Chinese Journal of Cancer

窑Review窑 

Antiangiogenic therapy: a novel approach to overcome tumor hypoxia  Fang Peng 1,2 , Ming Chen 1,2  1 

State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510060, P. R. China;  2  Department of Radiation Oncology, 

Sun Yat­sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China

揖Abstract铱

Key words: 

Hypoxia is a common phenomenon in solid tumors,  which can reduce the sensitivity of tumor cells to  radiotherapy and chemotherapy and, thus, is an important  factor affecting cancer therapy. In many tumors, including  cervical cancer, head and neck cancer, and soft tissue  sarcoma, the more severe hypoxia usually indicates the  worse prognosis. Since over 50 years ago when  Thomlinson and Gray found the resistance of hypoxic cells  to radiation therapy, researchers have been trying to solve  the problem of tumor hypoxia. Strategies to overcome tumor  hypoxia include: (1) increasing the oxygen level within the 

Correspondence to: Ming Chen; Tel: +86­20­61283621;  Fax: +86­20­61283621; Email: [email protected]  This paper was translated from Chinese into English  by  Translation and edited by Wei Liu. 

Medical 

Received: 2009­10­10; Accepted: 2010­06­09  Grants: National Natural Science Foundation of China (No.30872974);  Simcere Pharmaceutical Group Foundation 

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tumor (high­pressure oxygen inhalation, increasing  hemoglobin level, application of nicotinamide, etc.); (2)  elevating blood flow within the tumor; (3) applying hypoxic  cell sensitizers; (4) unequal fractionation irradiation therapy;  (5) applying biological reducing agents; (6) microwave and  thermotherapy; (7) gene therapy; and so on. However, the  clinical applications of the above methods to overcome  tumor hypoxia are unsatisfied. Tumor hypoxia remains an  enormous obstacle in cancer therapy.  Oxygen is supplied via the blood vessels and the  distance of oxygen diffusion from the capillary vessels is  only 100­200 滋m.   The abnormality of tumor blood vessels  (high disorder, tortuousness, swelling, and excessive  branching) leads to chaos of blood flow, hypoxia, and  accumulation of acidic materials. Researches on tumor  vascular pathology have resulted in antiangiogenic drugs for  cancer therapy. The potential advantages of antiangiogenic  drugs over conventional chemotherapy include: (1) the  targets of antiangiogenic drugs are tumor blood vessels,  which makes the drug delivery easy and a higher level of  drug accumulation at the target site; (2) antiangiogenic  drugs target the newly generated blood vessels, which have  715

Chinese Journal of Cancer  negligible toxicity on normal tissues; (3) gene expression in  vascular endothelial cells is relatively stable, which can  rarely induce drug resistance; (4) the angiogenesis­  dependent growth is a common characteristic of all tumors,  which will make antiangiogenesis a broad­spectrum therapy;  (5) antiangiogenesis has specific mechanisms and can  combine with other therapies. However, antiangiogenic  drugs also have some limitations: (1) because of the slow  onset, patients need continuous and long medication; (2)  antiangiogenic drugs have no effect on small non­vascular  lesions; (3) redundancy of signaling pathways can  undermine the efficacy of antiangiogenic drugs; (4)  antiangiogenic drugs can not ultimately eliminate cancer  stem cells, which stay in a quiescent state and resist  cytotoxicity of antiangiogenesis therapy. These  characteristics destine antiangiogenesis a low efficiency  when used alone. One strategy to address these issues is  to combine antiangiogenic therapy with other conventional  therapies (radiotherapy and chemotherapy), which can  target tumor blood vessels and tumor cells concurrently and  ultimately kill tumor tissues. Massive studies have confirmed  that single use of antiangiogenic drugs can not bring  long­term survival benefit, while combination of  antiangiogenesis and radiotherapy can often produce  additive or synergistic antitumor effect.  In recent years, many studies indicate that radiation  therapy combined with antiangiogenic drugs can improve  efficacy [1] . The mechanisms of this synergistic effect are very  complex, involving tumor cells themselves and tumor  microenvironment (including oxygen supply, matrix, and  blood vessels). Clarification of these mechanisms can guide  the clinical development of therapeutic protocols combining  antiangiogenesis and radiation. This review covers  pre­clinical and clinical research findings, and proposes that  antiangiogenic therapy is a new strategy to overcome tumor  hypoxia and improve the effect of radiation therapy. The  combination of angiogenic therapy and radiation therapy  may be a new combined therapy for cancer [2] . 

Oxygen plays an important role in the generation of  free radicals by ionizing radiation and subsequent radiation  damage and functions as a key mediator to stabilize  radiation injury by ionizing radiation. In the absence of  oxygen, more radiation damage is repaired; thereby the  effect of radiation is compromised. Radiosensitivity of  716

hypoxic cells is about 1/3 of that of hyperoxic cells. Thus,  radiation resistance of hypoxic cells is often the origin of  resistance to therapy [2] . 

Hypoxia is an important pathophysiologic feature in the  microenvironment of solid tumors [2] , which is caused by the  imbalance between oxygen supply and consumption. The  major mechanisms of tumor hypoxia include that (1)  disorder and dysfunction of intratumoral microvessels lead  to severe restricted oxygen perfusion (i.e. acute hypoxia);  (2) relative shortage of blood vessel density in rapidly  growing tumor causes restricted oxygen diffusion (i.e.  chronic hypoxia); and (3) tumor­ or treatment­related  anemia reduces the oxygen content in blood (i.e. anemic  hypoxia) [2,3] . 

Tumor hypoxia has two­sided functions. On the one  hand, hypoxia down­regulates cellular protein synthesis and  blocks cell proliferation; most cells stay at G0  phase or even  go to apoptosis or necrosis; on the other hand, hypoxia  prompts resistance of tumor cells to chemotherapy and  radiotherapy, and accelerates tumor progression.  Meanwhile, long­term hypoxia leads to the unstable  expression of genes regulating survival and apoptosis,  increasing mutation probability which can cause tolerance to  hypoxia and exacerbate the malignancy. Hypoxia can  promote tumor cells to overcome malnutrition and, by  proliferation, invasion, pervasion, and metastasis, to evade  the harsh microenvironment [1,2] . 

The survival, growth, and metastasis of solid tumors  are dependent on tumor blood vessels. Tumor will not grow  beyond 1­2 mm 3  in the absence of blood vessels [1] . Tumor  blood vessels have abnormal structure and functions. The  structural disorder manifests as increase of microvessel  density, tortuous morphology, dilation , multi­branch  bifurcation, thin vessel wall with many fractures, abnormal  endothelial cells (overlapping growth and breaking into the  vessel lumens), abnormal pericytes (loose or missing  cellular junction), uneven basement membrane. Such  abnormal structure leads to bloodstream disorders,  perfusion obstruction, increased leakage and increased  interstitial fluid pressure, impeding the delivery of drugs and  oxygen [3] .  2010; Vol. 29 Issue 8 

Chinese Journal of Cancer Tumor angiogenesis is the result of imbalance of a  variety of pro­angiogenic and antiangiogenic factors [4] .  Among these factors, vascular endothelial growth factor  (VEGF) is the most important angiogenesis­stimulating  factor. VEGF can maintain survival as well as induce  proliferation and migration of endothelial cells, recruit bone  marrow­derived hematopoietic progenitor or stem cells, and  increase vascular permeability [5] . Recent studies found that  VEGF is a negative regulator of the function of pericytes  and maturation of blood vessels [6] . Hypoxia is the strongest  stimulator of VEGF. Under hypoxia, hypoxia­inducible factor  1­alpha (HIF­1琢 )  transcription is up­regulated and then  activates VEGF transcription [4] , promoting the formation of  abnormal blood vessels. This vicious cycle further  exacerbates tumor hypoxia [1] . 

In 1971, Folkman first proposed that tumor growth and  metastasis were dependent on blood vessels and blocking  angiogenesis would be an effective strategy to inhibit tumor  growth. Targets of anti­angiogenic therapy include VEGF,  vascular endothelial cells, matrix metalloproteinases,  integrins, and so on. Antiangiogenic agents can be divided  into two categories: (1) antiangiogenic agents (AA) targeting  new blood vessels and (2) vascular­damaging agents (VA)  targeting existing vessels [4] .  In recent years, more and more antiangiogenic drugs  have been developed and some of them have been used in  clinic trials. Bevacizumab (Avastin), a recombinant  anti­VEGF monoclonal antibody, has been approved by the  US FDA for clinical use in 2004. In the phase III clinical  trials in patients with colorectal cancer, bevacizumab  combined with 5­fluorouracil­based conventional  chemotherapy extended the median survival time by  4 . 7 months [7] . The successful application of bevacizumab  confirmed the hypothesis of antiangiogenesis and has  tremendous impact on cancer therapy. Now bevacizumab  has been approved for treatment of advanced colorectal  cancer, non­small cell lung cancer, metastatic renal cell  cancer, breast cancer, and glioblastoma. Besides combining  with conventional chemotherapy, bevacizumab could  combine with radiation therapy safely and effectively [8] . In  September 2005, recombinant human endostatin has been  approved by China state food and drug administration  (SFDA). The phase III clinical trial of endostatin in China  also showed that combination of endostatin and NP regimen  (vinorelbine and cisplatin) significantly improved the efficacy  on advanced non­small cell lung cancer and safely  extended the median time of tumor progression [9,10] . It is  widely agreed that the effect of antiangiogenic drug alone is 

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very limited [1] . With the success of combination with  chemotherapy, antiangiogenic drugs are now combined  together with radiation therapy [11] . 

The initial rationale of antiangiogenic therapy is that  ischemia and hypoxia cause tumor death by 野 starvation 冶.  By the same reasoning, antiangiogenesis will cause  radiation resistance by reducing the oxygen delivery.  However, many experimental studies found that combination  of antiangiogenic drugs and radiation can improve cancer  treatment. The possible reasons include follows: (1) indirect  inhibition of tumor angiogenesis via VEGF and its receptor;  (2) direct improvement of sensitivity of endothelial cells to  radiotherapy, such as apoptosis of endothelial cells; (3)  direct improvement of radiosensitivity of tumor cells, such  as apoptosis of tumor cells; (4) decrease the proportion of  hypoxic cells and increase oxygen content in tumors.  In summary, the main target of antiangiogenesis is  tumor blood vessels and the main target of radiotherapy is  tumor cells. There is synergic effect between these two  therapies [1] . The following content focused on the fourth  possible mechanism. 

Pre­clinical and clinical studies have found that many  antiangiogenic drugs could overcome tumor hypoxia and  improve tumor response to radiation therapy when  administered at early stage [1] . These drugs include: DC101,  Bevacizumab, Trastuzumab, Erlotinib, SU5416,  Thalidomide, Vandetanib (ZD6474), Anginex, anti­VEGF  monoclonal antibody which belong to AA Category; and  ZD6126 which belongs to VA Category (Table 1).  DC101 is a specific anti­VEGFR2 monoclonal antibody.  Winkler  .  [12]  treated glioma­bearing nude mice with  combination therapy of radiation and DC101. Tumor hypoxia  began to decrease at the day 1 after DC101 administration,  most notably on day 5, and rose on day 8; radiotherapy was  applied at day 4­day 6 after DC101 administration, tumor  growth was significantly delayed and synergic effect was  achieved  [12] . Other studies have found that SU5416  [18] ,  Vandetanib [19] , Thalidomide [20]  and Anginex [15]  could increase  tumor oxygen to the maximum in 24 hours after treatment,  717

Chinese Journal of Cancer  Drug DC101 Bevacizumab

Trastuzumab

Increased tumor Enhanced radiation Model oxygenation therapy efficacy Yes Yes U87 human glioma xenografts Yes Yes Stage T3/T4 rectal cancer patients (phase I/II trials), MA148 human ovarian carcinoma, B16F10 murine melanoma, and SCK murine breast carcinoma xenografts Yes Not studied Her2+ MCF7 human breast cancer xenografts

Erlotinib SU5416

Yes Yes

Yes Yes

Vandetanib Thalidomide Anginex

Yes Yes Yes

Yes Yes Yes

Anti鄄 VEGF ZD6126

Yes No

Yes Yes

Mouse tumor xenografts Mouse liver cancer and FSAII fibrosarcoma xenografts Mouse liver cancer xenografts Mouse FSAII fibrosarcoma xenografts MA148 human ovarian carcinoma, B16F10 murine melanoma, and SCK murine breast carcinoma xenografts U87 human glioma xenografts Mouse KHT sarcoma xenografts

and Bevacizumab in 48 hours  [15] , which significantly  increased the radiation sensitivity.  Besides the pre­clinical animal studies, several clinical  . [8,13,14]  studies have also yielded some results. Willett  have carried out a phase I/II clinical trial of preoperative  neoadjuvant chemotherapy on 32 patients with stage T3/T4  rectal cancer. In this trial, the therapeutic regimen included  Bevacizumab (5 or 10 mg/kg, once per cycle), 5­FU (225  mg/ (m 2 .d), from the 2nd to 4th cycle), radiotherapy (50.4  Gy, 28 fractions), and surgery at 7­10 weeks after  chemoradiotherapy. Pathologic examination did not find  cancer tissues or tumor cells in the scar tissues. The results  showed that 5­year local control rate and overall survival  rate were 100% and the disease­free survival rate was  75%, of which 5 patients had metastasis. 

The mechanisms by which antiangiogenic drugs  overcome tumor hypoxia and the combination therapy of  antiangiogenesis and radiation improve efficacy are not fully  understood. Jain爷 s theory of normalization of tumor blood  vessels drew the most attention in this field [11,25] . This theory  states that the rational use of antiangiogenic drugs can  repair the abnormal vascular system in tumors before  regression, and then the repaired tumor blood vessels can  deliver oxygen and drugs to tumor cells more efficiently,  increasing the sensitivity to chemotherapy. Antiangiogenic  therapy can produce a specific 野 time window冶 , a break  when structure and function of tumor blood vessels and  718

Mechanism

References

Normalized tumor vasculature Normalized tumor vasculature

Normalized tumor vasculature and decreased oxygen consumption Normalized tumor vasculature Inhibited mitochondrial respiration

[12] [8,13鄄 15]

[16] [17] [18]

Decreased oxygen consumption Normalized tumor vasculature Normalized tumor vasculature

[19] [20] [15,21]

Not studied Not studied

[22] [23,24]

microenvironment temporarily become normalized. The  structure of tumor vascular resumes order (uniform  distribution and diameter, increased pericyte coverage, and  uniform basement membrane). The potential function of the  normalization of tumor blood vessels in tumor tissues is to  decrease interstitial fluid pressure in tumor tissues and  overcome hypoxia temporarily so that antitumor drugs can  easily access the inside of tumors, therefore, increase the  sensitivity to chemotherapy and improve efficacy [26] .  Besides the antiangiogenic drugs stated in Table 1,  many other direct or indirect antiangiogenic drugs, such as  TNP­470, Gleevec, Erbitux [25] , Sunitinib  [27] , TSU­ 68 [28] , and  KRN951 [29]  can normalize the tumor vascular system in a  variety of animal models. In addition, bevacizumab [14]  and  cediranib (AZD2171) [30]  in human tumors also confirmed the  tumor vascular normalization. In the time window of  normalization of tumor blood vessels, there are consistence  among the improvement of tumor tissue perfusion, overcome  hypoxia, improved sensitivity to radiotherapy, and the  dynamic changes in tumor morphology. Now studies have  identified the genes regulating tumor blood vessels  normalization, including regulator of G­protein signalling 5  (RGS5) [31] , prolyl hydroxylase domain 2 (PHD2) [32] , endothelial  nitric oxide synthase ( eNOS ) [ 33 ]  , and Roundabout 4  (Robo4) [34] . RGS5 and PHD2 inhibit the normalization of  tumor vessels, whereas eNOS and Robo4 promote this  process. A variety of tumor angiogenic factors are closely  related to the normalization of tumor vessels, such as  VEGF, placenta growth factor (PlGF) [35] , epidermal growth  factor receptor (EGFR) [36] , semaphorin 3A [37] , angiopoietin­1,  angiopoietin­2  [38] , platelet derived growth factor­C (PDGF­  C ) [39] , and so on. 2010; Vol. 29 Issue 8 

Chinese Journal of Cancer Although the theory of normalization of tumor vessels  has been widely accepted and confirmed by experiments, it  may not be the only underlining mechanism. Changes in the  tumor microenvironment after antiangiogenic therapy are so  complex that the normalization of tumor blood vessels may  not be the only early response. Ansiaux  . [18,19]  found that  treatment with SU5416 and Vandetanib increased oxygen in  tumor tissues; however, this effect was the result of  decrease of oxygen consumption which was not related to  the remodeling of tumor vessels and tumor perfusion.  Further studies revealed that SU5416 increased oxygen  content in tumor tissues by inhibiting mitochondrial  respiratory function. 

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Although tremendous development on the combination  therapy of antiangiogenesis and radiation are underway,  there are many problems to be solved. As the regulation of  tumor angiogenesis involves many vascular factors whose  mechanisms are extremely complex, single­target  antiangiogenic therapy may result of drug resistance. In  such scenarios multitarget drugs would be the direction of  future research. The combination therapy of  antiangiogenesis and radiation relies on a comprehensive  understanding of antitumor mechanism. In addition, the joint  clinical research is immature. There are many practical  issues to overcome, such as the best time and dose of drug  administration of combination therapy and the lack of  effective means to monitor treatment response. Therefore,  the comprehensive knowledge of the mechanism of the  combination therapy, tumor types and populations, the  optimal dose and time, therapeutic order, efficacy and  toxicity prediction will serve as the theoretic guidelines for  the development of more rational combination cancer  therapy.  Prevalence of tumor hypoxia seriously affects radiation  therapy. Antiangiogenic therapy represents a new way to  overcome the negative effects of tumor hypoxia. Certain  progress has been achieved in the clinical antiangiogenic  therapy in combination with chemotherapy. Antiangiogenic  therapy combined with radiation therapy is one of the hot  topics in radiation oncology and many clinical trials are  underway.

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