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PubMed2005

Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies.

Angiogenesis is a process by which new blood vessels are formed from preexisting vessels. New blood vessel formation by angiogenesis involves the degradation of extra-cellular matrix combined with sprouting and migration of endothelial cells from preexisting capillaries. Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through angiogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine regeneration. VEGF is both a vascular growth factor and a vascular permeability factor. Its expression can upregulate several proangiogenic and prometa-static molecules. As a central mediator of angiogenesis, VEGF has emerged as an important target for antiangiogenic therapy. In this review, the authors describe the essential characteristics of VEGF and the VEGF family of ligands and their receptors. They also provide an overview of the central role of VEGF in physiologic and pathologic angiogenesis, directly or indirectly. This review sheds light on the importance of VEGF-targeted antiangiogenic therapy based on the monoclonal antibodies against VEGF, small interfering RNA, and therapy directed against VEGF-VEGFR kinase. It also gives a brief overview of the natural products or dietary compounds that could be used as antiangiogenic agents. Therapeutic inhibition of vessel formation could be best suited to preventive strategies aimed at the suppression of angiogenesis in primary tumors in subjects at risk or of micrometastases after surgical removal of primary tumor.

Angiogenesis Inhibitors↗
PubMed2005

Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model.

We carried out this investigation to examine the effects on angiogenesis-mediated processes and to define anti-angiogenesis mechanisms for flavonoids. We examined the effects and mechanisms of the flavonoid resveratrol on angiogenesis and tumor growth using the chick chorioallantoic membrane (CAM) model of angiogenesis, the CAM tumor growth model, and the effect on p53 in fibroblast growth factor-2 (FGF2) stimulated human endothelial cells using immunoassay. Resveratrol demonstrated potent inhibition (effective dose50=0.7+/-0.1 microM) of FGF2-induced angiogenesis and tumor growth. Furthermore, resveratrol significantly (P<0.01) inhibited platelet/fibrin clot-promoted human colon and fibrosarcoma tumor growth in the CAM tumor model. Resveratrol in a concentration-dependent (1-3 microM) manner significantly promoted apoptosis in FGF2-stimulated endothelial cells by increasing p53 protein production. These data indicated potent anti-angiogenesis efficacy, inhibition of tumor growth, and clot-mediated enhanced tumor growth. These data suggest potential anticancer benefits as a chemopreventive and chemotherapeutic for the flavonoid resveratrol.

Angiogenesis Inhibitors↗
PubMed2005

Anti-angiogenesis efficacy of the garlic ingredient alliin and antioxidants: role of nitric oxide and p53.

Alliin, a compound derived from garlic, demonstrated dose-dependent inhibition of fibroblast growth factor-2 (FGF2)-induced human endothelial cell (EC) tube formation and angiogenesis in the chick chorioallantoic membrane (CAM) model. Additionally, alliin demonstrated potent inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis in the CAM model. The antioxidant vitamins C and E significantly (P < 0.001) enhanced the inhibitory efficacy of alliin on FGF2-induced EC tube formation and angiogenesis. Alliin significantly increased (P < 0.01) nitric oxide (NO) release into the CAM fluid, which was further enhanced by vitamins C and E. The NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME) reversed the anti-angiogenesis efficacy of alliin in the CAM model. Vitamins C and E significantly enhanced the anticancer efficacy of alliin in inhibiting colon and fibrosarcoma tumor growth. Alliin significantly inhibited both FGF2 and VEGF secretion from human fibrosarcoma cells in a concentration-dependent manner. Additionally, alliin up-regulated the p53 production in FGF2-stimulated EC. These data indicated a synergistic effect of antioxidants on the anti-angiogenesis and anticancer efficacy of alliin. These data also suggest the implication of cellular NO and p53 as mediators of anti-angiogenesis and anticancer effects of alliin.

Angiogenesis Inhibitors↗
PubMed2003

VEGF-receptor inhibitors for anti-angiogenesis.

Angiogenesis is deeply involved in the progression of major diseases such as cancer, diabetes, and rheumatoid arthritis. Molecular mechanism on angiogenesis was extensively studied, and several signaling systems including VEGF (VEGF-A), angiopoietin, PDGF, and ephrin were shown to be crucial for physiological angiogenesis. Interestingly, among these factors, VEGF appears to play key roles in most of the pathological angiogenesis, and other factors are considered to have additional effects on its development depending on the situation. VEGF binds and activates two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and stimulates endothelial cell growth, survival, and vascular permeability. VEGF induces not only tumor angiogenesis but also blood-vessel-dependent metastasis. Based on the importance of VEGF in diseases, many companies and institutes are now trying to generate appropriate small molecules as well as proteins that strongly antagonize the VEGF-VEGFR system. Several molecules quite effective for suppression of tumorigenesis and pathological angiogenesis in animal models are under clinical trials.

Angiogenesis Inhibitors↗
PubMed2003

Translating angiogenesis research into the clinic: the challenges ahead.

The field of angiogenesis research has evolved to become one of the most rapidly growing biomedical disciplines. The interest in basic angiogenesis research is sparked by the translational therapeutic potential aimed at developing anti-angiogenesis as a novel therapeutic modality for tumours and a number of non-oncological diseases, such as rheumatoid arthritis, psoriasis, diabetic retinopathy and age-dependent macula degeneration. The molecular determinants of the angiogenic cascade have been characterized in great detail over the last few years. Likewise, intense ongoing efforts are aimed at identifying and validating additional vascular specific determinants that may be exploited as therapeutic targets for pro-angiogenic and anti-angiogenic therapy. At the same time, a large number of angiomodulatory compounds are in various phases of clinical trials. These include the neutralizing vascular endothelial growth factor (VEGF) antibody Avastin, which has successfully passed phase III clinical trials for the combination with chemotherapy in colorectal cancers. In view of the dramatic progress in basic angiogenesis research, surprisingly little is known about the nature of the neovasculature in human tumours. The inclusion and exclusion criteria of clinical trials of anti-angiogenic compounds are devoid of angiogenesis-related parameters and reliable biomarkers to trace the efficacy of an anti-angiogenic intervention are largely missing. Based on a brief review of the biology of the angiogenic cascade, this review provides an overview of the current concepts of the angiogenic vasculature in human tumours and discusses some key unanswered questions in translating angiogenesis research into the clinic.

Angiogenesis Inhibitors↗
PubMed2000

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.

Angiogenesis Inhibitors↗
PubMed2000

Angiogenesis inhibitors. New agents in cancer therapy.

Tumours that do not develop a blood supply cannot grow larger than 1 to 2mm3. The growth of a tumour blood supply, called angiogenesis, is a complex process that greatly increases the likelihood of metastatic spread and aggressive tumour behaviour. Molecular processes involved in angiogenesis include stimulation of endothelial growth by tumour cytokine production (vascular endothelial growth factor), degradation of extracellular matrix proteins by metalloproteinases, and migration of endothelial cells mediated by cell membrane adhesion molecules called integrins. These processes are being targeted by several new types of agents broadly classified as angiogenesis inhibitors. Additionally, endogenous angiogenesis inhibitors have been discovered and one of them, endostatin, is currently undergoing clinical trials. The unique targets of these drugs make them distinct from traditional cytotoxic chemotherapeutic agents. Unlike cytotoxic chemotherapy, in which the biological effect of the drug produces the antitumour effect as well as the toxic effect, angiogenesis inhibitors may produce their biological effect independently of the toxic effect. This fact raises important questions among clinical investigators as to what is the most effective way to administer these drugs and monitor their effects. This paper details some of the scientific evidence making angiogenesis an important therapeutic target as well as issues regarding the structure of clinical trials with these new anticancer agents.

Angiogenesis Inhibitors↗
PubMed2000

Angiogenesis: new targets for the development of anticancer chemotherapies.

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.

Angiogenesis Inhibitors↗
PubMed2004

Angiogenesis inhibitors: current & future directions.

The field of angiogenesis modulation is at a major crossroad. A tremendous advancement in basic science in this field is providing an excellent support for the concept, which is in contrast to a lack of strong clinical support to date. With regard to the large gap between experimental data and clinical data, the best model of human malignancy is in human cancer patients and the best model of human ocular angiogenesis-mediated disorders such as diabetic retinopathy (DR) and age related macular degeneration (AMD) is in human RD and AMD patients. Additionally, clinical outcomes should include benefit/risk ratios, hard end points (mortality and quality of life as opposed to increased microvascular density with pro-angiogenic agents or tumor size reduction with anti-angiogenesis agents) as well as cost effectiveness. Experimental models should be used to provide guidance, placebo effect, comparative data, and mechanistic understanding as opposed to being used for expected clinical efficacy. We also have to understand existing strategies and how angiogenesis modulation can add further value (i.e. not to replace existing strategy but rather improve efficacy/safety). Recent investigation defined numerous strategies in the modulation of angiogenesis. Those strategies are driven from haemostatic, fibrinolytic, cell adhesion molecules, extracellular matrix, growth factors, and other endogenous systems involved in the modulation of angiogenesis.

Angiogenesis Inhibitors↗
PubMed2002

Peptidomimetics and angiogenesis.

Angiogenesis is the sprouting of new blood capillaries from surrounding preexisting blood vessels. This process is fundamental for embryonic development, wound healing and inflammation. In healthy adults angiogenesis is of minor importance. However, aberrant angiogenesis is essentially involved in disorders as diabetic retinopathy, rheumatoid arthritis and tumor growth, and blocking angiogenesis has emerged as a promising target for antagonizing these diseases. Therefore the development of new anti-angiogenic drugs is of great interest in academic and industrial research. This review focuses on the employment of peptidomimetics in inhibiting pathologic angiogenesis. It will survey the individual aspects of angiogenesis where the usage of peptidomimetics is favored and will consider the current progresses on this field.

Angiogenesis Inhibitors↗
PubMed1995

Prostaglandins and gangliosides of tumor microenvironment: their role in angiogenesis.

In the solid tumor the microenvironment is the space limited by the basement membrane of the microvessels and the neoplastic cells membrane. It includes the stroma and a liquid phase, the tumor interstitial fluid (TIF). We developed a method to sample TIF in vivo and found it rich in prostaglandins. In the rabbit cornea PGE1 induces neovascularization and acts as an angiogenesis factor. Before angiogenesis appears the ganglioside content of the cornea doubles with sharp reduction of the GM3/GD3 ratio. These gangliosides are not angiogenic but they influence the endothelial cell behavior. In particular when the PGE1 dose is insufficient to induce angiogenesis, enrichment of corneal tissue with GD3 or GM1 stimulates angiogenesis. However, when the corneal tissue is enriched with GM3, doses of PGE1, normally angiogenic fail to do so. The same was observed when bFGF substituted PGE1 as an angiogenesis trigger. The gangliosides tested acted as modulators of the angiogenic response by promoting the angiogenic capacity of molecules, such as PGE1 or bFGF, normally present in the tissue microenvironment. Several neoplastic cells, especially melanomas, shed gangliosides in the microenvironment. Their modulatory effect on angiogenesis may influence metastatic and/or primary tumor growth.

Alprostadil↗
PubMed2022

WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy.

Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53-/-] and [HBx,src,p53-/-,RPIA], while ppp2r1bb is downregulated in [tert x p53-/-]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53-/-,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1&#x3b2; expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated &#x3b2;-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1-OSR1-PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1-OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1-OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy.

Animals↗
PubMed1999

[Inhibition of tumor angiogenesis as a cancer treatment].

Angiogenesis is the process of new vessel formation from pre-existing vasculature. In preclinical as well as clinical research it has been demonstrated that tumour growth and formation of metastases are angiogenesis dependent. High microvessel density in most tumour types is associated with a bad prognosis. A variety of angiogenic stimuli and inhibitors have been discovered and are expressed in tumours of cancer patients. In addition to specific angiogenic factors, the synthesis and breakdown of the extracellular matrix, the adherence of endothelial cells, the coagulation process and the immune system are important for tumour-induced angiogenesis. Preclinical research has demonstrated that tumour growth can be inhibited by angiogenesis inhibitors. These findings stimulated the development of angiogenesis inhibitors, which are currently under investigation in phase I, phase II and phase III studies for toxicity and efficacy. In the future angiogenesis inhibitors, like insulin therapy in diabetes, may be used to inhibit tumour growth and to induce stabilization of the disease.

Angiogenesis Inducing Agents↗
PubMed1999

Establishment of a quantitative mouse dorsal air sac model and its application to evaluate a new angiogenesis inhibitor.

We have developed an improved mouse dorsal air sac model for quantifying in vivo tumor-induced angiogenesis. In our improved model, tumor angiogenesis is determined by measuring the blood volume in an area of skin held in contact with a tumor cell-containing chamber, using 51Cr-labeled red blood cells (RBC). The blood volume induced by murine B16-BL6 melanoma cells increased linearly with the cell number in the range from 2 x 10(5) to 5 x 10(6). Ten of 11 human tumor cell lines examined induced a significant increment in blood volume. For three representative human tumor cell lines (A549, WiDr. and HT1080 cells) that showed different angiogenic potencies, the levels of vascular endothelial growth factor (VEGF) produced by the tumor cells cultured under conditions of hypoxia and high cell density were correlated with the degree of in vivo angiogenesis. Using the improved model, it was confirmed that TNP-470, a well-known inhibitor, and borrelidin, an antibiotic from Streptomyces rochei, significantly inhibited the WiDr cell-induced angiogenesis. Borrelidin also inhibited spontaneous lung metastasis of B16-BL6 melanoma at the same dose that inhibited angiogenesis. Our results suggest that the improved mouse dorsal air sac model can be used for simple and quantitative measurement of tumor-induced angiogenesis and its inhibition.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Serologic angiogenesis factors and microvascular density in renal cell carcinoma: two independent parameters.

Renal Cell Carcinoma (RCC) is characterized by high intratumoral microvascular density (iMVD) and significantly elevated serologic titers of angiogenesis factors, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (vEGF) and angiogenin (Ag). The goal of the present study was to find whether a correlation exists between any of these factors and intratumoral microvascular density (iMVD). Serologic angiogenesis factors were determined directly before nephrectomy of a tumorous kidney in 12 patients (average age: 67.6 years [49-78] with localized clear-cell RCC (Robson I-II) (Quantikine', R&D Systems Europe, Abington, UK). Sections were taken in each case from the microscopically most aggressive area of the tumorous kidney preparations. Staining was carried out with a primary antibody against CD31 (DAKO M 0823, Hamburg, Germany). iMVD was counted at 160x magnification at five "hot spots" 200 x 200 microns in size, and the individual factors were then correlated with the areas of maximum and average iMVD (iMVDmax, iMVD-d). Average concentrations of 38 pg/ml +/- 68 were found for bFGF, 712 pg/ml +/- 791 for vEGF, and 358 ng/ml +/- 97 for Ag. iMVDmax was 20 +/- 11 per area, iMVD-d was 410/mm2 +/- 243. No correlation was found between microvascular density and serologic angiogenesis factors for any parameter. Actual tumor vascularization, expressed as iMVD, was not correlated with the 3 angiogenesis parameters which were studied. On the one hand, this raises the question whether angiogenesis can be measured at all with these parameters; on the other, it remains nuclear whether the continuous process of angiogenesis can be registered at all by chronologic, specific factor analysis.

Aged↗
PubMed2001

Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro.

Exponential tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent angiogenic inducers that act synergistically in vivo and in vitro. We assessed the effect of specific inhibitors of VEGF receptor (VEGFR)-2 tyrosine kinase activity in in vivo and in vitro models of VEGF- and bFGF-induced angiogenesis. In an implant mouse model of angiogenesis, VEGFR-2 inhibitors completely blocked angiogenesis induced by VEGF, and, surprisingly, also inhibited the effect of bFGF to various extents. In vitro, VEGF- and bFGF-induced bovine microvascular and aortic endothelial (BME and BAE) cell collagen gel invasion could be blocked by the VEGFR-2 inhibitors by 100 and approximately 90%, respectively. Similar results were obtained with VEGFR-1-IgG and VEGFR-3-IgG fusion proteins and with VEGFR-2 blocking antibodies. Both BME and BAE cells produce VEGF and VEGF-C, which is not modulated by bFGF. Thus, the unexpected inhibition of bFGF-induced angiogenesis by VEGFR-2 antagonists reveals a requirement for endogenous VEGF and VEGF-C in this process. These findings broaden the spectrum of mediators of angiogenesis that can be inhibited by VEGFR-2 antagonists and highlight the importance of these compounds as agents for inhibiting tumor growth sustained by both VEGF and bFGF.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Angiogenesis inhibition in solid tumors.

Angiogenesis plays a central role in a variety of physiologic and pathologic disease states. Because the growth and metastasis of malignant neoplasms require the presence of an adequate blood supply, pharmacologic inhibition of tumor-induced angiogenesis represents a promising target for antineoplastic therapy. A number of approaches to such inhibition are therefore under active investigation. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are among the best characterized of the various key elements in benign and neoplastic angiogenesis. In 1997, clinical trials were initiated to evaluate an anti-VEGF monoclonal antibody and a VEGFR-2 antagonist as therapy for patients with different types of solid tumors and hematologic neoplasms. Dose selection for these cytostatic agents requires translation from preclinical models, as these agents are likely to require chronic dosing at an optimal biological dose, rather than a maximally tolerated dose. For example, SU5416, a novel small-molecule inhibitor of VEGFR-2, administered at 145 mg/m2 intravenously twice weekly, is well tolerated and achieves the concentration levels required to inhibit endothelial cell proliferation in preclinical models. Because the mechanism of action of angiogenesis inhibitors is complementary to that of classic cytotoxic chemotherapy, preclinical models and subsequent clinical trials frequently explore combinations of these agents with cytotoxic chemotherapy, hoping to achieve additive or synergistic antitumor activity. It is hoped that the combination of angiogenesis inhibitors with cytotoxic chemotherapeutic agents will significantly improve survival and quality of life for cancer patients. As a result of favorable results from Phase 1 and 2 studies, randomized, multicenter clinical investigations of angiogenesis inhibitors are ongoing.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Up-regulated gene expression of angiogenesis factors in post-chemotherapeutic lung cancer tissues determined by cDNA macroarray.

The differential expressions of hundreds of tightly transcriptionally controlled genes in freshly isolated human lung cancers and respective normal lung tissues were analyzed by the cDNA macroarray technique. Three lung cancer patients received pre-operative chemotherapy with cisplatin containing regimens. After chemotherapy, these patients underwent surgery, and poly (A)-RNA expressions of 588 genes in the samples prepared from the lung cancer and normal lung tissues were compared. These expressions of the 588 genes were demonstrated by spotting onto a filter. Histogram analysis of gene expression revealed the tumors to show commonly up-regulated expression of angiogenesis and invasion related genes and adhesion molecules such as fibroblast growth factor 3 (FGFR3), matrix metalloproteinase (MMP)15, 16 and 10, integrin beta 4, integrin alpha 9, endonexin, and several types of collagens. Thus, post-chemotherapeutic tissues from lung cancer parents are characterized by remarkable up-regulation of molecules related to angiogenesis, invasion and adhesion. Tree view showed close clustering of angiogenesis related genes. Furthermore, when the angiogenesis related genes were selected and clustered, they were categorized into three groups depending upon gene expression profiles. These results suggest that angiogenesis related molecules are suitable candidates for target-based therapeutics and angiogenesis inhibitors are expected to be effective in lung cancer patients pretreated with chemotherapy.

Adenocarcinoma↗