In United States and other developed countries, one of the leading causes of morbidity and mortality is cancer. The estimated number of deaths due to cancer in United States during the year 2007 is 559,650 1. The dilemma caused by cancer brought about the intensive research efforts to come up with treatments and preventive measures to combat this disease. Recognition of the role of angiogenesis in the formation, growth, and metastasis of cancer resulted to the utilization of inhibitors as therapeutic regimen.
Angiogenesis is the process of blood-vessel-formation from already present capillaries. This process is a normal during embryo development for circulatory system formation, in the process of wound healing, and in the uterus during menstruation. The construction of vessels to convey blood that carries water, nutrients, and oxygen is necessary for the continuous nourishment of body cells 1.
Angiogenesis is a significant mechanism in the pathology of various diseases like cancer. The new blood vessels will provide the cancerous cells with oxygen and nutrients that will support its development and serve as vehicle for the cancerous cells to propagate in other areas of the body 2. Therefore, angiogenesis which is usually beneficial to the body in its normal state becomes a vehicle for cancer and adds to the pathological process of the disease in reaching other healthy cells.
Since angiogenesis is essential in the development and metastasis of cancer cells, every aspect of the blood vessel formation are possible targets for cancer therapy. The prevention of angiogenesis to occur deprives the cancerous cells the much needed nutrients and oxygen thus no further growth is possible. It also denies the cancer cells the means to spread or metastasize to other areas of the body. By depriving the cancer cells all the nutrients, water, and oxygen decreases its capacity to spread and eventually leads to the death of these monstrous cells. The objective of angiogenesis associated cancer therapies is to kill the cancerous cells through hindering the creation of new blood vessels3.
Certain chemicals produced by the body regulate the occurrence of angiogenesis. Among these substances that controls angiogenesis are the anti- and pro-angiogenic factors. The antiangiogenic factors or angiogenesis inhibitors are the substances that prevent the occurrence of angiogenesis3. The various known angiogenesis inhibitors include the following: Angioarrestin, Fibronectin fragment, Antiangiogenic antithrombin III, Cartilage-derived inhibitor (CDI) , Heparinases, Human chorionic gonadotropin (hCG), Metalloproteinase inhibitors (TIMPs), Prolactin 16kD fragment, Interferon alpha/beta/gamma, Kringle 5 (plasminogen fragment), and CD59 complement fragment 4 .
History of angiogenesis inhibitor development
More than 30 years ago, the history of angiogenesis inhibitors begun upon the creation of the hypothesis that the blood vessel formation is a significant target for anti-cancer therapeutic drugs. The individuals that first hypothesized that angiogenesis is important in the growth of cancer cells were Dr. Judah Folkman and Dr. Denekamp 5. The said hypothesis received its share of skepticism but little by little interest about it started to build up. However, intensive study on angiogenesis and the substances that will promote or hinder it occurred only after the discovery of the first angiogenesis inhibitor in 1975 by Dr. Henry Brem and Dr. Judah Folkman. Then in 1989 the detection of vascular endothelial growth factor (VEGF) by Dr. Napoleon Ferrera and Dr. Jean Plouet happened. The following years, research and experiments concerning angiogenesis inhibitors continued an in 2004, the first drug for treatment of colorectal cancer, Bevacizumab or Avastin, was approved by the U.S. Food and Drug Administration (FDA) 6.
Advantages and Argument
Angiogenesis inhibitors have various advantages like decreased toxicity potential compared to the traditional chemotherapy, reduced threats of drug resistance than other chemotherapeutic agents, and has various other uses aside from the traditional chemotherapy. The lower toxic attribute of angiogenesis inhibitor drugs enable these substances to be utilized with high safety in long-term therapies. At present, the natural angiogenesis inhibitors are considered as the most safe and least toxic among the drugs against cancer 7.
Despite the various studies that claim results of efficacy of angiogenesis inhibitors in laboratory trials, the capacity of these substances to treat cancer in the real setting remains controversial. The effectiveness of angiogenesis inhibitors like avastin to prolong lives of cancer patients has no solid proof as of press time yet the consumers of these drugs are already burdened by the immense high costs of these drugs. The patients that are suffering from cancer are showing optimism on the capacity of angiogenesis inhibitors to prolong their lives or even cure their cancer because there is no other option left but to hope that angiogenesis inhibitors will work as expected. They are somehow left with no other choice but to patronize the product and hope for the best. The cancer patients are already burdened with the disease and still they have another dilemma – the costly therapeutic drugs 8.
In this paper, I will present an overview of researches that indicate angiogenesis inhibitors as effective treatment for cancer, introduce the angiogenesis categories, and the types of angiogenesis inhibitors including their mechanisms. I will also scrutinize the constraints of angiogenesis inhibitors utilization as treatments to cancerous cells as well as the recent advances in the development of antiangiogenesis drugs.
Mechanisms of angiogenesis
Angiogenesis of cancer cells involves various stages that are catalyzed by the activity of angiogenic promoting factors or any signal emitted by cancer cells and the immune cells of the host. The most abundant angiogenic promoting factor identified is the vascular endothelial growth factor (VEGF). This factor interacts with the receptors located in the transmembrane of blood vessel endothelial cells namely Flt-1 and KDR. The reaction of the VEGF with its receptors catalyzes the successive intercellular signals by increasing the activity of receptor tyrosine kinase. The end result of the cascade of intercellular stimuli is the production of endothelial cells that will create the new blood vessels. It is recognized that the abundance of VEGF expression in a cancer case result to poor prognosis of the disease irrespective of the stage and grade of the cancer. The VEGF is not the only factor that promotes angiogenesis. Other factors are the following: platelet derived growth factor (PDGF), interleukin-8, basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF). The aforementioned other angiogenic promoting factors have individual receptors in which they react to produce an effect in the angiogenesis 9.
The general role of the angiogenesis inhibitors is to prevent the occurrence of blood vessel formation so as to sequester the growth, proliferation, and metastases of the cancer cells. The antiangiogenic drugs react with the pro-angiogenic factors present in the endothelial cells of existing blood vessels that supply the tumor cells. Through the interaction of the angiogenesis inhibitors with the pro-angiogenesis factors the interaction of the pro-angiogenic factors with its ligand will be blocked. The end result of the blockage of the interaction of pro-angiogenic factors and its ligand is the prevention of the catalysis of the endothelial proliferation and new blood vessels formation.
Various approaches of angiogenesis inhibition and approved medicines
All angiogenesis inhibitors can be classified into two categories: the exclusively antiangiogenic and the inclusive antiangiogenic inhibitors. The later aside from their antiangiogenic properties have other functions. Various inclusive antiangiogenic inhibitors as celecoxib and zolendronate were already utilized for other medicinal properties prior to the recognition of their antiangiogenic capacities. Avastin and VEGF-Trap are examples of the exclusively antiangiogenic drugs 10.
Angiogenesis inhibitors that are already utilized in the medical practice have three types. These are: Type I inhibitors – those that obstruct one angiogenic protein; Type II – those that stop the activity of 2-3 angiogenic proteins; and Type III- which has wide coverage of antiangiogenic targets. Avastin® which is an example of Type I neutralizes the VEGF released by cancerous cells. VEGF is the primary angiogenic factor secreted by the cancer cells have an estimated 60% reliability when targeted in antiangiogenic therapy. The type I antiangiogenesis drugs has the capacity to elicit an acquired drug resistance in patients. Through mixing type I antiangiogenic drugs with other angiogenesis inhibitors or other antiangiogenic therapeutic agents the problem of acquired drug resistance will be combated. The type II angiogenic inhibitors include Iressa which blocks cancer cell secretion of VEGF, TGF-alpha, and bFGF. These type II antiangiogenic agents as well can have increased efficacy in combination with other angiogenesis inhibitors. The third type of angiogenesis inhibitors (Type III) has the artificial analogue of fumagillin, the TNP-470 as an example. This drug has the widest anti-cancer capacity among the anti-angiogenesis agents 10.
Avastin® which is a Type I antiangiogenic drug has the generic name bevacizumab. This antiangiogenic drug is manufactured by Genentech Incorporated. The mode of action of Avastin® is binding with VEGF thus preventing the interaction of VEGF with its receptors (KDR and Flt-1) that are located in the surface of endothelial cells. Through the aforementioned mode of action Avastin® will hinder the formation of new blood vessels around cancer cells. The treatment of Avastin® to nude (without thymus) mice with colon cancer manifested decreased microvascular proliferation of cancer cell as well as prevention of the spread of the cancerous cells in the body of the mice11. At present, Avastin® (bevacizumab) is among the leading antiangiogenic drug available in the global market.
Constraints and problems
The discovery and introduction of antiangiogenic drugs are not devoid of problems. Among the primary problems related to angiogenesis inhibitors specifically Avastin® (bevacizumab) is the side effects of the drug on the host. The U.S. Food and Drug Administration warned the consuming public regarding Avastin’s capacity to produce brain hemorrhage conditions and nasal tissues deterioration. This side effect is collectively termed as the brain-capillary leak syndrome which includes the patient experiencing seizures, headaches, blindness, and other dilemmas associated with vision and the nervous system. The rebuttal of Avastin’s manufacturer (Genentech, Inc.) on this issue is that the aforementioned side effects only manifested in 0.1% of the 60,000 treatments done on clinical cases 12.
Another problem that is associated with the treatment of angiogenesis inhibitors like avastin is the expensive cost of these drugs. The price range of Avastin on a monthly basis varying according to the weight and cancer stage is from $4,000 to $9,000 13. This problem on the expensive costs of anti-cancer drugs limits the efficacy of antiangiogenesis drugs to those patients who can afford to sustain the cost during the whole period of the therapy. The governments involve should regulate the pricing of angiogenesis inhibitors because most of the people that are suffering from cancer can not afford the expensive costs of drugs.
The off label administration of angiogenesis inhibitors such as avastin is another problem in the medical industry. Various doctors of the eye have been prescribing Avastin to patients with macular degeneration when the FDA has only approved of avastin to be treatment for cancers. The manufacturer of avastin also tolerated this practice despite the lack of consent by the FDA to dispense drugs for ophthalmic purposes. The effectivity of avastin as treatment to macular degeneration is another additional problem. This drug have not undergone clinical trial for the treatment of macular degeneration thus the claims of ophthalmologists that by restricting the dispensing of avastin to cancer treatments those with eye problems will be deprived of a cheap effective drug has no basis. Before this drug should be used as therapeutic agent for eye problems it needs to undergo the proper clinical trials to prove its efficacy in this aspect and to prevent further problems such as side effects of off label drug administrations 14.
Included in the limitations of avastin are its side effects which can manifest even in normal doses administration of this drug. The severity of the side- effects ranges from mild and temporary to severe and permanent. The aforementioned side effects occurred in 1 percent of the populace that took this drug. The mild side effects of avastin are: changes in taste sensation, dry, scaly skin or changes in skin color, diarrhea, constipation, lack of energy or strength, loss of appetite, mouth sores, unusual pain, nausea or vomiting, and runny nose. The severity of side effects is already high when avastin consumers experience hemorrhages in the nose or gums, alterations in blood or urine test results, increased blood pressure, manifest slow healing wounds, and vision changes occurs 15.
Interactions with other drugs are another constraint of angiogenesis inhibitors. In the case of avastin, a drug to drug interaction occurs when avastin is taken along with irinotecan. People that are taking irinotecan should be cautious enough to consult their doctor before they take avastin. The interaction between the aforementioned medications does not necessarily indicate the avoidance of the usage of both drugs. Consultation with physicians can provide alternatives to manage or prevent the interactions between the two15.
Recent researches and issues
A study conducted evaluating the various angiogenic agents available concluded that Avastin has positive results as a therapy for colorectal and renal cancer cases. The role of angiogenesis inhibitors in treating cancers in said to be further established in the study. This is among the proofs that Avastin like other angiogenesis inhibitors have the capacity to stop the growth and proliferation of cancer cells. The potential of this drug as treatment for advanced cases of cancer is also implied in this study 15.
Recently, the manufacturer of avastin was immensely glad that their wonder drug was able to satisfy the breast cancer study goal. The clinical trials conducted on avastin as treatment for breast cancer involves the combination with another therapeutic agent called docetaxel. The study population was composed of 736 chemotherapy free patients. A two doses trial was conducted and the manufacturers are pleased that statistically significant improvement in the blockage of breast cancer cells growth was observed in comparison to the chemotherapy patient as well as a placebo. This new development of avastin has the potential to increase the market value of the product and Genentech as a whole. It can also serve as FDA’s basis for the approval of avastin as therapeutic agent for breast cancer cases16.
Aside from avastin various angiogenesis inhibitors are undergoing clinical trials to prove its efficacy in treatment of the different types of cancer. These clinical developments are composed of three phases. In phase I the routes of drug administration, method of dosing either single or in combination, and determination of the dose-limiting toxicity (DLT) are explored. A tool that is utilized in the phase I is the contrast-enhanced Dynamic Magnetic Resonance Imaging (DEMRI). This tool enables the assessment of antiangiogenic activity of the drugs. Phase II on the other hand, involves determination of the capability of the angiogenic inhibitors to cause partial or complete tumor death. The phase III involves the combination of angiogenic inhibitors with other therapeutic agents as test of efficacy.
Avastin has undergone all the three phases of clinical development with promising results. The VEGF-trap, a product of the company – Regeneron, which is also a monoclonal antibody that targets the VEGF-A is still in the phase I of clinical development. Other angiogenesis inhibitors that already undergone the phases I to III of the clinical development are: Thalidomide, an inhibitor of endothelial cell proliferation and a product of Grunenthal; and SU54 I6, a receptor tyrosine kinase inhibitor product of Sugen/Pharmacia 18.
We can expect more clinical trials regarding the efficacy of angiogenesis inhibitors such as avastin in the future. Companies that manufacture these products are pioneering in the conduct of such trials so as to establish the value of their products as therapy of cancer – one of the most dreaded disease conditions in the world today. The latest researches on angiogenesis inhibitors are focused on finding the appropriate therapeutic administration and therapeutic dose to elicit efficacy in the blockage of cancer cell growth and proliferation.
SUMMARY AND CONCLUSIONS
This paper reviewed angiogenesis in relation to cancer progression, history of the angiogenesis inhibitors, and the advantages of the utilization of antiangiogenic drugs in the treatment of cancer. It also examined the mechanisms of angiogenesis especially in cancerous cells, and the categories of the antiangiogenesis drugs. Although various constraints and problems are present concerning the angiogenesis inhibitors of these substances, the potential of these substances to solve the growing problem on cancer can not be ignored. The studies that concluded the efficacy of these antiangiogenic agents are significant indicators of the importance of these substances in the future of medicine. Future researches on angiogenesis inhibitors are highly suggested to improve the therapy and prolong the lives of cancer patients.
Angiogenesis inhibitors have great potential as treatment for cancer. However, further studies are needed to be conducted on the utilization of angiogenesis inhibitors in clinical trials involving cancer patients. The focus of future experimental researches should be the methodologies on how to administer these angiogenesis inhibitors in such as way as to have the patients feel that the drugs they are taking are worth their money. Efforts should as well be geared towards the introduction of these drugs to the poor members of the cancer victim populace. This can be done through ensuring that the cancer patients will have no further dilemma on the cost of the drugs, thus, governments of every country should coordinate with the manufacturers to address the problem.
The best method for the treatment whether it is by combination with certain chemotherapeutic agent as well as the effective dosage of the drug needs to be determined. More researches needs to be conducted to establish the efficacy of angiogenesis inhibitors in stopping the growth and metastasis of cancer cells. The means to conquer cancer is already several steps away and humanity should not stop here.
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