Angiogenesis Inhibitors: Perspectives for Medical, Surgical and Radiation Oncology

Abstract

In the past decade, many angiogenesis inhibitors have been developed for clinical use in oncology. Surgeons, radiotherapists as well as medical oncologists have been investigating with much effort and enthusiasm the translation of these agents from the preclinical setting into treatment strategies of patients. Recently, for the first time in history, the angiogenesis inhibitor bevacizumab (avastin), a humanized anti-vascular endothelial growth factor (VEGF) antibody, showed a survival benefit of 4.7 months in a phase III clinical trial in patients with advanced colorectal cancer when this agent was given in combination with chemotherapy. At the annual meeting of the American Association of Clinical Oncology 2005, similar results of bevacizumab in lung, breast and ovarian cancer clinical trials have been shown. These landmark studies proofed for the first time in the clinical setting that Dr. Folkman back in 1971 was right by proposing: "in order to stop tumor growth, one should attack its blood supply". Nowadays it seems trivial to propose such a hypothesis, at that time it was a very provocative hypothesis and it took more than 30 years to proof this hypothesis in the clinic. Although one may be excited about this major finding, there is no time to relax. The survival benefit of bevacizumab is only about 4 months. Therefore more potent antiangiogenic agents and more active treatment strategies are urgently warranted. Newer angiogenesis inhibitors that are currently in preclinical or early clinical development have shown in preclinical experiments improved antitumor activities. In addition, combinations of biological agents that interfere in multiple biological pathways in cancer growth including chemotherapy, are of major clinical interest as well. The multimodality approach in which surgeons, radiotherapists and medical oncologists collaborate needs to be explored as well. In a variety of cancer types, like breast colon and lung cancer, these specialists should design multimodality strategies based on current standard treatment in which they incorporate angiogenesis inhibitors in the right time frame of surgery and radiotherapy. In this review we will bring you up to date on the clinical development of angiogenesis inhibitors and we will summarize the multimodality strategies that are under development.

Endostatin enhances radioresponse in breast cancer cells via alteration of substance P levels

“…Therefore, rmES treatment induces cell death rather than inhibiting cell proliferation, suggesting that ES treatment is more suitable as adjuvant therapy or in combination with RT. Results of this study confirm those of previous studies and demonstrate that rmES potentiates the cytotoxic effects of RT (5,6,(27)(28)(29)(30). Of note, however, is that the results do not indicate the benefits of combination therapy.…”

“…Findings of various studies have shown that the addition of anti-angiogenic agents to RT increases clinical efficacy (5). Reports have suggested that ES may effectively enhance the effects of RT for tumor cells in vitro (3,6).…”

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

“…After cooling, the resulting precipitate was collected by filtration and washed with ethanol. The crude product was suspended in water (elimination of NH 4 3-Chlorophenyl 6-hexamethylenetetrammoniomethyl-2-oxo-2H-1-benzopyran-3-carboxylate chloride salt (26c) was obtained as described for 26a after the reaction of hexamethylenetetramine (1.8 g, 12.8 mmol) with 3-chlorophenyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (25c) (2 g, 5.7 mmol). The resulting precipitate was collected by filtration and washed with cold CHCl 3 : mp 210°C.…”

“…Indeed, many efforts are now focussed on the search of compounds interfering with the cancer cell invasion process and expressing antiangiogenic properties [1]. Examples of drugs, among which monoclonal antibodies and small molecules, are currently under clinical investigation and some of them have recently been approved for use in man in the treatment of several cancers associated or not with conventional chemotherapies or radiation therapies [2][3][4][5][6][7][8][9]. These drugs comprise vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) inhibitors (monoclonal antibodies) as well as VEGF and EGF receptor tyrosine kinase inhibitors (small-molecule inhibitors), but also matrix metalloproteinase (MMP), urokinase (uPA), cycloogygenase-2 (COX-2) or methionine aminopeptidase inhibitors [1].…”

“…1), expressed a marked potency in inhibiting cancer cell invasion in vitro and tumour growth in vivo [10]. Simple natural and synthetic coumarins such as esculetin (3), osthole (4) and the synthetic 6-nitro-substituted coumarin (5) (Fig. 1) are also known for a long time to exert anti-cancer properties, but, for most of them, by an unknown mechanism [11][12][13][14].…”