Cancer is one of the leading causes of death worldwide, and roughly one in every five individuals is known to develop some form of cancer during his / her lifetime. Although, there are several ways to treat cancers, such as chemotherapy, radiation therapy, and surgery and they have demonstrated commendable success in slowing down the uncontrolled growth of malignant cells, shrinking tumors and selectively eliminating transformed cells, there are several side effects (mostly caused due to off-target toxicity) that have severe detrimental effects on patients and thereby, significantly lower the quality of life. Some of the prominent side effects of anti-cancer therapies include skin problems, nausea, fatigue, and cardiac and respiratory complications. Moreover, despite undergoing multiple lines of treatment (using the aforementioned interventions) there are still chances that the disease may relapse. Therefore, there is still a pressing need for more specific and potent drugs / therapies to combat this complex, life threatening clinical condition.
Vascular disrupting agents (VDAs) are a class of anti-cancerous drugs that specifically target the already established mature tumor blood vessels instead of blocking the formation of new blood vessels. Blood vessels play a very important role in the growth of tumor. These abnormal blood vessels supply oxygen and nutrients to tumor cells and the associated cells and may lead to metastasis formation. As one single blood vessel supplies oxygen and nutrients to many tumor cells, therefore the disruption of this vessel may result in killing of thousands of tumor endothelial cells downstream. The following figure provides a diagrammatic description of the mode of action of VDAs on tumor cells.
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VDAs target the endothelial cells of tumor blood vessel that are involved in processes like migration, adhesion, cohesion, and proliferation which further alternates the shape of the endothelial cells, break the cell-to-cell junctions, thereby, leading to loss of cohesion and ultimately resulting in ischemia and tumor necrosis. They have shown greatest effect in combination with conventional chemotherapy or other modes of treatment that selectively target and attack cancer cells. Presently, there are multiple small molecule VDAs, which have been / are being developed for the treatment of a variety of oncological conditions, including colorectal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma and ovarian cancer.
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VDAs can be mainly grouped into two categories [A] biological VDAs (ligand-directed) and [B] small molecule VDAs (tubulin binding agents and flavonoids). Amongst these, the small molecule VDAs are the more popular considering that they are in the more advanced stages of development. These molecules work by tubulin depolymerization, microtubule destabilization or by cytokine production. These agents have gained much attention recently, as they have entered in phase II and III of clinical studies. Certain (phase II) trials, evaluating combinations of VDAs with other therapeutic agents, have demonstrated notable efficacy in treating various cancer indications, such as sarcomas, ovarian cancers, and prostate cancers. As a result, clinical trials evaluating combination therapies, involving VDAs are likely to increase in the foreseen future.
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