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Anti-Cancer Potential of Tumor-Vascular Disrupting Agents

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Anti-Cancer Potential of Tumor-Vascular Disrupting Agents Review: Clinical Trial Outcomes Anticancer potential of tumor vascular disrupting agents: review of the latest clinical evidence Clin. Invest. (2012) 2(10), 985–993 Solid tumors differ from normal tissue by having a low vascular density, Bruce C Baguley* & Mark J McKeage leading to various forms of vascular stress. Tumor vascular disrupting agents Auckland Cancer Society Research Centre, (VDAs) act to potentiate this stress, increasing vascular permeability and Faculty of Medical & Health Sciences, The decreasing blood flow. Two main classes of tumor VDAs have progressed University of Auckland, Private Bag 92019, so far to clinical trial: the ‘flavonoid’ class, represented by vadimezan, and New Zealand *Author for correspondence: the tubulin poisons, represented by fosbretabulin (combretastatin A-4 E-mail: [email protected] phosphate). Both classes have been tested clinically, generally in combination with cytotoxic drugs such as carboplatin and paclitaxel. An important feature of trials is the measurement of effects on tumor vascular permeability and blood flow. Dynamic contrast-enhanced MRI, using a gadolinium-based biomarker, has been commonly employed. Promising clinical results, as well as indications of efficacy as tumor VDAs, have been obtained in Phase II clinical trials. However, Phase III trials have not yet demonstrated an increase in patient survival. Keywords: antivascular • combination chemotherapy • combretastatin • DMXAA • dynamic contrast-enhanced MRI • tubulin • tumor blood flow • vascular permeability Solid tumors develop in a network of blood vessels that are essential for their growth and survival. In human cancer, the net growth rate of this network is relatively slow with a doubling time in the order of 3 months [1]. The tumor cells within the network therefore have a high rate of turnover, since their individual doubling times are in the order of 1 week [2]. The proliferation of tumor cells also leads to a low vascular density as compared with normal tissues, together with the generation of hypoxia and metabolic stress in some areas. These in turn activate HIF-1, leading to increased production of cytokines such VEGF (also known as vascular permeability factor) and other cellular responses. An important effect of VEGF is to act on the vascular endothelium, increasing vascular permeability and, hence, the interstitial pressure within tumor tissue; this is associated with inefficient drainage by the lymphatic system. Other inflammatory cytokines, such as TNF produced by innate immune cells, may contribute increased permeability of the tumor vasculature [3] and to a reduction in its efficiency. It has been recognized for several decades [4,5] that the above properties of tumor vasculature provide potential targets for chemotherapy, and two distinct approaches have been developed. The first recognizes that net tumor growth is required for new blood vessel development (angiogenesis); this led to the devel- opment of a large number of so-called antiangiogenic drugs of which bevaci- zumab is the best known clinical example [6]. The second approach, which will be discussed in this review, is based on the principle that since tumor vasculature was already inefficient, application of further stress on the vascular endothelium would lead to selective compromise of tumor vascular function. Tumor vascular disrupting agents (VDAs) could lead to catastrophic vascular failure, cessation of 10.4155/CLI.12.98 © 2012 Future Science Ltd ISSN 2041-6792 985 Review: Clinical Trial Outcomes Baguley & McKeage tumor blood flow and extravasation of blood cells into development has focused on two main classes, often tissue. This would in turn lead, after several hours, referred to as flavonoids and mitotic poisons(Figure to hemorrhagic tumor necrosis. The earliest clinical 1) and both were developed mainly with the use of studies examining the potential of tumor vascular transplantable mouse tumor models. The first class is disruption may well have been the trials of Coley’s named after flavone acetic acid (FAA), which was orig- toxins [7], which undoubtedly affected endothelial cell inally identified as a potential antitumor drug because function. However, more recent work has focused on of unexpectedly high activity against a murine colon low-molecular weight drugs as tumor VDAs. carcinoma [11]. It was subsequently shown to act by induction of necrosis of such tumors [12] as a conse- Control of tumor blood flow quence of disruption of tumor blood flow[10] . FAA Capillary blood flow is a function of vessel diame- was initially advanced to Phase I clinical trial as the ter, pressure difference along the length of the cap- acetic acid ester, based on its activity against murine illary and blood viscosity [8]. Gaps in the junctions solid tumors, but it was realized subsequently that the between adjacent endothelial cells not only increase ester was rapidly hydrolyzed by esterases in plasma to vascular permeability but also allow the movement of FAA, and FAA itself was tested in a large number of lymphocytes and granulocytes between the vascular patients in multiple trials [13]. A combination trial of compartment and tissue, as well as leakage of plasma FAA with IL-2 was also undertaken [14]. These trials into the tissue. The induction of such gaps reduces the did not attempt to examine effects on the tumor vas- pressure difference along the length of the capillary, culature because it was assumed at that stage that FAA reduces vessel diameter and increases blood viscosity, had a direct effect on tumor cells; all trials produced all of which compromise blood flow. Strict control of negative results. vascular permeability is therefore essential for nor- Development of analogues of FAA was conducted mal tissue function and a number of tissue responses in several laboratories, but the most fruitful concerned act to maintain vascular permeability in the normal derivatives of the tricyclic analog xanthenone-4-acetic range. One mechanism for such control involves plate- acid (XAA), which, while chemically not a flavonoid, lets; increased vascular permeability allows platelets is included in the flavonoid class of tumor VDAs. The to leave the capillary and make contact with colla- synthetic opportunities provided by XAA, whereby gen in the basement membrane. Such contact causes new molecules could be produced by combining two degranulation of platelets and the release of sphin- phenyl derivatives, led to the elaboration of an exten- gosine-1-phosphate, which acts to decrease vascular sive series [15]. The most active of the XAA series was permeability [9]. Certain features of tumor tissue, such a 5,6-dimethyl derivative called DMXAA, ASA404 as low vascular density and the presence of inflamma- or vadimezan [16]. The effect of vadimezan appears to tory cytokines, lead to an overall increase in vascular involve a combination of a direct effect on the tumor permeability in comparison with that of normal tis- vasculature including increased vascular permeabil- sues and, consequently, a lowered tolerance to further ity [17], endothelial cell apoptosis [18] and decreased permeability increases. This represents a potential tumor blood flow, and an indirect antivascular effect Achilles’ heel that might be exploited therapeutically. medicated by cytokines such as TNF, as well as other However, it should be kept in mind that compensa- vasoactive compounds [19]. tory processes are still operating in tumor tissue and The second class of tumor VDAs stems from early that any induced increase in vascular permeability is experimental studies showing that the mitotic poi- generally reversible and is followed by a tissue reaction son colchicine disrupted the vasculature of murine that lowers permeability again. Studies of mice have tumors [20]. Subsequent studies showed that mitotic shown that physically induced failure of tumor blood poisons such as podophyllotoxin, vincristine and vin- flow for more than 4 h is necessary to prevent reversal blastine [21] and vinca alkaloids in general [22] had a and to induce irreversible changes, leading to hemor- vascular disrupting effect similar to that of colchicine. rhagic necrosis [10]. Strategies for selective disruption Further work identified a number of further mitotic of tumor vasculature must therefore recognize the poisons, mainly natural products, which showed effi- necessity for the induction of a sustained effect on cacy as tumor VDA [23] and in particular identified the tumor blood supply in the face of physiological combretastatin A-4 [24]. Lack of solubility was a signif- responses that might restore it. icant problem with combretastatin A-4, as with other natural products, and a key advance was the synthesis Development of tumor VDAs of phosphate prodrugs, which had the advantage of Although many different potential tumor VDAs have being water soluble and of releasing active drug into been examined at the experimental level, clinical the blood through the action of serum phosphatases. 986 www.future-science.com (2008)future (Epub science ahead group of print) Anticancer potential of tumor vascular disrupting agents Review: Clinical Trial Outcomes This approach led to the prodrug combretastatin A-4 phosphate (fosbretabulin), which showed excellent O H CO activity [25], as well as to several other prodrugs such 3 [26] [27] [28] as OXi4503 , BNC105 and CKD-516 . O H3CO The cellular action of this class of drugs appears H C O OH 3 OCH P to involve effects on actin as well as tubulin, lead-
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