Over the past few decades, we’ve seen a revolution in our thinking about cancer, how to overcome it, and, when the disease persists, how to control it over the long term. This revolution stems from the recognition that cancer can’t develop and progress without an adequate blood supply to deliver nutrients and metabolites to the tumor. This means that an expanding vascular network is needed to keep pace with the growing mass of cells.
The overall process, known as neovascularization, refers to various aspects of blood vessel growth. The best studied of these aspects is the generation of new blood vessels from pre-existing vessels, a multifaceted process known as angiogenesis.
As one of the so-called hallmarks of cancer, angiogenesis offers a promising angle on slowing tumor progression and preventing relapses after surgery and other treatments. In some cases, blocking this process could also enhance the effectiveness of mainstream chemotherapy and radiotherapy.
To understand why angiogenesis has garnered so much research attention, it’s helpful to consider cancer at its incipient phases of growth. Every cancer starts out as a microscopic nest of abnormal cells that’s devoid of any blood supply. This cluster grows to about one or two cubic millimeters in size, roughly the size of the tip of a ballpoint pen. At this point, oxygen and nutrient diffusion become limited, and the abnormal cells may either die or simply remain in a dormant state.
In order for the tumor’s diameter to increase further, neovascularization is required. This occurs with the help of growth factors (angiogenic signals) that may be produced in response to inflammation, such as from surgery or an infection. Also, the more oxygen-deprived a cluster of cancer cells is at the center of the mass, the more growth factors are produced in that area to stimulate capillary growth.
The sudden surge in vascular growth that takes place in response to angiogenic signals is referred to as the angiogenic switch, the point at which new blood vessels begin to form in and around the microscopic cluster of cells. The expanding network of capillaries enables the mass of mutated cells to grow into a detectable cancer. And only after the vascular network forms can the tumor’s growth rate begin to increase exponentially. Like a racecar that has been idling and then accelerates onto a super highway, angiogenesis enables tumor growth to literally take off.
Angiogenesis has been implicated not only in tumor growth, but also the deadly process of metastasis. Why would this be the case? Keep in mind that blood vessels not only provide the tumor with nutrients, but also give the cancer access to the entire bloodstream. This is an open invitation for the spreading of cancer, or metastasis, to take place. For these reasons, anything that interferes with angiogenesis could be a tremendous boon to cancer therapy.
Ever since Judah Folkman’s pioneering research on tumor angiogenesis in the early 1970s, anti-angiogenic therapy has been regarded as a promising cancer treatment, perhaps best used in tandem with surgery, radiation and chemotherapy. And yet, today’s clinically approved anti-angiogenic drugs are only effective for a minority of cancer patients and malignancies.
This fact has dampened much of the early optimism for using anti-angiogenesis as an effective cancer therapy. More recently, however, hopes for targeting tumor angiogenesis have been renewed with the realization that plant-derived substances and other natural medicines could offer a more comprehensive approach to the problem.
Overcoming the Challenges of Targeting Tumor Angiogenesis
To understand how a natural medicine approach could prove effective, it’s helpful to look more closely at the reasons the drug-based approach has fallen short. The most serious limitation concerns the fact that tumor cells can mutate sufficiently to circumvent the effects of anti-angiogenic drugs. Thus, while many people show a good initial response, they later develop resistance to the drugs.
The resistance issue first reared its head with Avastin (generic name: bevacizumab), one of the most widely used of anti-angiogenesis drugs. Avastin specifically targets VEGF (vascular endothelial growth factor), which is thought to be of paramount importance for the control of tumor angiogenesis. Nevertheless, many tumors inevitably develop resistance to Avastin, resulting in a decline in the agent’s effectiveness over time. Multiple molecular pathways are known to support angiogenesis, and targeting multiple pathways at once may be needed to overcome the problem of treatment resistance.
Another major drawback is that some of these drugs are quite toxic. For example, common side effects of Avastin include generalized weakness, nausea, vomiting, poor appetite, constipation, pain (mostly abdominal pain), upper respiratory infection, and low white blood cell count, which can increase the risk of infection. Less commonly, patients taking Avastin may develop a perforation in the stomach or intestine. Cuts or surgical wounds can be slow to heal or may not fully heal, which is why surgery must be postponed for a few days whenever taking Avastin.
Given these drawbacks and limitations, integrative medicine practitioners have been exploring the use of natural, non-toxic agents that can be taken as supplements on a daily basis. It is hoped that this approach will be able to overcome the limitations of mainstream therapy. As we saw with the Avastin example, however, finding the most critical molecular targets could prove quite challenging as each tumor and its microenvironment consists of many different cell types, some of which are the host’s own immune cells. Moreover, tumors are genetically unstable populations of cells, and this instability results in a steady increase in the number of different angiogenic factors produced as the cancer evolves to an advanced stage.
For these reasons, the optimal anti-angiogenic supplement strategy should include a mixture of non-toxic natural compounds that, in turn, impact multiple mechanisms, including those involved in angiogenesis and much more. Below are three key principles for using natural medicines or supplements supplements (herbal, nutritional, nutraceutical) to block or control angiogenesis:
- The supplements should be non-toxic or have a wide margin of safety, enabling daily use in order to have a more frequent or constant protective impact, thus targeting the more sustained angiogenesis that drives cancer’s growth and spread.
- To reduce the chances of resistance, the supplements should be capable of modulating as many angiogenic pathways as possible, including, for example, endothelial cell migration, hypoxia, lymphangiogenesis, and tumor-promoting fibroblasts and inflammation.
- The supplements should be able to impact multiple cancer-promoting pathways other than the angiogenic pathways, such as cyclooxygenase-2 (COX-2), epidermal growth factor receptor, the nuclear factor kappa-B transcription factor, the protein kinases, and other pathways.
With these principles in mind, we can now identify biological response modifiers in the natural world that may play a valuable role in cancer control and prevention, as well as possibly serving as adjuncts to mainstream treatment. It turns out that a large group of natural compounds, also referred to as either nutraceuticals or pharmaconutrients, exhibits antiangiogenic effects as well as other types of anticancer activities. The remainder of this article provides a concise overview of ten of the most promising of these natural products.
Natural Products for Blocking Angiogenesis
Most of the published clinical trials of anti-angiogenic cancer therapy have reported improved response rates and progression-free survival (lowering recurrence rates), but no increase in overall survival compared to standard chemotherapy alone. But what if the anti-angiogenic therapy was non-toxic and could be received on an ongoing basis? And what if multiple anti-angiogenic agents could be used concurrently and implemented in much earlier stages of the cancer, rather than waiting until the disease had become more advanced and aggressive?
Specific nutritional and botanical supplements are thought to play a role in the prevention and control of cancer by modulating angiogenesis. These natural products include the following: curcumin, resveratrol, green tea catechins, silybin, reishi mushroom, omega-3 fatty acids, scutellaria, ashwagandha, diindolylmethane, and convolvulus. A number of these substances are capable of inhibiting tumor angiogenesis by blocking VEGF and many other pathways at the same time. What follows is a brief survey of some of these effects.
1) Curcumin. The East Indian spice turmeric is a rich source of the polyphenol curcumin. This supplement has dozens of well-documented anti-cancer effects, mainly attributed to its impact on the immune response, antioxidant response, programmed cell death (apoptosis), cell cycle regulation and tumor progression. Curcumin inhibits angiogenesis in a huge variety of cancer cells, through the modulation of many cell-signalling pathways. For example, curcumin was shown to suppress VEGF secretion from tumors while also significantly improving the survival of mice with VEGF-expressing tumors, as reported in the 14 August 2014 issue of Oncotarget. Although this supplement has extremely poor bioavailability, this problem is readily solved by using either a phytosome or liposome form of curcumin. Alternatively, combining curcumin with biopiperine (from black pepper) boosts the supplement’s bioavailability by some 2000 percent.
2) Resveratrol. Found in grapes, berries, chocolate, and some nuts, resveratrol is a polyphenol known mainly for its antioxidant and anti-inflammatory properties, as well as its ability to promote cardiovascular health. Resveratrol has been shown to decrease glucose consumption in cancer cell lines while also inhibiting VEGF expression, as reported in the October 2013 issue of Human & Experimental Toxicology. Thus, part of the agent’s anti-cancer impact entails a coupling of anti-angiogenesis with a calorie-restricting pathway. In principle, the latter effect could be further exploited by following a low-calorie diet. The anti-angiogenic effects have been studied mostly in brain and mammary (breast) tumors. Because of resveratrol’s low bioavailability, it is best to use the supplement in either phytosome or liposome form.
3) Green tea catechins. Green tea consumption has been linked with lower rates of cancer and heart disease. A specific group of green tea polyphenols called catechins are though to account for most of the tea’s anti-cancer impact. The main compound of interest is EGCG, a major green tea catechin that blocks VEGF and other aspects of tumor angiogenesis. Research suggests that green tea extract may help prevent tumor recurrences, possibly due to inhibition of matrix metalloproteinases (MMP-2 and MMP-9) and epidermal growth factor receptor (EGFR)-related pathways. A study conducted at the University of Texas Health Science Center at Tyler (TX) indicates that EGCG inhibits pancreatic tumor growth, invasion, metastasis and angiogenesis, as reported in the January 2008 issue of Frontiers in Bioscience.
4) Silybin. Silybin, also known as Silibinin, is the primary active component of silymarin, a standardized extract of milk thistle seeds. In animal studies, silybin’s tumor-killing effects have been shown to be mediated through inhibition of both tumor cell proliferation and angiogenesis, as reported in the January 2013 issue of Nutrition and Cancer. Classified as a flavonolignan, silybin is also known to target various elements of the tumor microenvironment, thus rendering it more effective for preventing, retarding, or reversing the cancer process. When taken as a phytosome, Silybin shows a nearly five-fold increase in absorption compared to standard milk thistle extracts.
5) Scutellaria. Scutellaria baicalensis, commonly known as Chinese skullcap (and sometimes called wogonin), is a frequent component of Traditional Chinese Medicine protocols for cancer therapy. This herb has been shown to inhibit both angiogenesis and lymphangiogenesis, the formation of lymphatic vessels from pre-existing lymphatic vessels, an angiogenic process that also fuels tumor growth. The anti-tumor and anti-metastatic actions of scutellaria may be linked with inhibition of VEGF-induced lymphangiogenesis, as reported in the April 2012 issue of PloS One. Some research suggests that scutellaria may have efficacy against advanced-stage prostate cancer. Scutellaria contains the anti-inflammatory compounds baicalin and baicalein, which together may account for most of its anti-cancer impact.
6) Reishi. Reishi mushroom (scientific name: Ganoderma lucidum) has long been regarded as among the most valuable medicines in Traditional Chinese Medicine. Inhibition of angiogenesis is among the anti-tumor mechanisms of reishi, and laboratory studies have demonstrated effects against tumor growth, invasion, and metastasis. When used in tandem with conventional treatments, improvements in immunity and quality of life have been noted in advanced-stage cancer patients. The beta-glucan compounds in reishi mushroom are known to activate dendritic cells (DCs), which in turn induce the activation of T cells against cancer. Most of the anti-angiogenic and anti-tumor effects are attributed to the triterpenoid compounds in reishi, as reported in the August 2013 issue of Expert Opinion in Investigational Drugs.
7) Omega-3s. Omega-3 fatty acids are highly unsaturated fatty acids found in coldwater fish, algae, flaxseed and various nuts. The U.S. food supply is largely deficient in these essential fatty acids, and yet there is ample evidence that these nutrients are critical to the control of inflammation and a host of cancer-related processes. Much research has shown that omega-3s can inhibit the production of VEGF, platelet-derived growth factor (PDGF), and other key angiogenic mediators, as reported in the August 2009 European Journal of Cancer. The highest quality omega-3 products are processed under oxygen-free conditions and use molecular distillation to remove all impurities.
8) Diindolylmethane. Diindolylmethane, or DIM, is a metabolite of indole–3–carbinol (I3C), and both compounds exist naturally in cruciferous vegetables like kale and broccoli. Upon contact with gastric acid in the stomach, I3C is converted to a number of active compounds, mainly DIM. DIM has been shown to stimulate a number of anti-cancer processes and to increase the urinary excretion of toxic estrogen metabolites. In laboratory studies, DIM was shown to block tumor angiogenesis in animal models for both breast and prostate cancers. At least part of DIM’s anti-angiogenic effect may entail inhibition of the VEGF receptor, as reported in the 5 May 2015 issue of Chemico-Biological Interactions.
9) Ashwagandha. Ashwagandha (Withania somnifera) is a well-known adaptogenic herb that helps counteract the effects of stress and supports cardiovascular, immune, cognitive and joint comfort and functioning. Research has shown that ashwagandha inhibits inflammatory processes that support the growth and spread of malignant tumors. A large number of withanolides have been isolated from the roots and leaves of this herb. Amongst these compounds, Withaferin A, a potent VEGF inhibitor and one of the most bioactive constituents of Ashwagandha, has been shown to inhibit tumor cell growth, metastasis and angiogenesis. In one animal study, withaferin A exerted strong anti-angiogenic activity at doses that were 500-fold lower than those previously reported to block tumor growth, as reported in the February 2004 issue of Angiogenesis. Ashwagandha is widely used as a dietary supplement for reducing stress and bolstering resilience.
10) Convolvulus. Convolvulus arvensis (CA) is a species of bindweed in the morning glory family and is native to Europe and Asia. Chemical analyses of the extracts from this plant have shown a mixture of polysaccharides and proteins, including proteoglycans that have been shown to inhibit tumor growth and angiogenesis. In a mouse study of fibrosarcoma, high doses of CA inhibited tumor growth by 70%, and the tumor growth inhibition occurred at non-toxic doses. In other studies, significant anti-angiogenic activities were observed with CA, as reported in the December 2014 Journal of Complementary and Integrative Medicine.
CA is the sole active ingredient in a supplement known as C-Statin. In a small pilot clinical study, C-Statin was combined with another product called Imm-Kine, which contains a beta-1,3-glucan derived from baker’s yeast (Saccharomyces cerevisiae) and a bacterial cell wall extract from Lactobacillus fermentum. The combined effect of C-Statin and Imm-Kine on blood plasma VEGF concentrations was examined in 10 people with advanced-stage metastatic cancer. The study found a statistically significant reduction in VEGF concentrations over time among these patients.
Although this study was too small to provide meaningful data for an impact on survival, it is among the very few clinical studies to have examined the effects of natural products on tumor angiogenesis. Moreover, several well-documented case reports have indicated that the C-Statin/Imm-Kine combo may have had a favorable impact on survival in Stage IV cancers of the breast, ovaries, colon, and pancreas. Of course, well-designed clinical trials will be needed to put such observations to the test.
Supplementing the Anti-Cancer Lifestyle
The anti-angiogenic supplements described in this article have been shown to help prevent tumor growth and spread. Evidence for their anti-angiogenic activities stems mainly from animal and cell culture studies. Nevertheless, these natural products are already in widespread use among humans because they display a wide margin of safety, are readily available as dietary supplements, and tend to be inexpensive when compared to pharmaceuticals.
Dr. Keith Block, medical director of the Block Center for Integrative Cancer Treatment in Skokie, Illinois, has proposed a multi-agent strategy for cancer management and long-term disease control, using an approach he refers to as multifocal angiostatic therapy (MAT). According to Block and his colleague Mark McCarty, the MAT strategy “seeks to impede cancer-induced angiogenesis by addressing multiple targets that regulate the angiogenic capacity of a cancer and/or the angiogenic responsiveness of endothelial cells, using measures that are preferentially, but not exclusively, nutraceutical.”
The MAT supplement regimen includes a number of supplements (including several addressed in this article), along with a low-fat, high-fiber vegan diet, exercise training, and, where feasible, the drug tetrathiomolybdate and a salicylate. Since angiogenesis is a process relatively restricted to the growing tumor, Dr. Block’s team believes the MAT regimen could provide an attractive, non-toxic approach to the prevention and control of malignant disease.
In conclusion, natural products for blocking tumor angiogenesis have the advantage of a wide margin of safety and relatively low cost, enabling daily supplementation and thus the potential for a more sustained impact on cancer prevention and management. Supplement strategies for curbing angiogenesis may ultimately prove to be more effective than pharmaceutical strategies, though controlled studies comparing these two vastly different paradigms for cancer control are unlikely in the near future.
M. Nathaniel Mead, MSc, is a nutritional oncology research consultant for several integrative medicine clinics in the Research Triangle of North Carolina. He can be reached at: email@example.com
Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, Generali D, Nagaraju GP, et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 2015;35 Suppl:S224-43.
Sagar SM, Yance D, Wong RK. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 2. Curr Oncol. 2006;13(3):99-107
Granci V, Dupertuis YM, Pichard C. Angiogenesis as a potential target of pharmaconutrients in cancer therapy. Curr Opin Clin Nutr Metab Care. 2010;13(4):417-22
Kumar G, Mittal S, Sak K, Tuli HS. Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives. Life Sci. 2016;148:313-28.
Fu Z, Chen X, Guan S,Yan Y5, Lin H, Hua ZC. Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway. Oncotarget. 2015;6(23):19469-82.
Bimonte S, Barbieri A, Palma G, Luciano A, Rea D, Arra C. Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer. Biomed Res Int. 2013;2013:810423.
Fouad MA, Agha AM, Merzabani MM, Shouman SA. Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: calorie restriction is the force to the cytotoxicity. Hum Exp Toxicol. 2013;32(10):1067-80.
Chen JC, Chen Y, Lin JH, Wu JM, Tseng SH. Resveratrol suppresses angiogenesis in gliomas: evaluation by color Doppler ultrasound. Anticancer Res. 2006 Mar-Apr;26(2A):1237-45.
Garvin S, Ollinger K, Dabrosin C. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. 2006 Jan 8;231(1):113-22.
Green Tea Catechins
Shankar S, Ganapathy S, Hingorani SR, Srivastava RK. EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front Biosci. 2008;13:440-52.
Gu JW, Makey KL, Tucker KB, Chinchar E, Mao X, Pei I, Thomas EY, Miele L. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression. Vasc Cell. 2013;5(1):9. doi: 10.1186/2045-824X-5-9.
Deep G, Agarwal R. Targeting tumor microenvironment with silibinin: promise and potential for a translational cancer chemopreventive strategy. Curr Cancer Drug Targets. 2013;13(5):486-99
Mateen S, Raina K, Agarwal R. Chemopreventive and anti-cancer efficacy of silibinin against growth and progression of lung cancer. Nutr Cancer. 2013;65 Suppl 1:3-11.
Deep G, Gangar SC, Rajamanickam S, Raina K, Gu M, Agarwal C, Oberlies NH, Agarwal R. Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling. PLoS One. 2012;7(4):e34630.
Kimura Y, Sumiyoshi M. Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Phytomedicine. 2013;20(3-4):328-36.
Song X, Yao J, Wang F, Zhou M, Zhou Y, Wang H, Wei L, Zhao L, Li Z, Lu N, Guo Q. Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein. Toxicol Appl Pharmacol. 2013;271(2):144-55.
Liu JJ, Huang TS, Cheng WF, Lu FJ. Baicalein and baicalin are potent inhibitors of angiogenesis: Inhibition of endothelial cell proliferation, migration and differentiation. Int J Cancer. 2003;106(4):559-65.
Cao QZ, Lin ZB. Ganoderma lucidum polysaccharides peptide inhibits the growth of vascular endothelial cell and the induction of VEGF in human lung cancer cell. Life Sci. 2006;78(13):1457-63.
Stanley G, Harvey K, Slivova V, Jiang J, Sliva D. Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells. Biochem Biophys Res Commun. 2005;330(1):46-52.
Wu GS, Guo JJ, Bao JL, Li XW, Chen XP, Lu JJ, Wang YT. Anti-cancer properties of triterpenoids isolated from Ganoderma lucidum - a review. Expert Opin Investig Drugs. 2013;22(8):981-92
Wang W, Zhu J, Lyu F, Panigrahy D, Ferrara KW, Hammock B, Zhang G. ω-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:13-20
Zhang G, Panigrahy D, Mahakian LM, Yang J, Liu JY, Stephen Lee KS, Wettersten HI, Ulu A, Hu X, Tam S, Hwang SH, Ingham ES, Kieran MW, Weiss RH, Ferrara KW, Hammock BD. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6530-5.
Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W, Dennison A. The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer. 2009;45(12):2077-86
Nayak D, Amin H, Rah B, Ur Rasool R, Sharma D, Gupta AP, Kushwaha M, Mukherjee D, Goswami A. A therapeutically relevant, 3,3'-diindolylmethane derivative NGD16 attenuates angiogenesis by targeting glucose regulated protein, 78kDa (GRP78). Chem Biol Interact. 2015;232:58-67.
Kong D, Banerjee S, Huang W, Li Y, Wang Z, Kim HR, Sarkar FH. Mammalian target of rapamycin repression by 3,3'-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells. Cancer Res. 2008;68(6):1927-34.
Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res. 2007;67(7):3310-9.
Saha S, Islam MK, Shilpi JA, Hasan S. Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A. In Silico Pharmacol. 2013;1:11.
Vanden Berghe W, Sabbe L, Kaileh M, Haegeman G, Heyninck K. Molecular insight in the multifunctional activities of Withaferin A. Biochem Pharmacol. 2012;84(10):1282-91.
Mohan R, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner BP, Rougas J, Pribluda VS. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis. 2004;7(2):115-22.
Convolvulus plus Beta-Glucan
Mahmoudi M, Zamani Taghizadeh Rabe S, Zamani Taghizadeh Rabe S, Emami SA. A study to investigate the biological activity of proteoglycan mixture extract from Convolvulus arvensis. J Complement Integr Med. 2014;11(4):265-72.
Meng XL, Riordan NH, Casciari JJ, Zhu Y, Zhong J, González MJ, Miranda-Massari JR, Riordan HD. Effects of a high molecular mass Convolvulus arvensis extract on tumor growth and angiogenesis. P R Health Sci J. 2002;21(4):323-8
Torello CO, Souza-Queiroz J, Queiroz ML. β-1,3-Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour-bearing mice. Clin Exp Pharmacol Physiol. 2012;39(3):209-17.
Integrative Medicine Strategy
McCarty MF, Block KI. Multifocal angiostatic therapy: an update. Integr Cancer Ther. 2005;4(4):301-14