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Cornelius P, Mayes BA, Petersen JS, Turnquist DJ, Dufour PJ, Dannenberg AJ, Shanahan JM, Carver BJ. Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity. Mol Cancer Ther 2024; 23:595-605. [PMID: 38530115 PMCID: PMC11063762 DOI: 10.1158/1535-7163.mct-23-0574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/07/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.
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Albini A, Noonan D, Santi L. Angiogenesis at the Interface between Basic and Clinical Research. Int J Biol Markers 2018; 14:202-6. [PMID: 10669947 DOI: 10.1177/172460089901400402] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The field of antiangiogenesis has shown a remarkably rapid evolution from the discovery at the bench to translation into the clinic. Currently a wide variety of compounds are in clinical trial as inhibitors of angiogenesis, and new compounds are being frequently added. The target cell of most angiogenesis inhibitors is the endothelial cell, with inhibitors that selectively affect a number of endothelial cell functions acquired during angiogenesis, including activation, proliferation, migration, invasion and survival. The endothelial cell may also be targeted by chemotherapeutic agents currently in use. The high doses and intermittent treatment schedules used to fight resistant tumor cells may be altered towards lower doses and chronic administration to obtain selective inhibition of angiogenic factor-stimulated endothelial cells as adjuvant therapy. Finally, gene therapy is a promising route for the delivery of novel protein inhibitors of angiogenesis, and is actively being investigated.
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Affiliation(s)
- A Albini
- National Institute for Cancer Research, Advanced Biotechnologies Center, Genova, Italy
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Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model. Target Oncol 2014; 10:189-98. [PMID: 25185646 DOI: 10.1007/s11523-014-0334-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
Abstract
Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.
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Ji W, Yang M, Praggastis A, Li Y, Zhou HJ, He Y, Ghazvinian R, Cincotta DJ, Rice KP, Min W. Carbamoylating activity associated with the activation of the antitumor agent laromustine inhibits angiogenesis by inducing ASK1-dependent endothelial cell death. PLoS One 2014; 9:e103224. [PMID: 25068797 PMCID: PMC4113355 DOI: 10.1371/journal.pone.0103224] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/26/2014] [Indexed: 11/18/2022] Open
Abstract
The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis.
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Affiliation(s)
- Weidong Ji
- No.1 Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mei Yang
- Breast Disease Center, Guangdong Women and Children Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Alexandra Praggastis
- Department of Chemistry, Colby College, Waterville, Maine, United States of America
| | - Yonghao Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Huanjiao Jenny Zhou
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Yun He
- No.1 Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Roxanne Ghazvinian
- Department of Chemistry, Colby College, Waterville, Maine, United States of America
| | - Dylan J. Cincotta
- Department of Chemistry, Colby College, Waterville, Maine, United States of America
| | - Kevin P. Rice
- Department of Chemistry, Colby College, Waterville, Maine, United States of America
- * E-mail: (WM); (KPR)
| | - Wang Min
- No.1 Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail: (WM); (KPR)
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Griffioen AW, Mans LA, de Graaf AMA, Nowak-Sliwinska P, de Hoog CLMM, de Jong TAM, Vyth-Dreese FA, van Beijnum JR, Bex A, Jonasch E. Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 2012; 18:3961-3971. [PMID: 22573349 DOI: 10.1158/1078-0432.ccr-12-0002] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy. EXPERIMENTAL DESIGN Phase II trials of VEGF pathway-targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy. Primary tumor tissues were obtained and assessed for angiogenesis parameters. Results were compared with similar analyses on untreated tumors. RESULTS Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor. Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues, among which VEGFR-1 and VEGFR-2, angiopoietin-1 and angiopoietin-2 and platelet-derived growth factor-B. In addition, apoptosis in tumor and endothelial cells was induced. Interestingly, in sunitinib-pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab-pretreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment. CONCLUSION This study describes, for the first time, the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF-targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation. The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors.
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Affiliation(s)
- Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Laurie A Mans
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Annemarie M A de Graaf
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Patrycja Nowak-Sliwinska
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Céline L M M de Hoog
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Trees A M de Jong
- Division of Immunology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Florry A Vyth-Dreese
- Division of Immunology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Judy R van Beijnum
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Axel Bex
- Department of Urology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Eric Jonasch
- Department of Genitourinary Oncology, MD Anderson Cancer Center, Houston, TX, USA
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Zhong Z, Wan Y, Shi S, Han J, Zhang Z, Sun X. Co-delivery of Adenovirus and Carmustine by Anionic Liposomes with Synergistic Anti-tumor Effects. Pharm Res 2011; 29:145-57. [DOI: 10.1007/s11095-011-0521-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 06/27/2011] [Indexed: 10/18/2022]
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Ciric E, Sersa G. Radiotherapy in combination with vascular-targeted therapies. Radiol Oncol 2010; 44:67-78. [PMID: 22933894 PMCID: PMC3423684 DOI: 10.2478/v10019-010-0025-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Accepted: 04/20/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. CONCLUSIONS Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised.
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Affiliation(s)
- Eva Ciric
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Gregor Sersa
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
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Raju H, Chandrappa S, Ramakrishna MK, Nagamani TS, Ananda H, Byregowda SM, Rangappa KS. Synthesis, Characterization and Anti-Angiogenic Effects of Novel 5-Amino Pyrazole Derivatives on Ehrlich Ascites Tumor [EAT] Cells in-Vivo. ACTA ACUST UNITED AC 2010. [DOI: 10.4236/jct.2010.11001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Newcomb EW, Lukyanov Y, Alonso-Basanta M, Esencay M, Smirnova I, Schnee T, Shao Y, Devitt ML, Zagzag D, McBride W, Formenti SC. Antiangiogenic effects of noscapine enhance radioresponse for GL261 tumors. Int J Radiat Oncol Biol Phys 2008; 71:1477-84. [PMID: 18640497 DOI: 10.1016/j.ijrobp.2008.04.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Revised: 02/29/2008] [Accepted: 04/18/2008] [Indexed: 01/24/2023]
Abstract
PURPOSE To assess the effects of noscapine, a tubulin-binding drug, in combination with radiation in a murine glioma model. METHODS AND MATERIALS The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation, or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation, tumors were resected and immunostained to measure proliferation rate, apoptosis, and angiogenic activity. RESULTS Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, and 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, and a decrease in tumor vessel density compared with tumors treated with radiation alone. CONCLUSION Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation, resulting in a significant tumor growth delay. An antiangiogenic mechanism contributed to the effect. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug.
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Affiliation(s)
- Elizabeth W Newcomb
- Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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Griffioen AW. Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 2008; 57:1553-8. [PMID: 18438662 PMCID: PMC2491426 DOI: 10.1007/s00262-008-0524-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Accepted: 04/14/2008] [Indexed: 11/18/2022]
Abstract
Ongoing angiogenesis has been shown to possess immune suppressive activity through several mechanisms. One of these mechanisms is the suppression of adhesion receptors, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin—adhesion molecules involved in leukocyte interactions—on the vascular endothelium. This phenomenon, when happening to the tumor endothelium, supports tumor growth due to escape from immunity. Since angiogenesis has this immune suppressive effect, it has been hypothesized that inhibition of angiogenesis may circumvent this problem. In vitro and in vivo data now show that several angiogenesis inhibitors are able to normalize endothelial adhesion molecule expression in tumor blood vessels, restore leukocyte vessel wall interactions, and enhance the inflammatory infiltrate in tumors. It is suggested that such angiogenesis inhibitors can make tumors more vulnerable for the immune system and may therefore be applied to facilitate immunotherapy approaches for the treatment of cancer.
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Affiliation(s)
- Arjan W Griffioen
- Department of Pathology, Research Institute for Growth and Development (GROW), University Hospital Maastricht, AZ Maastricht, The Netherlands.
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Seed MP. Section Review Oncologic, Endocrine & Metabolic: Angiogenesis inhibition as a drug target for disease: an update. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.12.1617] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Abstract
PURPOSE Glioblastoma multiforme (GBM) is the most frequent and incurable brain tumor in adults. Although temozolomide (TMZ) does not cure GBM, it has demonstrated anti-GBM activity and has improved survival (8-14 months) and quality of life. We studied the mechanisms by which TMZ affects 2 human GBM cell lines; U251-MG and U87-MG, aiming to unravel the drug-activated cascades to enable the development of combination therapies that will improve the efficacy of TMZ. MATERIALS AND METHODS The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay was used to assess cell viability. Modulation of gene expression by TMZ therapy was assayed by gene profiling and verified by quantitative real-time polymerase chain reaction. Protein levels influenced by the treatment were studied by Western blots and immunocytochemistry. RESULTS Increasing concentrations of TMZ decreased cell viability in a concentration-dependent manner. The expression of 1,886 genes was altered >2-fold after TMZ treatment. We focused on the 81 genes similarly altered by TMZ treatment in both cell lines to neutralize tissue-specific characteristics. Fourteen target genes of hypoxia-inducible factor (HIF-1), were found to be up-regulated after TMZ treatment including vascular endothelial growth factor (VEGF). HIF-1alpha expression was constant at the mRNA level; however, its post-treatment protein levels increased compared with those of untreated control cells. DISCUSSION The genetic analyses suggest that treatment with TMZ activates stress mechanisms in GBM cells that include the angiogenesis-inducing proteins HIF-1alpha and VEGF. We propose that treatment with TMZ be supplemented with either an antibody to VEGF or down-regulators of HIF-1alpha to improve clinical results of TMZ in the treatment of GBM.
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Teicher BA. Combination of Antiangiogenic Therapy with Other Anticancer Therapies. Angiogenesis 2008. [DOI: 10.1007/978-0-387-71518-6_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Chandru H, Sharada AC, Bettadaiah BK, Kumar CSA, Rangappa KS, Jayashree K. In vivo growth inhibitory and anti-angiogenic effects of synthetic novel dienone cyclopropoxy curcumin analogs on mouse Ehrlich ascites tumor. Bioorg Med Chem 2007; 15:7696-703. [PMID: 17869527 DOI: 10.1016/j.bmc.2007.08.051] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Revised: 08/27/2007] [Accepted: 08/28/2007] [Indexed: 11/29/2022]
Abstract
In the present study, four novel dienone cyclopropoxy curcumin analogs 1a-4a were synthesized by nucleophillic substitution reaction with cyclopropyl bromide. The tumor inhibitory and anti-angiogenic effects of the synthetic compounds were studied on mouse Ehrlich ascites tumor (EAT) in vivo. The compounds 1a-4a increased the life span (% ILS) of EAT bearing mice with corresponding significant reduction in ascites volume and cell number and induced apoptotic bodies in EAT cells. Anti-angiogenic studies of the compounds demonstrated significant reduction of microvessel density (MVD) in the peritoneum wall sections of mice and induced avascular zone in CAM model. Our findings demonstrate that the tumor growth inhibitory effects of synthetic dienone cyclopropoxy curcumin analogs 1a-4a could be mediated by promoting apoptosis and inhibiting tumor angiogenesis. However, the compounds need to be explored further to assess its clinical relevance.
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Affiliation(s)
- H Chandru
- Department of Biochemistry, Yuvaraja's College, University of Mysore, Mysore 570005, India
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Little RF, Aleman K, Kumar P, Wyvill KM, Pluda JM, Read-Connole E, Wang V, Pittaluga S, Catanzaro AT, Steinberg SM, Yarchoan R. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood 2007; 110:4165-71. [PMID: 17846226 PMCID: PMC2234790 DOI: 10.1182/blood-2007-06-097568] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m(2)) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T(1)S(1)). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at (http://www.clinicaltrials.gov) as no. NCT00020449.
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Affiliation(s)
- Richard F Little
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1868, USA
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Ramnath N, Adjei AA. Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors. Lung Cancer 2007. [DOI: 10.3109/9781420020359.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Patterson DM, Rustin GJS. Vascular damaging agents. Clin Oncol (R Coll Radiol) 2007; 19:443-56. [PMID: 17459681 DOI: 10.1016/j.clon.2007.03.014] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2007] [Revised: 02/21/2007] [Accepted: 03/22/2007] [Indexed: 12/27/2022]
Abstract
To provide a comprehensive overview on vascular targeting agents and the application of radiobiological principles in pre-clinical and clinical studies, we completed a comprehensive review of published medical studies on vascular targeting agents using Pub Med. Vascular targeting agents are now divided into vascular disrupting agents (VDAs), which target the pre-existing tumour vasculature, and angiogenesis inhibitors (AIs), which prevent the formation of new blood vessels. Modest success has been seen when VDAs and AIs are used as single agents and therefore combination therapies that can work in a complimentary and synergistic manner, targeting both the tumour cells and endothelial cells, are needed. Radiobiological principles have been used to increase our understanding of these agents, and can explain the increased efficacy of combination treatments. In particular, the alteration of the tumour microenvironment by AIs and VDAs can lead to enhanced efficacy when combined with chemotherapy or radiotherapy, with phase II/III trials showing encouraging results. The optimal use and scheduling of AIs and VDAs remains to be determined. Further understanding of the mechanisms of action of these potentially very exciting anti-neoplastic agents is urgently required.
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Affiliation(s)
- D M Patterson
- Department of Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.
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Amikura K, Matsuno S, Egawa S. Synergistic Antitumor Effect of an Angiogenesis Inhibitor (TNP-470) and Tumor Necrosis Factor in Mice. Surg Today 2006; 36:1069-74. [PMID: 17123135 DOI: 10.1007/s00595-006-3289-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2005] [Accepted: 05/16/2006] [Indexed: 10/23/2022]
Abstract
PURPOSE We investigated the potentiation of combination therapy using tumor necrosis factor (TNF) with TNP-470, a potent angiogenesis inhibitor. METHODS We evaluated the antitumor effect in vivo against subcutaneous (s.c.) MC38 mouse colon adenocarcinoma tumors in C57BL/6 mice. The mice were treated with a single bolus injection via the tail vein of 3 or 8 microg rhTNF in 0.5% bovine serum albumin/normal saline (BSA/NS), or with 0.5% BSA/NS alone as a control, with or without TNP-470 pretreatment, given as 30 or 60 mg/kg x 2 days, s.c. DNA synthesis in human umbilical endothelial cells (HUVEC) was assessed by [(3)H]thymidine uptake after incubation with TNF, with or without TNP-470. RESULTS The antitumor effect of TNP-470 pretreatment combined with 3 microg recombinant human (rh) TNF injection resulted in an 80% reduction of tumor volume compared with the control. This was significantly better than that induced by 3 microg rhTNF alone (P < 0.005). DNA synthesis in HUVEC was inhibited by TNF with TNP-470 in a dose-dependent manner, but there was no enhanced effect against MC38 in vitro. CONCLUSIONS These results suggest that the combination of the angiogenesis inhibitor TNP-470 and TNF might have a synergistic antitumor effect on solid tumors in vivo.
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Affiliation(s)
- Katsumi Amikura
- First Department of Surgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
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Horsman MR, Siemann DW. Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies. Cancer Res 2006; 66:11520-39. [PMID: 17178843 DOI: 10.1158/0008-5472.can-06-2848] [Citation(s) in RCA: 215] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vascular-targeting agent (VTA) have now emerged: those that prevent the angiogenic development of the neovasculature of the tumor and those that specifically damage the already established tumor vascular supply. When used alone neither approach readily leads to tumor control, and so, for VTAs to be most successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy.
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Affiliation(s)
- Michael R Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
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Willett CG, Kozin SV, Duda DG, di Tomaso E, Kozak KR, Boucher Y, Jain RK. Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol 2006; 33:S35-40. [PMID: 17145523 PMCID: PMC2686124 DOI: 10.1053/j.seminoncol.2006.08.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)-targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.
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Affiliation(s)
- Christopher G Willett
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA
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21
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Nieder C, Wiedenmann N, Andratschke N, Molls M. Current status of angiogenesis inhibitors combined with radiation therapy. Cancer Treat Rev 2006; 32:348-64. [PMID: 16713103 DOI: 10.1016/j.ctrv.2006.03.006] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Revised: 03/27/2006] [Accepted: 03/27/2006] [Indexed: 02/06/2023]
Abstract
Angiogenesis inhibitors combined with cytotoxic chemotherapy have recently entered routine oncological practice. Several rationales exist for combining these agents with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. More than 20 different anti-angiogenic agents have been studied in preclinical animal tumor models. This systematic review compares the results of preclinical studies published before February 2006. The combination of vascular endothelial growth factor (VEGF) inhibitors with irradiation consistently resulted in improved tumor growth delay (at least additive effects), despite different radiation schedules, drugs and doses, and combination regimens. Only two studies evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). While anti-VEGF receptor (VEGFR) antibody treatment improved the outcome, a VEGFR tyrosine kinase inhibitor showed negative results. For agents interfering with other pathways, the results are also not consistent, although most studies were positive. Trimodal approaches seem to improve tumor growth delay even further. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, combretastatin A-4, thalidomide and different receptor tyrosine kinase inhibitors, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.
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Affiliation(s)
- Carsten Nieder
- Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
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Shintani S, Li C, Mihara M, Klosek SK, Terakado N, Hino S, Hamakawa H. Anti-tumor effect of radiation response by combined treatment with angiogenesis inhibitor, TNP-470, in oral squamous cell carcinoma. Oral Oncol 2005; 42:66-72. [PMID: 16140034 DOI: 10.1016/j.oraloncology.2005.06.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2005] [Accepted: 06/17/2005] [Indexed: 11/22/2022]
Abstract
Blocking angiogenesis may enhance conventional anticancer treatments such as radiation therapy. In this study, we examined the effects of the angiogenesis inhibitor TNP-470 on human OSCC cell lines HSC2 and KB, with combining radiation therapy in the nude mouse. We evaluated cell-induced neovascularization with dorsal air sac assay, and selected two cells (HSC2: low, KB: high) with different level of cell-induced angiogenesis. The angiogenesis inhibitor TNP-470 was given 30 mg/kg s.c. daily on day 1-5, and irradiation, 8 Gy x 1, was administered on day 1 each week for 3 weeks. Significant inhibition of tumor growth relative to untreated controls was achieved in KB cells showing high induced angiogenesis with both TNP-470 (P < 0.01) and radiation (P < 0.01) and combining TNP-470 and radiation (P < 0.01). We saw little effect of TNP-470 either alone or in addition to the effect of radiation on the HSC2 cells showing low induced angiogenesis. These results suggested that TNP-470 significantly enhanced the effect of radiation on the cells with high neovascularization. These findings indicated that individual evaluation of each tumor neovascularization potential will be important before deciding the anti-angiogenesis treatment.
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Affiliation(s)
- Satoru Shintani
- Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, 454 Shitsukawa, Toon city, Ehime 791-0295, Japan.
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Abstract
The process of formation of new vessels from pre-existing capillaries is called angiogenesis. Angiogenesis is a complex process which involves distinct cells, soluble components and factors related to the extra-cellular matrix and which is highly important in a large variety of physiological and pathological processes in the body. Angiogenesis regulation takes place through a perfect equilibrium between the production and release of different stimulatory and inhibitory factors which vary in relation to needs and tissue types. A large number of diseases are characterized by alterations in the angiogenic process, either by an insufficiency or by excessive angiogenesis. The requirement of blood vessel proliferation for tumor growth was observed more than a century ago. Angiogenic treatment would have an indirect antitumoral action, inhibiting tumor vascularization and impairing the supply of essential nutrients for tumoral growth and development.
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Affiliation(s)
- José L Mauriz
- Departamento de Fisiología, Universidad de León, León, Spain
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Lal B, Xia S, Abounader R, Laterra J. Targeting the c-Met Pathway Potentiates Glioblastoma Responses to γ-Radiation. Clin Cancer Res 2005; 11:4479-86. [PMID: 15958633 DOI: 10.1158/1078-0432.ccr-05-0166] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Resistance to current cytotoxic therapies limits the treatment of most solid malignancies. This results, in part, from the overactivation of receptor tyrosine kinases and their downstream pathways in tumor cells and their associated vasculature. In this report, we ask if targeting the multifunctional mitogenic, cytoprotective, and angiogenic scatter factor/hepatocyte growth factor (SF/HGF)/c-Met pathway potentiates antitumor responses to gamma-radiation. EXPERIMENTAL DESIGN Endogenous expression of SF/HGF and c-Met was targeted in U87 MG human malignant glioma cells and xenografts using chimeric U1/ribozymes. The effects of U1/ribozymes +/- gamma-radiation on glioma cell proliferation, apoptosis, xenograft growth, and animal survival were examined. RESULTS U1/ribozymes knocked down SF/HGF and c-Met mRNA and protein levels, sensitized cells to gamma-radiation (P < 0.005), and enhanced radiation-induced caspase-dependent cytotoxicity in vitro (P < 0.005). Intravenous U1/ribozyme therapy as liposome/DNA complexes or radiation alone modestly and transiently inhibited the growth of s.c. U87 xenografts. Combining the therapies caused tumor regression and a 40% tumor cure rate. In animals bearing intracranial xenografts, long-term survival was 0% in response to radiation, 20% in response to intratumoral adenoviral-based U1/ribozyme delivery, and 80% (P < 0.0005) in response to combining U1/ribozymes with radiation. This apparent synergistic antitumor response was associated with a approximately 70% decrease in cell proliferation (P < 0.001) and a approximately 14- to 40-fold increase in apoptosis (P < 0.0001) within xenografts. CONCLUSIONS Targeting the SF/HGF/c-Met pathway markedly potentiates the anti-glioma response to gamma-radiation. Clinical trials using novel SF/HGF/c-Met pathway inhibitors in glioma and other malignancies associated with c-Met activation should ultimate include concurrent radiation and potentially other cytotoxic therapeutics.
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Affiliation(s)
- Bachchu Lal
- Department of Neurology, The Johns Hopkins University School of Medicine and The Kennedy Krieger Research Institute, Baltimore, Maryland 21205, USA
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Tong Y, Zhang X, Tian F, Yi Y, Xu Q, Li L, Tong L, Lin L, Ding J. Philinopside A, a novel marine-derived compound possessing dual anti-angiogenic and anti-tumor effects. Int J Cancer 2005; 114:843-53. [PMID: 15645493 DOI: 10.1002/ijc.20804] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Philinopside A is a novel sulfated saponin isolated from the sea cucumber, Pentacta quadrangulari. The effects of philinopside A on angiogenesis and tumor growth were assessed in a series of models in vitro and in vivo. Our results demonstrated that philinopside A significantly inhibited the proliferation, migration and tube formation of human microvascular endothelial cells (HMECs) in a dose-dependent manner, with average IC(50) values of 1.4 +/- 0.17, 0.89 +/- 0.23 and 0.98 +/- 0.19 microM, respectively. Rat aortas culture assay provides a close imitation of in vivo angiogenesis process and 2-10 microM philinopside A suppressed the formation of new microvessels in cultured rat aortas. Philinopside A 2-10 nmol/egg obviously inhibited angiogenesis in chick embryo chorioallantoic membrane assay. In addition, philinopside A manifested strong anti-tumor activities both in vitro and in vivo. Through immunofluorescent analysis, we found the compound reduced mouse sarcoma 180 tumor volume by inducing apoptosis of tumor and tumor-associated endothelial cells. An examination of the effects of philinopside A on the angiogenesis-related receptor tyrosine kinases (RTKs) showed that philinopside A broadly inhibited all tested RTKs, including vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor (FGF) receptor-1, platelet-derived growth factor (PDGF) receptor-beta and epithelial growth factor (EGF) receptor, with IC(50) values ranging from 2.6-4.9 microM. These results suggest that philinopside A is a promising anti-cancer agent that possesses dual cytotoxic and anti-angiogenic effects that were at least partly due to its inhibitory effects on RTKs.
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Affiliation(s)
- Yunguang Tong
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China
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Gruber G, Hess J, Stiefel C, Aebersold DM, Zimmer Y, Greiner RH, Studer U, Altermatt HJ, Hlushchuk R, Djonov V. Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy. Br J Cancer 2005; 92:41-6. [PMID: 15597101 PMCID: PMC2361731 DOI: 10.1038/sj.bjc.6602278] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, β3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of β3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of β3-integrin. The impact of immunoreactivity for β3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. β3-integrin was expressed in 61% (50 of 82) of the patients. Kaplan–Meier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with β3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. β3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.
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Affiliation(s)
- G Gruber
- Department of Radiation Oncology, University of Bern, Switzerland
| | - J Hess
- Department of Radiation Oncology, University of Bern, Switzerland
| | - C Stiefel
- Department of Radiation Oncology, University of Bern, Switzerland
| | - D M Aebersold
- Department of Radiation Oncology, University of Bern, Switzerland
| | - Y Zimmer
- Department of Radiation Oncology, University of Bern, Switzerland
| | - R H Greiner
- Department of Radiation Oncology, University of Bern, Switzerland
| | - U Studer
- Department of Radiation Oncology, University of Bern, Switzerland
| | | | - R Hlushchuk
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland
| | - V Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland. E-mail:
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Jia L, Zhang MH, Yuan SZ, Huang WG. Antiangiogenic therapy for human pancreatic carcinoma xenografts in nude mice. World J Gastroenterol 2005; 11:447-50. [PMID: 15637766 PMCID: PMC4205360 DOI: 10.3748/wjg.v11.i3.447] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the anti-tumor effects of antiangiogenic therapy (a combination of TNP-470, an antiangiogenic compound, with gemcitabine, an antimetabolite) on human pancreatic carcinoma xenografts and its mechanism.
METHODS: A surgical orthotopic implantation (SOI) model was established by suturing small pieces of SW1990 pancreatic carcinoma into the tail of pancreas in nude male mice. Mice then received either single therapy (n = 24) or combined therapy (n = 32). Mice receiving single therapy were randomly divided into control group, G100 group receiving 100 mg/kg gemcitabine IP on d 0, 3, 6 and 9 after transplantation, and T30 group receiving 30 mg/kg TNP-470 s.c on alternate days for 8 wk. Mice receiving combined therapy were randomly divided into control group, T15 group, G50 group and combination group (TNP-470 30 mg/kg and gemcitabine 50 mg/kg). Animals were killed 8 wk after transplantation. Transplanted tumors, liver, lymph node and peritoneum were removed. Weight of transplanted tumors, the T/C rate (the rate of mean treated tumor weight to mean control tumor weight), change of body weight, metastasis rate, and 9-wk survival rate were investigated. Tumor samples were taken from the control group, T30 group, G100 group and combination group. PCNA index (PI) and microvessel density (MVD) were investigated by immunohistochemical staining for PCNA and factor VIII, respectively.
RESULTS: There was a significant inhibitory effect on primary tumor growth of pancreatic carcinoma in G100 group, compared to T30 group, whereas tumor metastasis was significantly inhibited in T30 group compared to G100 group. There was no significant improvement in survival rate in these two groups. No significant inhibitory effect on tumor growth and metastasis in T15 group and G50 group. However, significant anti-tumor and anti-metastatic effects were observed in the combination group with a significant improvement in survival rate. The inhibitory effect on tumor growth in combination group enhanced 2 times in comparison with G50 group and 5 times in comparison with T15 group. Moreover, 25% of the animals bearing tumors were cured by the combination therapy. The levels of MVD and PI were 14.50±5.93 and 0.41±0.02, 12.38±1.60 and 0.30±0.07, 7.13±2.99 and 0.37±0.03, and 5.21±1.23 and 0.23±0.02 respectively in the control group, G100 group, T30 group and combination group. A significant inhibitory effect on PI level and MVD level was observed in G100 group and T30 group respectively whereas both MVD and PI levels were significantly inhibited in the combination group (P<0.05).
CONCLUSION: Antiangiogenic therapy shows significant anti-tumor and anti-metastatic effects, and is helpful to reduce the dosage of cytotoxic drugs and the side effects. These effects are related to the antiangiogenic effect of TNP-470 and cytotoxic effect of gemcitabine.
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Affiliation(s)
- Lin Jia
- Department of Digestive Diseases, First People's Municipal Hospital of Guangzhou, Guangzhou Medical College, Guangzhou 510180, Guangdong Province, China.
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Affiliation(s)
- Jennifer A Doll
- Division of Hematology/Oncology, Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA
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Blackhall FH, Shepherd FA. Angiogenesis inhibitors in the treatment of small cell and non-small cell lung cancer. Hematol Oncol Clin North Am 2004; 18:1121-41, ix. [PMID: 15474338 DOI: 10.1016/j.hoc.2004.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Angiogenesis is believed to play a critical role in cancer; however, antiangiogenic therapy has not been demonstrated to improve the survival of patients who have lung cancer. In this article, the evidence that supports a role for angiogenesis in the pathogenesis of lung cancer, trials of antiangiogenic agents in lung cancer performed to date, and the lessons learned from these studies are discussed.
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Affiliation(s)
- Fiona H Blackhall
- Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX England, UK
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Purow B, Fine HA. Progress Report on the Potential of Angiogenesis Inhibitors for Neuro-Oncology. Cancer Invest 2004; 22:577-87. [PMID: 15565816 DOI: 10.1081/cnv-200027141] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
New therapies for brain tumors are urgently needed. Brain tumors are highly vascularized, supporting the potential of anti-angiogenic therapies in their treatment. The promise of blocking tumor growth through inhibiting new blood vessel formation with anti-angiogenic agents has been heralded as a therapeutic breakthrough, and pre-clinical data supported this enthusiasm. However, early clinical trials in humans have been somewhat disappointing. Nonetheless, great optimism for these agents remains, and many new anti-angiogenic agents and strategies are being evaluated pre-clinically and in clinical trials. A number of issues need to be considered in the application of these agents to neuro-oncology. In this review, we discuss the biology of blood vessel formation in the brain and brain tumors as it relates to anti-angiogenic therapies. The difficulties inherent in performing clinical trials of anti-angiogenic therapies in patients with brain tumors are outlined. Finally, we consider numerous individual antiangiogenic and antivascular therapies now in pre-clinical testing or in clinical trials.
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Affiliation(s)
- Benjamin Purow
- Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4089, USA
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Tran HT, Blumenschein GR, Lu C, Meyers CA, Papadimitrakopoulou V, Fossella FV, Zinner R, Madden T, Smythe LG, Puduvalli VK, Munden R, Truong M, Herbst RS. Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol 2004; 54:308-14. [PMID: 15184994 DOI: 10.1007/s00280-004-0816-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2004] [Accepted: 03/15/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors. EXPERIMENTAL DESIGN Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml x min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml x min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed. RESULTS The administered regimen of paclitaxel (225 mg/m(2) i.v. over 3 h) and carboplatin (AUC 6 mg/ml x min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease. CONCLUSIONS The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.
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Affiliation(s)
- Hai T Tran
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, TX 77030, USA.
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Sridhar SS, Shepherd FA. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. Lung Cancer 2004; 42 Suppl 1:S81-91. [PMID: 14611919 DOI: 10.1016/s0169-5002(03)00308-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
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Affiliation(s)
- Srikala S Sridhar
- Department of Medicine, Division of Hematology Oncology of the University Health Network, Princess Margaret Hospital Division, and the University of Toronto, 610 University Avenue, Suite 5-104, Toronto, ON, Canada M5G 2M9
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Laterra JJ, Grossman SA, Carson KA, Lesser GJ, Hochberg FH, Gilbert MR. Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study. Neuro Oncol 2004; 6:15-20. [PMID: 14769135 PMCID: PMC1871972 DOI: 10.1215/s1152851703000127] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2003] [Accepted: 07/25/2003] [Indexed: 11/19/2022] Open
Abstract
Suramin is a polysulfonated naphthylurea that inhibits the function of growth factors and growth factor receptors implicated in glioma progression, angiogenesis, and radioresistance. The safety and benefits of combining inhibitors of angiogenesis and growth factors with cytotoxic therapies in patients with neoplasms of the central nervous system remain unclear. The objectives of this phase 2 study were to determine the safety of administering suramin with standard cranial radiotherapy (RT) and to estimate survival using this approach in patients with newly diagnosed glioblastoma multiforme (GBM). Fifty-five patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled in this multicenter phase 2 study. Patients received suramin by a conventional intermittent fixed-dosing regimen for 1 week prior to and during cranial RT (60 Gy in 30 fractions, weeks 2-7). Patients with stable or responsive disease at week 18 received an additional 4 weeks of suramin (weeks 19-22). The median survival for suramin-treated patients was 11.6 months, with 1-year and 18-month survival rates of 49% (95% confidence interval [CI], 36%-62%) and 18% (95% CI, 8%-28%), respectively. Overall, 55% of the patients (30/55) had greater than grade 2 toxicity at least possibly related to suramin therapy. Two patients died of possibly related neurologic events (i.e., stroke, elevated intracranial pressure). Otherwise, toxicities were generally transient and self-limited. Administration of suramin using an intermittent fixed-dosing regimen during cranial RT was generally well tolerated. However, overall survival is not significantly improved when compared with the New Approaches to Brain Tumor Therapy GBM database or other comparable patient populations.
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Affiliation(s)
- John J Laterra
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
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Gorski DH, Leal AD, Goydos JS. Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. J Am Coll Surg 2003; 197:408-18. [PMID: 12946796 DOI: 10.1016/s1072-7515(03)00388-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Vascular endothelial growth factor-A (VEGF-A) is an important mediator of angiogenesis in normal and neoplastic tissues. Total VEGF-A levels have been associated with melanoma progression, but the relative contributions of each isoform is unknown. To determine whether differences in the production of any or all of the major VEGF-A isoforms are related to stage of progression, we compared message levels for the three major isoforms of VEGF in melanoma specimens from different stages of progression.Primary melanomas (N = 18), primary recurrences (N = 5), regional dermal metastases (N = 11), nodal metastases (N = 12), normal lymph nodes (N = 18), and distant metastases (N = 9) were prospectively collected. Samples from the horizontal and vertical growth phases of primary tumors were also collected from five additional patients. Message levels for the three major VEGF-A isoforms were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and normalized to beta-actin mRNA levels. There was a marked increase in the expression of all three VEGF-A isoforms from the vertical growth phase tissue as compared with the horizontal growth phase tissue. Primary tumors, local recurrences, regional dermal metastases, nodal metastases, and distant metastases all produced more VEGF(121) and VEGF(165) than negative nodes. Nodal metastases produced the highest level of these two isoforms, higher even than distant metastases. There was no significant difference in VEGF(189) message among the groups. Melanomas in the vertical growth phase produce more VEGF-A (all isoforms) than in the horizontal growth phase. Nodal metastases produce the highest levels of VEGF(121) and VEGF(165), but not VEGF(189) as compared with other stages of progression. These data suggest that the soluble forms of VEGF-A might be an important factor in melanoma metastasis to regional lymph nodes.
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Affiliation(s)
- David H Gorski
- Division of Surgical Oncology, UMDNJ-Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
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Abstract
Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
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Affiliation(s)
- Frances A Shepherd
- Division of Hematology Oncology, Department of Medicine, University Health Network, Princess Margaret Hospital Division, University of Toronto, 610 University Avenue, Suite 5-104, Ont., M5G 2M9, Toronto, Canada.
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Fine HA, Wen PY, Maher EA, Viscosi E, Batchelor T, Lakhani N, Figg WD, Purow BW, Borkowf CB. Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 2003; 21:2299-304. [PMID: 12805330 DOI: 10.1200/jco.2003.08.045] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. PATIENTS AND METHODS Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. RESULTS A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. CONCLUSION This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.
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Affiliation(s)
- Howard A Fine
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1911, Building 10, Room 12S245, Bethesda, MD 20892-1911, USA.
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Ma J, Li S, Reed K, Guo P, Gallo JM. Pharmacodynamic-mediated effects of the angiogenesis inhibitor SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral glioma xenograft models. J Pharmacol Exp Ther 2003; 305:833-9. [PMID: 12626639 DOI: 10.1124/jpet.102.048587] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The objective of this study was to determine the tumor distribution of temozolomide, an alkylating agent, in the absence and presence of the angiogenesis inhibitor 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]indolin-2-one (SU5416), a specific vascular endothelial cell growth factor receptor 2 inhibitor. The study was conducted in nude rats bearing either subcutaneous or intracerebral tumors that overexpressed vascular endothelial cell growth factor. For both tumor locations, animals were assigned to either of two treatment groups, SU5416 (25 mg/kg, dissolved in dimethyl sulfoxide) or vehicle control, dimethyl sulfoxide (710 microl/kg) administered i.p. every day for a total of nine doses. Twenty-four hours after the last dose of SU5416 or dimethyl sulfoxide, temozolomide was administrated as a steady-state infusion regimen designed to achieve target plasma concentrations (Cp) of 20 microg/ml. In addition to the measurement of temozolomide Cp, tumor interstitial fluid unbound concentrations of temozolomide were evaluated by microdialysis. In subcutaneous tumors, SU5416 treatment produced a 24% reduction in steady-state temozolomide Ct values (p < 0.05) as well as 21% reductions in tumor/plasma concentration ratios (Ct/Cp; p = 0.11) compared with controls. In intracerebral tumors, steady-state temozolomide Ct and Ct/Cp ratios were significantly increased by 2-fold in the SU5416 treatment group compared with control. The apparent paradoxical effect of SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral tumors is discussed in the context of physiological changes (for example, interstitial fluid pressure and microvessel density) and the sampling region in the tumor. It is proposed that the net balance of antiangiogenic drug-mediated pharmacodynamic actions will determine how drug disposition in tumors may be affected.
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Affiliation(s)
- Jianguo Ma
- Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111, USA
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te Velde EA, Vogten JM, Gebbink MFGB, van Gorp JM, Voest EE, Borel Rinkes IHM. Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model. Br J Surg 2002; 89:1302-9. [PMID: 12296902 DOI: 10.1046/j.1365-2168.2002.02183.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Background
Tumour-induced microvascular networks have become attractive targets in cancer therapy. Strategies that target both tumour cells and vasculature have not been investigated in models of early metastatic colorectal disease. The efficacy of a combination of conventional chemotherapy with a potent angiogenesis inhibitor (endostatin or angiostatin) in a murine model of early colorectal liver metastasis was studied.
Methods
Sixty-six mice were subjected to intrasplenic injection of C26 tumour cells to induce colorectal liver metastases. Control animals received phosphate-buffered saline (n = 8) or citrate buffer (n = 8). Treatment included conventional chemotherapy (n = 9), endostatin (n = 8), high-dose (n = 5) or low-dose (one-tenth of optimal dose; n = 10) angiostatin, as well as the combination of either of these drugs with chemotherapy (n > 5). Clinical appearance was scored daily using a semiquantitative scale. Liver weight, macroscopic and histological tumour involvement (hepatic replacement area; HRA) were measured upon death at day 12.
Results
Treated mice displayed significantly better clinical scores than controls, except for those animals treated with low-dose angiostatin with or without chemotherapy. Treatment with conventional chemotherapy resulted in a decrease in HRA from 42·3 to 29·1 per cent (P < 0·001). The addition of angiostatin or endostatin to conventional chemotherapy improved antitumoral efficacy, in a multiplicative manner, resulting in a HRA of approximately 3·5 per cent (P < 0·001).
Conclusion
The addition of angiostatin or endostatin to conventional chemotherapy enhanced antitumoral efficacy in a murine model of early colorectal liver metastasis.
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Affiliation(s)
- E A te Velde
- Department of Surgery and Laboratory of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Herbst RS, Madden TL, Tran HT, Blumenschein GR, Meyers CA, Seabrooke LF, Khuri FR, Puduvalli VK, Allgood V, Fritsche HA, Hinton L, Newman RA, Crane EA, Fossella FV, Dordal M, Goodin T, Hong WK. Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer. J Clin Oncol 2002; 20:4440-7. [PMID: 12431966 DOI: 10.1200/jco.2002.04.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
PURPOSE Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.
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Affiliation(s)
- Roy S Herbst
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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Abstract
It is accepted that novel therapeutic approaches are needed for the majority of patients with malignant brain tumors. The vascularity of many primary brain tumors and the encouraging preclinical studies suggest that antiangiogenic agents have the potential to become an important component of multimodality treatment of patients with brain tumors. The understanding of the biology of angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of brain tumor neovasculature. Neuroimaging techniques evaluating the angiogenic process and the impact of antiangiogenic agents will be an important tool for the rapid development of these novel therapeutic agents.
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Affiliation(s)
- Michael J Fisher
- Division of Oncology, Children's Hospital of Philadelphia, ARC 907B, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4399, USA
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Raju U, Nakata E, Yang P, Newman RA, Ang KK, Milas L. In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistic considerations. Int J Radiat Oncol Biol Phys 2002; 54:886-94. [PMID: 12377342 DOI: 10.1016/s0360-3016(02)03023-7] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE Selective cyclooxygenase-2 inhibitors have been reported to enhance the tumor response to radiation in vivo, but the cellular mechanisms underlying the radiosensitizing effect are not understood. In the present study, we investigated several possible mechanisms using a murine sarcoma cell culture system. METHODS AND MATERIALS Cells derived from a murine sarcoma, designated NFSA, were cultured in vitro and exposed to different (either single or split) doses of radiation with and without a pretreatment of SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-yl] benzene sulfonamide), a selective cyclooxygenase-2 (COX-2) inhibitor. The cells were assayed for clonogenic survival to determine the radiosensitizing effect of SC-236. In addition, MTT assay and TUNEL assay were performed to determine the effects of SC-236 and radiation on the cell survival and cell cycle distribution. RNase protection assay was performed on the total RNA extract using probes that encoded for selected cell cycle regulatory proteins, such as cyclins and cyclin-dependent kinases. To monitor the extent of COX-2 activity and its role in radiosensitization, the cellular content of prostaglandin E2, a major metabolite of COX-2 activity on arachidonic acid, was also determined. RESULTS The cell clonogenic survival assay showed that SC-236 significantly enhanced tumor cell radiosensitivity: 50 microM SC-236 increased it by a factor of 1.51 at the 0.1 cell survival level. Treatment with SC-236 (50 microM, 3 days) removed the "shoulder" region on the radiation survival curve, suggesting that the drug inhibited repair of sublethal radiation damage. The inhibition was confirmed by split-dose experiments where two doses (3 Gy each) of radiation were given 4 h apart. The cells exposed to radiation only repaired the damage by a factor of 1.44, whereas those treated with SC-236 plus radiation repaired it by a factor of 1.1 only. Whereas SC-236 induced apoptosis in these NFSA cells, radiation did not. No further increase in apoptosis was observed when the cells were exposed to both SC-236 and radiation, suggesting that SC-236 did not render tumor cells more susceptible to radiation-induced apoptosis. The RNase protection assay showed that SC-236 (50 microM, 3 days) inhibited the expression of cyclins A and B, as well as cyclin-dependent kinase-1. Inhibition of these cell cycle regulatory elements by SC-236 was associated with the arrest of cells in the radiosensitive G2-M phase (67%), determined by flow cytometry. CONCLUSIONS SC-236 significantly enhanced radiosensitivity of tumor cells; the magnitude of sensitivity was dependent on the drug's concentration. The likely mechanisms involve accumulation of cells in the radiosensitive G2-M phase of the cell cycle and inhibition of repair from sublethal radiation damage.
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Affiliation(s)
- Uma Raju
- Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
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Abstract
Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.
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Affiliation(s)
- Edward S Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston 77030, USA.
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Hess C, Vuong V, Hegyi I, Riesterer O, Wood J, Fabbro D, Glanzmann C, Bodis S, Pruschy M. Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer 2001; 85:2010-6. [PMID: 11747347 PMCID: PMC2364010 DOI: 10.1054/bjoc.2001.2166] [Citation(s) in RCA: 127] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.
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MESH Headings
- Adenocarcinoma/blood supply
- Adenocarcinoma/drug therapy
- Adenocarcinoma/pathology
- Adenocarcinoma/radiotherapy
- Administration, Oral
- Angiogenesis Inhibitors/administration & dosage
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Apoptosis/drug effects
- Cell Division/drug effects
- Colonic Neoplasms/blood supply
- Colonic Neoplasms/drug therapy
- Colonic Neoplasms/pathology
- Colonic Neoplasms/radiotherapy
- Combined Modality Therapy
- Endothelium, Vascular/cytology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/radiation effects
- Enzyme Inhibitors/administration & dosage
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use
- Humans
- Mice
- Mice, Nude
- Neoplasm Proteins/antagonists & inhibitors
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/radiotherapy
- Phthalazines/administration & dosage
- Phthalazines/pharmacology
- Phthalazines/therapeutic use
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Pyridines
- Radiotherapy, Adjuvant
- Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
- Receptors, Growth Factor/antagonists & inhibitors
- Receptors, Vascular Endothelial Growth Factor
- Xenograft Model Antitumor Assays
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Affiliation(s)
- C Hess
- Department of Radiation Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland
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Stebbing J, Benson C, Eisen T, Pyle L, Smalley K, Bridle H, Mak I, Sapunar F, Ahern R, Gore ME. The treatment of advanced renal cell cancer with high-dose oral thalidomide. Br J Cancer 2001; 85:953-8. [PMID: 11592764 PMCID: PMC2375104 DOI: 10.1054/bjoc.2001.2025] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2001] [Revised: 05/29/2001] [Accepted: 07/05/2001] [Indexed: 11/18/2022] Open
Abstract
Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-alpha, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34-76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1-29), 7 (32%; 95% CI: 14-55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8-45) had stable disease for between 3 and 6 months. We also measured levels of TNF-alpha, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD > or = 3 months or an objective response, a statistically significant decrease in serum TNF-alpha levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (> or = grade II, 10 patients), constipation (> or = grade II, 11 patients) and neuropathy (> or = grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies.
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Affiliation(s)
- J Stebbing
- Department of Medical Oncology, The Royal Marsden Hospital, London SW3 6JJ, UK
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Burke PA, DeNardo SJ. Antiangiogenic agents and their promising potential in combined therapy. Crit Rev Oncol Hematol 2001; 39:155-71. [PMID: 11418313 DOI: 10.1016/s1040-8428(01)00115-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
One of the most promising strategies for treating cancer is the addition of antiangiogenic therapy to therapeutic regimens. Angiogenesis, or the growth of new blood vessels from preexisting vessels, is essential both for the growth of a primary tumor and for successful metastasis. As a result of intense research in this field, a number of antiangiogenic agents have been identified and have demonstrated varying degrees of success in inhibiting the growth of solid tumors and metastases in preclinical and clinical studies. The real potential of antiangiogenic agents for cancer therapy resides in strategic combinations with each other, with chemotherapy, with radiation, and with tumor-targeting agents, such as radioimmunotherapy. Along with this new opportunity to develop synergistic therapy comes the challenging complexities of the physiologic systems regulating angiogenesis. These multifaceted systems could intimidate investigators seeking to take advantage of the potential synergy in combined cancer therapy. To aid in these efforts, this overview of key antiangiogenic agent mechanisms, combination strategies and initial studies of the potential synergy with chemotherapy, radiation and radioimmunotherapy is presented.
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Affiliation(s)
- P A Burke
- Division of Hematology/Oncology, Department of Internal Medicine, Davis Medical Center, University of California, 1508 Alhambra Boulevard, Sacramento, CA 95816, USA
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Presta M, Rusnati M, Dell'Era P, Tanghetti E, Urbinati C, Giuliani R, Leali D. Examining new models for the study of autocrine and paracrine mechanisms of angiogenesis through FGF2-transfected endothelial and tumour cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2001; 476:7-34. [PMID: 10949652 DOI: 10.1007/978-1-4615-4221-6_2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumour neovascularization. Several growth factors and cytokines have been shown to stimulate endothelial cell proliferation in vitro and in vivo and among them FGF2 was one of the first to be characterised. FGF2 is a Mr 18,000 heparin-binding cationic polypeptide that induces proliferation, migration, and protease production in endothelial cells in culture and neovascularization in vivo. FGF2 interacts with endothelial cells through two distinct classes of receptors, the high affinity tyrosine-kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix. Besides experimental evidence for paracrine mode of action for FGF2, some observations raise the hypothesis that FGF2 may also play an autocrine role in endothelial cells. FGF2 may therefore represent a target for anti-angiogenic therapies. In order to assess the angiostatic potential of different classes of compounds, novel experimental models have been developed based on the autocrine and/or the paracrine capacity of FGF2.
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Affiliation(s)
- M Presta
- Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy
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Aebersold DM, Beer KT, Laissue J, Hug S, Kollar A, Greiner RH, Djonov V. Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx. Int J Radiat Oncol Biol Phys 2000; 48:17-25. [PMID: 10924967 DOI: 10.1016/s0360-3016(00)00573-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: </= 80: baseline, 81-110: risk ratio = 2.71, 111-130: risk ratio = 4.55, > 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.
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Affiliation(s)
- D M Aebersold
- Department of Radiation Oncology, University of Berne, Inselspital, Berne, Switzerland
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48
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Kruger EA, Figg WD. TNP-470: an angiogenesis inhibitor in clinical development for cancer. Expert Opin Investig Drugs 2000; 9:1383-96. [PMID: 11060750 DOI: 10.1517/13543784.9.6.1383] [Citation(s) in RCA: 93] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.
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Affiliation(s)
- E A Kruger
- National Cancer Institute/NIH, Medicine Branch, 9000 Rockville Pike, Bethesda, MD 20892, USA
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McDonnell CO, Hill AD, McNamara DA, Walsh TN, Bouchier-Hayes DJ. Tumour micrometastases: the influence of angiogenesis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2000; 26:105-15. [PMID: 10744927 DOI: 10.1053/ejso.1999.0753] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Many cancer patients have undetected micrometastatic disease at first presentation which ultimately progresses. Angiogenesis-the development of an independent blood supply-is a key event in the growth of metastases. Improved understanding of the influence of angiogenesis on micrometastatic growth may lead to new therapeutic intervention. METHODS This study examines current concepts of the significance of micrometastases and the role of angiogenesis in their development and destruction. A comprehensive review of the literature on micrometastasis and angiogenesis was performed using the Medline database between 1966 and 1999. CONCLUSIONS Advances in technology have improved our ability to diagnose metastatic disease, but micrometastases in loco-regional lymph nodes and at distant sites can only be detected by sophisticated histological techniques. While the significance of micrometastases remains controversial, there is increasing evidence that micrometastatic status provides useful prognostic information and should be part of standard staging techniques. Anti-angiogenic therapy has the potential to favourably influence management of certain cancers by manipulating a number of key events in the metastatic process.
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Affiliation(s)
- C O McDonnell
- Royal College of Surgeons in Ireland, Department of Surgery, Dublin 9, Ireland
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Zhu Z, Witte L. Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to the receptors of vascular endothelial growth factor. Invest New Drugs 2000; 17:195-212. [PMID: 10665474 DOI: 10.1023/a:1006314501634] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical and pre-clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent good targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. We have produced a panel of antibodies directed against the VEGF receptor 2, KDR/F1k-1. These antibodies potently block VEGF/KDR/F1k-1 interaction, and inhibit VEGF-stimulated activation of the receptor and proliferation of human endothelial cells. Further, the antibodies significantly inhibited tumor-associated angiogenesis in several animal models. Antagonists of VEGF and/or its receptors may offer higher specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy. Anti-angiogenesis therapy represents a novel strategy for the treatment of cancer and other human disorders where pathological angiogenesis is involved.
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Affiliation(s)
- Z Zhu
- Department of Molecular and Cell Biology, ImClone Systems Incorporated, New York, NY 10014, USA.
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