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Advances in Experimental Medicine and... 2007Angiogenesis, the formation of new blood vessels from host vasculature, is critical for tumor growth and metastases. -Curcumin, a novel small-molecular-weight compound,... (Review)
Review
Angiogenesis, the formation of new blood vessels from host vasculature, is critical for tumor growth and metastases. -Curcumin, a novel small-molecular-weight compound, has been shown to inhibit carcinogenesis in different organs and the common link between these actions is its antiangiogenic effect. Curcumin is a direct inhibitor of angiogenesis and also downregulates various proangiogenic proteins like vascular endothelial growth factor and basic fibroblast growth factor. Curcumin's antiangiogenic effect is also in part due to its inhibitory effect on signal transduction pathways, including those involving protein kinase C and the transcription factors NF-kappaB and AP-1. Curcumin has an inhibitory effect on two groups of proteinases involved in angiogenesis that are the members of the matrix metalloproteinase family and the urokinase plasminogen activator family. Cell adhesion molecules are upregulated in active angiogenesis and curcumin can block'this effect, adding further dimensions to curcumin's antiangiogenic effect. Curcumin shows a dose-dependent inhibition on tumor necrosis factor, a versatile cytokine, which has its effect on angiogenesis through the signal transduction pathways, expression of proangiogenic factors, and cell adhesion molecules. Curcumin's effect on the overall process of angiogenesis compounds its enormous potential as an antiangiogenic drug.
Topics: Angiogenesis Inhibitors; Animals; Curcumin; Humans; Models, Biological
PubMed: 17569211
DOI: 10.1007/978-0-387-46401-5_7 -
Cancer Treatment Reviews Jun 2020When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and... (Review)
Review
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic
PubMed: 32335505
DOI: 10.1016/j.ctrv.2020.102017 -
American Journal of Kidney Diseases :... Aug 2007Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to... (Review)
Review
Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to the therapeutic armamentarium for the treatment of patients with metastatic disease. However, because the same growth factors are expressed in the kidneys, these treatment molecules have renal side effects. EGFR is expressed mainly in tubules (mainly distal and collecting segments) and mesangial and parietal epithelial cells. EGF is involved in maintaining tubular integrity and is a potent mitogen for cultured mesangial cells. Few cases of acute renal failure have been reported related to EGFR inhibitors. VEGF and VEGF receptors are still highly expressed in the kidney. VEGF is expressed in podocytes in the glomerulus, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is essential for the proper development and maintenance of the filtration function of the kidney glomerulus. The most common renal class effects of VEGF antagonists are both manageable; hypertension and proteinuria commonly regressive on drug withdrawal. There was a dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received targeted therapies. Furthermore, few patients with glomerulonephritis or thrombotic microangiopathy secondary to treatment were reported. Hypertension is believed to be nitric oxide dependent, whereas proteinuria seems to be related to downregulation of podocyte tight junction protein. This article reviews data relating to hypertension and proteinuria associated with the use of these drugs.
Topics: Angiogenesis Inhibitors; Humans; Hypertension; Kidney; Kidney Diseases
PubMed: 17660022
DOI: 10.1053/j.ajkd.2007.04.025 -
Current Oncology Reports Apr 2013Castration resistant prostate cancer (CRPC) treatment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel,... (Review)
Review
Castration resistant prostate cancer (CRPC) treatment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel, sipuleucel-T, abiraterone and enzalutamide. Though androgen deprivation and chemotherapy remain the main therapeutic approaches for this disease, a series of targeted agents is also in development for the treatment of CRPC. Tasquinimod is a quinolone-3-carboxamide with antiangiogenic and antitumor activity in preclinical models of prostate cancer. A recent Phase II trial with this agent has demonstrated a significant clinical activity in asymptomatic or minimally symptomatic, chemotherapy-naïve, CRPC patients. A confirmatory Phase III trial of tasquinimod in prostate cancer is underway. Because of its antiangiogenic and immunomodulatory properties tasquinimod represents a novel targeted therapy with a unique mechanism of action.
Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Immunomodulation; Male; Prostatic Neoplasms; Quinolines; Quinolones; Randomized Controlled Trials as Topic; Tumor Microenvironment
PubMed: 23334511
DOI: 10.1007/s11912-013-0295-7 -
PloS One 2016Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.
METHODS
Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).
RESULTS
A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.
CONCLUSIONS
In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
Topics: Angiogenesis Inhibitors; Bevacizumab; Glioblastoma; Humans; Recurrence; Salvage Therapy; Thalidomide
PubMed: 27007828
DOI: 10.1371/journal.pone.0152170 -
The Annals of Pharmacotherapy 2004To review the pharmacology, pharmacokinetics, and pivotal clinical trials for bevacizumab, emphasizing its use in colorectal cancer. (Review)
Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, and pivotal clinical trials for bevacizumab, emphasizing its use in colorectal cancer.
DATA SOURCES
A PubMed/MEDLINE search was conducted (1966-April 2004) using the following terms: bevacizumab, Avastin, anti-VEGF, anti-angiogenesis, and colorectal cancer. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer.
STUDY SELECTION AND DATA EXTRACTION
Preclinical and clinical trials that used bevacizumab for the treatment of colorectal cancer and other malignancies were selected from the data sources. All published, randomized clinical trials evaluating bevacizumab in colorectal cancer were included in this review.
DATA SYNTHESIS
Despite advances in chemotherapy, current therapeutic options for metastatic disease provide only temporary benefit for most patients. Bevacizumab is the first anti-cancer agent shown to provide benefit for patients with cancer by inhibiting angiogenesis. Bevacizumab has shown significant activity in the treatment of many cancers, including metastatic colorectal cancer. When used in combination with fluorouracil-based chemotherapy, bevacizumab improves overall response rates, time to progression, and survival in patients with metastatic colorectal cancer. Common toxicities associated with bevacizumab include hypertension, bleeding episodes, and thrombotic events.
CONCLUSIONS
Although clinical knowledge on the effectiveness of bevacizumab is limited, early data indicate that it is a promising agent, with a novel mechanism of action, for patients with metastatic cancer, including colorectal cancer.
Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Colorectal Neoplasms; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic
PubMed: 15187215
DOI: 10.1345/aph.1D470 -
American Journal of Health-system... Nov 2013The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of ziv-aflibercept in combination therapy for metastatic colorectal cancer (mCRC) are... (Comparative Study)
Comparative Study Review
PURPOSE
The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of ziv-aflibercept in combination therapy for metastatic colorectal cancer (mCRC) are reviewed.
SUMMARY
Ziv-aflibercept (Zaltrap, Regeneron Pharmaceuticals and sanofi-aventis) is a novel recombinant fusion protein that targets the angiogenesis signaling pathway of tumor cells by blocking vascular endothelial growth factor (VEGF) receptors that play a key role in tumor growth and metastasis; it is a more potent VEGF blocker than bevacizumab. Ziv-aflibercept is approved by the Food and Drug Administration for use in combination with fluorouracil, irinotecan, and leucovorin (the FOLFIRI regimen) for second-line treatment of patients with mCRC who have disease progression during first-line oxaliplatin-based chemotherapy. A Phase III trial demonstrated that relative to FOLFIRI therapy alone, the use of ziv-aflibercept was associated with significantly improved patient response, overall survival, and progression-free survival in patients with good performance status at baseline, including some who had received prior bevacizumab therapy. The most common grade 3 or 4 adverse effects associated with ziv-aflibercept use in clinical studies were neutropenia, hypertension, and diarrhea; the U.S. product labeling warns of potential hemorrhage and other treatment-related risks.
CONCLUSION
Current clinical data are insufficient to directly compare ziv-aflibercept and bevacizumab when used with standard combination chemotherapy as first- or second-line regimens for mCRC. The role of ziv-aflibercept is currently limited to the second-line setting in combination with irinotecan-based regimens in mCRC patients who have not received irinotecan previously. The role of ziv-aflibercept in chemotherapy for other tumor types is yet to be determined.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Rate; Vascular Endothelial Growth Factor A
PubMed: 24128964
DOI: 10.2146/ajhp130143 -
Bulletin Du Cancer Nov 2007Developments in the knowledge of molecular biology of cancer over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of... (Review)
Review
Developments in the knowledge of molecular biology of cancer over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of cancer evolution. Several strategies have been developed to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Anti-angiogenic drugs recently marketed or still under clinical development, may interact with the kidneys. Clinical and pathological, and mechanisms of their renal toxicity are presented in this article.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Humans; Hypertension; Kidney; Neoplasms; Neovascularization, Pathologic; Proteinuria; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factors
PubMed: 18055316
DOI: No ID Found -
Cancer Science Apr 2003Invasion and subsequent establishment of metastasis are devastating events for patients with cancer, but past therapeutic approaches have paid relatively little... (Review)
Review
Invasion and subsequent establishment of metastasis are devastating events for patients with cancer, but past therapeutic approaches have paid relatively little attention to these important issues. Hepatocyte growth factor (HGF) and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Activation of the c-Met receptor integrates multiple signal transduction pathways involved in cell-cell and cell-matrix interactions, cellular migration, and breakdown of the extracellular scaffold. Paracrine activation of the c-Met receptor by stromal-derived HGF mediates tumor-stromal interactions that facilitate invasion and metastasis. Likewise, aberrant expression of the c-Met receptor and autocrine or mutational activation of c-Met receptor tyrosine kinase are closely associated with the progression of malignant tumors. Based on this background, NK4, a competitive antagonist of HGF-c-Met association was prepared so as to block cancer invasion and metastasis. NK4, an internal fragment of HGF, binds to but does not activate the c-Met receptor, thereby competitively antagonizing the biological activities of HGF. Unexpectedly, NK4 was subsequently shown to be an angiogenesis inhibitor as well, and this angioinhibitory activity is independent of its action as an HGF-antagonist. Importantly, NK4 protein or NK4 gene therapy have been shown to inhibit tumor invasion, metastasis and angiogenesis, effectively converting malignant tumors into benign tumors. Targeting tumor invasion-metastasis and angiogenesis with NK4 seems to have considerable therapeutic potential for cancer patients.
Topics: Angiogenesis Inhibitors; Animals; Genetic Therapy; Hepatocyte Growth Factor; Humans; Mitogens; Neoplasms; Proto-Oncogene Proteins c-met
PubMed: 12824898
DOI: 10.1111/j.1349-7006.2003.tb01440.x -
The Oncologist 2010Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor... (Review)
Review
Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor 2 (VEGFR-2) to exert its function. Pazopanib inhibits VEGF-induced endothelial cell proliferation in vitro and angiogenesis in vivo and demonstrates antitumor activity in mouse models. Furthermore, the pazopanib concentration resulting in maximal inhibition of VEGFR-2 phosphorylation in vivo was in line with the steady-state concentration required to inhibit growth of tumor xenografts, suggesting that pazopanib's mechanism of action is indeed through VEGFR-2 inhibition. In a phase I trial, a generally well-tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR-2 phosphorylation in preclinical models. Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non-small cell lung cancer. Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression-free survival time observed with this agent in a placebo-controlled, randomized trial. This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.
Topics: Angiogenesis Inhibitors; Animals; Disease-Free Survival; Humans; Indazoles; Neoplasms; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2
PubMed: 20511320
DOI: 10.1634/theoncologist.2009-0274