumors to cytotoxic agents. Our recent Phase II clinical trial in glioblastoma patients shows that the normalization window— identified using advanced magnetic resonance imaging (MRI) techniques—can last one to four months, and the resulting changes in tumor vasculature correlate with circulating molecular and cellular biomarkers in these patients.
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