Combination Of Angiogenesis Inhibitors Research Articles

Tumor Delivery of Chemotherapy Combined with Inhibitors of Angiogenesis and Vascular Targeting Agents

Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most are used in polytherapy regimens. This review looks at recent progress and our own preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways, and vascular targeting agents with conventional chemotherapy, discussing the factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated with drug distribution and activity are reviewed. Modalities to improve drug delivery and strategies for optimizing combination therapy are examined.

Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma

Angiogenesis inhibitors targeting the VEGF signaling pathway have been US FDA approved for various cancers including glioblastoma (GBM), one of the most lethal and angiogenic tumors. This has led to the routine use of the anti-VEGF antibody bevacizumab in recurrent GBM, conveying substantial improvements in radiographic response, progression-free survival and quality of life. Despite these encouraging beneficial effects, patients inevitably develop resistance and frequently fail to demonstrate significantly better overall survival. Unlike chemotherapies, to which tumors exhibit resistance due to genetic mutation of drug targets, emerging evidence suggests that tumors bypass antiangiogenic therapy while VEGF signaling remains inhibited through a variety of mechanisms that are just beginning to be recognized. Because of the indirect nature of resistance to VEGF inhibitors there is promise that strategies combining angiogenesis inhibitors with drugs targeting such evasive resistance pathways will lead to more durable antiangiogenic efficacy and improved patient outcomes. Further identifying and understanding of evasive resistance mechanisms and their clinical importance in GBM relapse is therefore a timely and critical issue.

Angiogenesis Inhibitors: Implications for Combination with Conventional Therapies

Angiogenesis is associated with tumor development and malignancy and is a validated target for cancer treatment. Preclinical and clinical evidence substantiates the feasibility of combining angiogenesis inhibitors with conventional anticancer therapy. This review discusses recent progress in combining antiangiogenic drugs, mainly acting on the VEGF/VEGFR pathway, with chemotherapy and other conventional therapies. Strategies for the optimization of combination therapy and the selection of appropriate treatment regimens are examined. As new drugs are entering clinical trials, reliable biomarkers are needed to stratify patients for antiangiogenic therapy, to identify resistant patients and to monitor response to treatment.

Targeting multiple angiogenic pathways for the treatment of neuroblastoma

Purpose Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon- β (IFN- β) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts. Methods Subcutaneous and retroperitoneal neuroblastoma xenografts (NB-1691 and SK-N-AS) were used. Continuous delivery of IFN- β was achieved with adeno-associated virus vector-mediated, liver-targeted gene transfer. Rapamycin was delivered intraperitoneally (5 mg/kg per day). After 2 weeks of treatment, tumor size was measured, and tumor vasculature was evaluated with intravital microscopy and immunohistochemistry. Results Rapamycin and IFN- β, alone and in combination, had little effect on tumor cell viability in vitro. In vivo, combination therapy led to fewer intratumoral vessels (69% of control), and the remaining vessels had an altered phenotype, being covered with significantly more pericytes (13× control). Final tumor size was significantly less than controls in all tumor models, with combination therapy having a greater antitumor effect than either monotherapy. Conclusion The combination of IFN- β and rapamycin altered the vasculature of neuroblastoma xenografts and resulted in significant tumor inhibition. The use of combinations of antiangiogenic agents should be further evaluated for the treatment of neuroblastoma and other solid tumors.

The effect of photodynamic therapy on tumor angiogenesis.

Photodynamic therapy (PDT), the activation of a photosensitive drug in tumor tissue with light of specific wavelength, has been used effectively to treat certain solid tumors. Though therapeutic responses are encouraging, PDT-mediated oxidative stress can act as an angiogenic switch that ultimately leads to neovascularization and tumor recurrence. This article explores the effect of PDT on angiogenesis in different tumor models. Overexpression of proangiogenic vascular endothelial growth factor, cyclooxygenase-2 and matrix metalloproteases has often been reported post-illumination. Recent clinical studies have demonstrated that inhibiting angiogenesis after chemotherapy and radiotherapy is an attractive and valuable approach to cancer treatment. In this review, we report the effective therapeutic strategy of combining angiogenesis inhibitors with PDT to control and treat tumors.

The Interaction of Radiation Therapy and Antiangiogenic Therapy

Since its beginning in the early 1970s, the field of angiogenesis research has grown rapidly and it has now become apparent that the endothelial cell is a critical regulator of the malignant phenotype. Multiple antiangiogenic agents have now been used in the clinic yet a better understanding of the process of angiogenesis is still needed before these agents can be successfully incorporated into clinical practice. Although antiangiogenic agents offer great therapeutic potential, preclinical and clinical studies suggest that these agents will have a delayed onset of activity and may only induce disease stabilization for patients with advanced malignancy. The use of radiation therapy for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with antiangiogenic agents. Thus, the use of angiogenesis inhibitors in combination with radiation therapy should help to overcome the limitations of each leading to enhanced efficacy and diminished toxicity. The goal of this review is to provide an update of ongoing progress and current challenges related to the use of angiogenesis inhibitors with radiation therapy.

Hypericin-mediated photodynamic therapy in combination with Avastin (bevacizumab) improves tumor response by downregulating angiogenic proteins

Photodynamic therapy (PDT) is a therapeutic modality in which a photosensitizer is locally or systemically administered followed by light irradiation of suitable wavelength to achieve selective tissue damage. In addition, PDT is an oxygen-consuming reaction, that causes hypoxia mediated destruction of tumor vasculature that results in effective treatment. However, the hypoxic condition within tumors can cause stress-related release of angiogenic growth factors and cytokines and this inflammatory response could possibly diminish the efficacy of PDT by promoting tumor regrowth. In such circumstances, PDT effectiveness can be enhanced by combining angiogenesis inhibitors into the treatment regimen. Avastin (bevacizumab), a vascular endothelial growth factor (VEGF) specific monoclonal antibody in combination with chemotherapy is offering hope to patients with metastatic colorectal cancer. In this study we evaluated the combination of hypericin-mediated PDT and Avastin on VEGF levels as well as its effect on overall tumor response. Experiments were conducted on bladder carcinoma xenografts established subcutaneously in Balb/c nude mice. Antibody array, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to assess VEGF concentrations in the various treatment groups. Our results demonstrated that the targeted therapy by Avastin along with PDT can improve tumor responsiveness in bladder tumor xenografts. Immunostaining showed minimal expression of VEGF in tumors treated with combination therapy of PDT and Avastin. Angiogenic proteins e.g., angiogenin, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and interleukins (IL-6 and IL-8) were also found to be downregulated in groups treated with combination therapy.

인체폐암세포 조직배양계(histocultures)에서 티라파자민의 약력학

Hypoxia in solid tumors is known to contribute to intrinsic chemoresistance. Histocultures are in vitro 3 dimensional cultures of tumor tissues and maintain the characteristic microenvironment of human solid tumors in vivo including hypoxia and multicellular structure. In this study, we evaluated the pharmacodynamics of tirapazamine(TPZ), a hypoxia-selective cytotoxin, in human non small cell lung cancer(NSCLC) cells grown as monolayers and histocultures. Antiproliferative activity of TPZ was determined after various conditions of drug exposure, and cell cycle arrest and apoptosis were also measured using flow cytometry. In monolayers, hypoxia selectivity measured by hypoxic/normoxic cytotoxicity ratio was increased with longer exposure. Lower cytotoxicity of TPZ was observed in histocultures compared to monolayers, however, a similar level of cytotoxicity was obtained with longer exposure of 96 hr. TPZ induced arrest and apoptosis in both culture conditions, which were greatly enhanced under hypoxic condition. Our data clearly showed the different pharmacodynamics of TPZ in monolayers and histocultures. Antiproliferative activity of TPZ against human solid tumors can be improved with longer drug exposure by exploiting drug delivery systems or by combining angiogenesis inhibitors to maintain drug concentration in tumor tissues.

Combining radiotherapy and angiogenesis inhibitors: Clinical trial design

Radiotherapy (RT) plays a vital role in the multimodality treatment of cancer. Recent advances in RT have primarily involved improvements in dose delivery. Future improvements in tumor control and disease outcomes will likely involve the combination of RT with targeted therapies. Preclinical evaluations of angiogenesis inhibitors in combination with RT have yielded promising results with increased tumor "cure." It remains to be seen whether these improvements in tumor control in the laboratory will translate into improved outcomes in the clinic. Multiple differences between these agents and cytotoxic chemotherapy must be taken into account when designing clinical trials evaluating their effectiveness in combination with RT. We discuss important considerations for designing clinical trials of angiogenesis inhibitors with RT.

Radiation Combined With Antiangiogenic and Antivascular Agents

Angiogenesis is critical for a number of physiologic and pathophysiologic processes, and angiogenesis inhibitors are now being used in the treatment of cancer. Although antiangiogenic agents offer great therapeutic potential, preclinical and clinical trial results suggest that these agents will have a delayed onset of activity and may only induce disease stabilization for patients with advanced malignancy. The use of radiation therapy for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with antiangiogenic agents. Thus, the use of angiogenesis inhibitors in combination with radiation therapy should help to overcome the limitations of each leading to enhanced efficacy and diminished toxicity. The goal of this review is to provide an overview and discussion of the combination of angiogenesis inhibitors with radiation therapy.

Prospects for therapeutic inhibition of neuroblastoma angiogenesis

Despite aggressive therapy, survival for advanced stage neuroblastoma remains poor with significant long-term morbidity in disease survivors. High-risk disease features are strongly correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. However, challenges include the well-known clinical heterogeneity and embryonal origins of this disease, which suggests a complex regulation of neovascularization that may be distinct from epithelial-derived carcinomas. We will review what is understood about angiogenesis-related signaling in neuroblastoma. In particular, we will present evidence that angiogenesis-related molecules are differentially expressed in primary neuroblastomas in a pattern suggesting promotion of a pro-angiogenic phenotype in high-risk tumors and an anti-angiogenic phenotype in low-risk tumors. We will also discuss a variety of vascular inhibition strategies that have been used in neuroblastoma preclinical models including specific inhibition of vascular endothelial growth factor (VEGF) and methionine aminopeptidase 2 (MetAP2). Recent observations that the combination of angiogenesis inhibitors with conventional chemotherapy provides synergy without additive toxicity, suggests the potential use of angiogenesis inhibitors as an adjunct between cycles of conventional cytotoxic therapy. Further identification of critical angiogenic signaling pathways and evaluation of specific inhibitors in preclinical neuroblastoma models should provide justification for future selection and evaluation of angiogenesis inhibitors in clinical trials for high-risk neuroblastoma patients.

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.

Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors.

Id proteins bind basic helix-loop-helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus-neu mice were bred with Id1-/-Id3+/- mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.

Combined effects on tumor growth and metastasis by anti-estrogenic and antiangiogenic therapies in MMTV-neu mice.

Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. Recent work carried out in our laboratory on a transgenic model of breast cancer displaying many similarities to its human counterpart, has shown that liposome-mediated angiostatin cDNA delivery partially inhibits both local and metastatic growth. However, it is now recognized that anti-angiogenesis strategy alone cannot completely arrest tumor growth and spread, and this led to the suggestion that approaches based on different molecular mechanisms could usefully be combined. In the present work, we investigated whether tamoxifen, a classical antiestrogen agent widely used in human therapy, could improve the results obtained with angiostatin alone. Further reduction of local growth was achieved with the combined regimen with respect to angiostatin or tamoxifen alone, while, as expected, no metastatic growth was detected in either group. We therefore conclude that a combination of angiogenesis inhibitors with antiestrogen drugs might be useful in humans and that other associations between conventional and gene transfer-mediated therapy are worth investigating and will soon become important components of anticancer therapy.

Angiogenesis Research: Guidelines for Translation to Clinical Application

Angiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either "direct" or "indirect" and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.

Combination of angiogenesis inhibitor TNP-470 with cytotoxic drugs in experimental therapy of nasopharyngeal carcinoma.

This study was conducted to evaluate the effectiveness of angiogenesis inhibitor 6-O-(N-chloroacetyl-carbamoyl)-fumagillol (TNP-470. AGM-1470) in the treatment of nasopharyngeal carcinoma (NPC) alone and in combination with cytotoxic agents. Forty-two male BALB/c nude mice bearing human NPC cell line CNE-2 were randomized into 6 groups: those treated with saline solution, TNP-470, cisplatin (DDP), fluorouracil (5-FU), TNP-470 + DDP, and TNP-470 + 5-FU, respectively. In every treatment group, tumor growth was suppressed significantly. The combination of 5-FU with TNP-470 showed significant enhancement in antitumor efficacy. TNP-470 also enhanced the inhibitory effect of DDP, although not to statistical significance. All animals gained in body weight, although treatment with 5-FU caused slight, reversible diarrhea of 2 to 3 days' duration. The results showed that TNP-470 suppressed the growth of the human NPC cell line and enhanced the antitumor effect of 5-FU without increasing its toxicity. The combination of angiogenesis inhibitors with conventional cytotoxic agents is promising in the treatment of NPC.

Clinical strategy for the development of angiogenesis inhibitors.

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.