**2. Anti-angiogenesis therapy**

#### **2.1 Properties of anti-angiogenesis therapy**

Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. It is a sequence of events that is fundamental to a broad array of physiological processes occurring in our body, including embryogenesis, development, the menstrual cycle and wound healing. Yet, it is also linked to many pathological situations such as cancer, chronic inflammation, ischemic diseases and endometriosis development (Griffioen *et al.*, 2000). In general, the turnover of capillary endothelial cells is extremely slow in physiological angiogenesis. However, in the normal endometrium and in tumors, the turnover rate is altered to a more rapid state in promoting angiogenesis. Angiogenesis involve activation of angiogenic factors, dissolution of basement membranes by proteases derived from vascular endothelial cells, migration and proliferation of the endothelial cells, and capillary tube formation. And various angiogenic factors are needed to regulate each step (Table 2).

Under normal physiological conditions, angiogenesis is well controlled by the local balance between endogenous angiogenesis stimulators and angiogenesis inhibitors, although the regulatory mechanism is still not clear. During wound healing, the expression of vascular endothelial growth factor (VEGF), one of the most potent angiogenic stimulators, is significantly upregulated to promote wound healing by restoring blood flow to the injured tissues. As wound healing resolves, the expression of VEGF is downregulated and most angiogenic capillaries regress, resulting in a residual normal vascularity (Tonnesen *et al.*, 2000). Other studies indicates that a number of endogenous angiogenic inhibitors are present in the normal retina to balance the stimulatory effect of VEGF in the regulation of angiogenesis and vascular permeability (Ma *et al.*, 2005). These studies suggest that endogenous angiogenic inhibitors can be used to balance the effect of angiogenic stimulators. Anti-angiogenic therapies have already been experimentally proven to be effective in preventing metastasis and shrinking the established experimental tumors to be formed (Camp-Sorrell, 2003). Angiogenesis therapeutic approaches can be divided into two major classes: (1) interference with the process of neovascularization and (2) directly destroying immature blood vessels.

Green Tea for Endometriosis 285

growth, endometriosis is shown to be highly dependent on angiogenesis, which makes the

Most of the studies on the role of angiogenesis in endometriosis have been performed in animal models so far. Still, more experiments are urgently needed to distinguish the effect of angiogenesis inhibitors on physiological and pathological angiogenesis. Like in a recently published study, the effect of angiogenesis inhibition was studied in nude mice. VEGF-A inhibitors were administered immediately after implantation of cultured human endometrium fragments (Hull *et al.*, 2003). The results showed impaired lesion formation, which concluded that angiostatic agents may be effective in the treatment of endometriosis. And recently, encouraging results have been achieved with the use of Avastin, a humanized anti-VEGF antibody, on cancer. This approach of neutralizing VEGF provided the first proof of concept that anti-angiogenesis is applicable in humans (Ferrara, 2002; McCarthy, 2003). Yet, it still needs clinical trial to make a more concrete result on the anti-angiogenesis effect. With prior to clinical testing to commence, the optimal mode of delivery and the best indication of antiangiogenic therapy would still need to be determined. However, the encouraging results of some anti-angiogenic drugs and the pressing need for new therapeutic approaches make angiogenesis an attractive novel target for the treatment of patients with endometriosis.

The limitation of anti-angiogenesis therapy is that the patient's immune system may be compromised (Calabrese *et al.*, 2000). This would make the patient more susceptible to infection and delay wounds healing. In addition, patients may experience reproductive problems and damage to the fetus, if the patient was pregnant while taking the antiangiogenic drug. Other research has reported such therapy can enhance heart problems, elevating blood pressure and bleeding or blood clots could increase. Since angiogenesis inhibitor therapy is still under investigation, the definite possible complications and side

Tea (*Camellia sinensis*) is an aromatic beverage prepared from boiling or simmering of cured leaves. Apart from water, tea is one of the most popular consumed beverages worldwide, with a consumption of 120mL/day/capita (Graham, 1992). Of the different varieties of tea, the most commonly found on the market are white, green, oolong and black tea. And over the last few decades, green tea has been subjected to many scientific and medical studies on

achievements in the field of cancer research applicable to endometriosis.

**2.3 Limitations** 

effects are still unknown.

**3.1 Properties of green tea** 

Anti-aging Anti-bacterial Anti-inflammatory Anti-angiogenic Anti-cancer Lowering blood fat

**3. Green tea and its clinical values** 

its potential health beneficial effects (Table 3).

Prevent tooth decay and clear bad breath

Enhanced skin whitening Table 3. Benefits of green tea

Interleukin-1 Interleukin-6 Interleukin-8 Epidermal growth factor Basic fibroblast growth factors Insulin-like growth factors Platelet-derived growth factor Platelet-derived endothelial cell growth factor Vascular endothelial growth factor Endometriosis protein-I Ovarian steroids Estradiol Angiogenin Proliferin Pleiotropin Tumor necrosis factor-α Hepatocyte growth factor Transforming growth factor -α and -β Placenta growth factor

Table 2. Angiogenic factors in endometriosis

Although they may not necessarily directly kill tumor cells, angiogenesis inhibitors significantly enhance the efficacy of standard chemotherapy and radiation therapy by inhibiting tumor growth and tumor metastasis. Therefore, this type of therapy may need to be administered over a long period of time. In the normal healthy body, the process of angiogenesis is dormant and the angiogenesis switch is kept "off" with inhibitors being dominant over stimulators. Since anti-angiogenesis therapy is a targeted therapy aimed specifically at the angiogenic stimulators and the angiogenic microvascular endothelial cells, anti-angiogenesis therapy usually produces only mild side effects and is less toxic to most healthy cells. But as physiological angiogenesis is important in wound healing and reproduction, bleeding, blood clotting, heart function, the immune system, and the reproductive system, the unknown consequences on long-term treatment with antiangiogenic agents would still be a great concern (Board *et al.*, 2006; Cabebe *et al.*, 2007).

#### **2.2 Anti-angiogenesis potentials for endometriosis**

To date, endometriosis is often treated by hormonal medication, which aims at achieving a hypoestrogenic state. However, hormonal therapy would only suppress the symptoms associated with endometriosis, but not eradicating the ectopic implant. Moreover, significant side effects hinder the continuation of treatment (Saltiel *et al.*, 1991). Long-term hormonal therapy, therefore, is not an attractive option. Alternatively, endometriosis can also be treated surgically. Conservative surgery consists of ablation of endometriosis lesions, resulting in pain relief, but high symptoms recurrence has been reported in a majority of patients (Vercellini *et al.*, 2009). While definitive surgery includes removal of uterus, with or without ovaries, giving more permanent symptom relief, this therapy would result in the end of reproductive life. Therefore, an effective therapeutic agent for endometriosis would be a compound that not only prevents the development of endometriosis lesions, but would also be effective against the growth of established lesions. In cancer, endothelial cells have been shown to play a pivotal role in tumor cell survival and growth. In analogy with tumor

Although they may not necessarily directly kill tumor cells, angiogenesis inhibitors significantly enhance the efficacy of standard chemotherapy and radiation therapy by inhibiting tumor growth and tumor metastasis. Therefore, this type of therapy may need to be administered over a long period of time. In the normal healthy body, the process of angiogenesis is dormant and the angiogenesis switch is kept "off" with inhibitors being dominant over stimulators. Since anti-angiogenesis therapy is a targeted therapy aimed specifically at the angiogenic stimulators and the angiogenic microvascular endothelial cells, anti-angiogenesis therapy usually produces only mild side effects and is less toxic to most healthy cells. But as physiological angiogenesis is important in wound healing and reproduction, bleeding, blood clotting, heart function, the immune system, and the reproductive system, the unknown consequences on long-term treatment with antiangiogenic agents would still be a great concern (Board *et al.*, 2006; Cabebe *et al.*, 2007).

To date, endometriosis is often treated by hormonal medication, which aims at achieving a hypoestrogenic state. However, hormonal therapy would only suppress the symptoms associated with endometriosis, but not eradicating the ectopic implant. Moreover, significant side effects hinder the continuation of treatment (Saltiel *et al.*, 1991). Long-term hormonal therapy, therefore, is not an attractive option. Alternatively, endometriosis can also be treated surgically. Conservative surgery consists of ablation of endometriosis lesions, resulting in pain relief, but high symptoms recurrence has been reported in a majority of patients (Vercellini *et al.*, 2009). While definitive surgery includes removal of uterus, with or without ovaries, giving more permanent symptom relief, this therapy would result in the end of reproductive life. Therefore, an effective therapeutic agent for endometriosis would be a compound that not only prevents the development of endometriosis lesions, but would also be effective against the growth of established lesions. In cancer, endothelial cells have been shown to play a pivotal role in tumor cell survival and growth. In analogy with tumor

Interleukin-1 Interleukin-6 Interleukin-8

Epidermal growth factor Basic fibroblast growth factors Insulin-like growth factors Platelet-derived growth factor

Endometriosis protein-I Ovarian steroids Estradiol Angiogenin Proliferin Pleiotropin

Tumor necrosis factor-α Hepatocyte growth factor

Placenta growth factor

Platelet-derived endothelial cell growth factor

Vascular endothelial growth factor

Transforming growth factor -α and -β

Table 2. Angiogenic factors in endometriosis

**2.2 Anti-angiogenesis potentials for endometriosis** 

growth, endometriosis is shown to be highly dependent on angiogenesis, which makes the achievements in the field of cancer research applicable to endometriosis.

Most of the studies on the role of angiogenesis in endometriosis have been performed in animal models so far. Still, more experiments are urgently needed to distinguish the effect of angiogenesis inhibitors on physiological and pathological angiogenesis. Like in a recently published study, the effect of angiogenesis inhibition was studied in nude mice. VEGF-A inhibitors were administered immediately after implantation of cultured human endometrium fragments (Hull *et al.*, 2003). The results showed impaired lesion formation, which concluded that angiostatic agents may be effective in the treatment of endometriosis. And recently, encouraging results have been achieved with the use of Avastin, a humanized anti-VEGF antibody, on cancer. This approach of neutralizing VEGF provided the first proof of concept that anti-angiogenesis is applicable in humans (Ferrara, 2002; McCarthy, 2003). Yet, it still needs clinical trial to make a more concrete result on the anti-angiogenesis effect. With prior to clinical testing to commence, the optimal mode of delivery and the best indication of antiangiogenic therapy would still need to be determined. However, the encouraging results of some anti-angiogenic drugs and the pressing need for new therapeutic approaches make angiogenesis an attractive novel target for the treatment of patients with endometriosis.

#### **2.3 Limitations**

The limitation of anti-angiogenesis therapy is that the patient's immune system may be compromised (Calabrese *et al.*, 2000). This would make the patient more susceptible to infection and delay wounds healing. In addition, patients may experience reproductive problems and damage to the fetus, if the patient was pregnant while taking the antiangiogenic drug. Other research has reported such therapy can enhance heart problems, elevating blood pressure and bleeding or blood clots could increase. Since angiogenesis inhibitor therapy is still under investigation, the definite possible complications and side effects are still unknown.
