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Xuesi Chen - One of the best experts on this subject based on the ideXlab platform.
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nanoparticles composed of pegylated alternating copolymer Combretastatin A4 conjugate for cancer therapy
Macromolecular Bioscience, 2021Co-Authors: Yu Zhang, Xinming Liu, Xueping Wang, Chunsheng Xiao, Xuesi ChenAbstract:Chemotherapy using vascular targeting agents is an emerging new approach for cancer therapy. Combretastatin A4 (CA4) is a leading vascular-disrupting agent that targets the tumor blood vasculature for clinical tumor elimination. However, the extremely poor water solubility of CA4 hinders its biomedical applications. In this study, nanoparticles composed of novel PEGylated alternating copolymer-CA4 conjugates are designed to improve the therapeutic efficiency of CA4. First, an alternating copolymer with an alkene-pendant is synthesized by mPEG-OH-initiated ring-opening copolymerization. Then, side carboxyl groups are introduced by a thio-ene "click" chemical reaction, followed with CA4 conjugation through the Yamaguchi-reaction, resulting in the target copolymer, mPEG-b-P(PA-alt-GCA4). Interestingly, the polymer-drug conjugates can self-assemble into nanoparticles with an average diameter of 55.6 nm. The in vitro drug release and cytotoxicity of the obtained CA4-NPs toward 4T1 cells are investigated. Finally, the antitumor efficiency is evaluated in a 4T1-tumor bearing murine model. The in vivo test results demonstrate that CA4-NPs inhibited tumor growth much more efficiently at doses of 30 and 60 mg kg-1 , compared with the control group.
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Combretastatin A4 nanodrug induced mmp9 amplification boosts tumor selective release of doxorubicin prodrug
Advanced Materials, 2019Co-Authors: Zhaohui Tang, Xuesi Chen, Jian Jiang, Na ShenAbstract:Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes Combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.
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co administration of Combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma
Acta Biomaterialia, 2019Co-Authors: Yalin Wang, Dawei Zhang, Wantong Song, Zhaohui Tang, Kazuo Sakurai, Guanyi Wang, Yingmin Liu, Ziling Liu, Xuesi ChenAbstract:Abstract Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/Combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg−1 plus sorafenib 30 mg·kg−1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment. Statement of Significance Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/Combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.
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an eximious and affordable gsh stimulus responsive poly α lipoic acid nanocarrier bonding Combretastatin A4 for tumor therapy
Biomaterials Science, 2019Co-Authors: Dawei Zhang, Zhaohui Tang, Na Shen, Zhilin Liu, Chenguang Yang, Xuesi ChenAbstract:Due to poor penetration of cytotoxic-drug-loaded-nanomedicines, more and more attention has been paid to nanodrugs of vascular disrupting agents (VDAs). However, traditional VDA nanodrugs lack tumor-selectivity, so new nano-carriers for tumor-selective CA4 delivery are urgently needed. Here, a novel PEGylated poly(alpha-lipoic acid) graft Combretastatin A4 (PALA-g-mPEG/CA4) nanoparticle with glutathione (GSH) stimulus responsive ability was prepared from alpha-lipoic acid in a simple approach, which can accumulate and release CA4 selectively in a tumor site. Furthermore, this simple system has potential application value for tumor-targeting delivery and GSH sensitive release of other drugs.
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correction an eximious and affordable gsh stimulus responsive poly α lipoic acid nanocarrier bonding Combretastatin A4 for tumor therapy
Biomaterials Science, 2019Co-Authors: Zhilin Liu, Dawei Zhang, Zhaohui Tang, Na Shen, Chenguang Yang, Xuesi ChenAbstract:Due to poor penetration of cytotoxic-drug-loaded-nanomedicines, more and more attention has been paid to nanodrugs of vascular disrupting agents (VDAs). However, traditional VDA nanodrugs lack tumor-selectivity, so new nano-carriers for tumor-selective CA4 delivery are urgently needed. Here, a novel PEGylated poly(alpha-lipoic acid) graft Combretastatin A4 (PALA-g-mPEG/CA4) nanoparticle with glutathione (GSH) stimulus responsive ability was prepared from alpha-lipoic acid in a simple approach, which can accumulate and release CA4 selectively in a tumor site. Furthermore, this simple system has potential application value for tumor-targeting delivery and GSH sensitive release of other drugs.
Liyan Qiu - One of the best experts on this subject based on the ideXlab platform.
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Water-Soluble Combretastatin A4 Phosphate Orally Delivered via Composite Nanoparticles With Improved Inhibition Effect Toward S180 Tumors
Journal of pharmaceutical sciences, 2017Co-Authors: Yurun Shen, Liyan QiuAbstract:Abstract Combretastatin A4 phosphate (CA4P) is a novel vascular disrupting agent for cancer therapy. However, frequent dosing and negative patient compliance have been encountered over CA4P by injection administration due to its quite short-term action and acute side effects. Therefore, it is significant to develop an oral formulation of CA4P. We established a novel method to prepare CA4P-loaded nanoparticles (CA4P-NPs) for oral administration by combining methoxy poly(ethylene glycol)-b-polylactide (PELA) and poly(d,l-lactic-co-glycolic acid) (PLGA) polymers. Transport study in vitro was evaluated on Madin-Darby canine kidney cell models, and antitumor effect evaluation in vivo was performed on S180 subcutaneous xenotransplanted tumor models in mice. The highest entrapment efficiency of CA4P-NPs was achieved when the weight ratio of PELA to PLGA was optimized to 1:1. The apparent permeability coefficient of CA4P-NPs was found to be 2.08-fold higher than that of free CA4P in transport study. CA4P-NPs reached an absolute bioavailability of 77.6% with the tumor inhibition ratio of 41.2% that was significantly superior to free CA4P. These results suggest a promising application of this composite nanoparticle for the oral delivery of water-soluble drugs.
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Drug resistance reversal by Combretastatin-A4 phosphate loaded with doxorubicin in polymersomes independent of angiogenesis effect.
The Journal of pharmacy and pharmacology, 2017Co-Authors: Jinfang Zhu, Liyan QiuAbstract:Objectives This study aimed to evaluate that the polymersomes (Ps-DOX-CA4P) dual-loaded with Combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) overcame drug resistance and sensitized tumour cells to chemotherapeutic drugs. Methods Ps-DOX-CA4P were prepared by solvent evaporation method using mPEG-b-PLA as carriers. The potential capability of CA4P to reverse DOX resistance was verified by cytotoxicity test, apoptosis assay and cellular uptake of DOX. The comparison between free drugs and drug-loaded polymersomes was also made on a single-layer cell model and multicellular tumour spheroids to display the superiority of the drug vehicles. Furthermore, we put the emphasis on the investigation into underlying mechanisms for CA4P overcoming DOX resistance. Key findings Results showed Ps-DOX-CA4P achieved increased uptake of DOX, enhanced cytotoxicity and apoptotic rate in MCF-7/ADR cells as well as MCF-7/ADR tumour spheroids. The potential molecular mechanisms may be related to inhibiting P-glycoprotein function by downregulating protein kinase Cα, stimulating ATPase activity, depleting ATP and increasing intracellular reactive oxygen species levels. Conclusions The findings validated the sensitization property of CA4P on DOX independent of its well-known angiogenesis effect, which would provide a novel and promising strategy for drug-resistant cancer therapy.
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Reverse micelles-in-microspheres with sustained release of water-soluble Combretastatin A4 phosphate for S180 tumor treatment
Journal of materials chemistry. B, 2016Co-Authors: Liyan QiuAbstract:Combretastatin A4 phosphate (CA4P), the water-soluble phosphate pro-drug of Combretastatin A4 (CA4), acts as a novel vascular disrupting agent (VDA). It strongly inhibits tubulin polymerization and selectively exerts action against tumor blood vessels. However, its quite short half-life (∼30 min) results in a short action time and consequently limits its application. Therefore, it is beneficial to develop a sustained-release preparation of CA4P for relatively long action duration. On the other hand, conventional PLGA microspheres display poor encapsulation capability for water-soluble small molecules due to rapid diffusion outside. Hence, we developed CA4P-loaded microspheres (CA4P-MS) composed of methoxy poly(ethylene glycol)-b-polylactide (PELA) reverse micelles and PLGA with a nano-in-micro sea-island structure. The CA4P encapsulation efficiency of CA4P-MS reached 92.88%. More interestingly, sustained drug release was achieved, which contributed to the prolonged inhibition effect on S180 tumor during a 30-day period with one-time subcutaneous administration. In conclusion, our study established a biodegradable polymer based platform to construct microspheres for water-soluble small molecular compounds with sustained release and a long-lasting action.
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Co-Encapsulation of Combretastatin-A4 Phosphate and Doxorubicin in Polymersomes for Synergistic Therapy of Nasopharyngeal Epidermal Carcinoma.
Journal of biomedical nanotechnology, 2015Co-Authors: Jinfang Zhu, Liyan QiuAbstract:In this study, we designed biodegradable polymersomes for co-delivery of an antiangiogenic drug Combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) to collapse tumor neovasculature and inhibit cancer cell proliferation with the aim to achieve synergistic antitumor effects. The polymersomes co-encapsulating DOX and CA4P (Ps-DOX-CA4P) were prepared by solvent evaporation method using methoxy poly(ethylene glycol)-b-polylactide (mPEG-PLA) block copolymers as drug carriers. The resulting Ps-DOX-CA4P has vesicles shape with uniform sizes of about 50 nm and controlled co-encapsulation ratios of DOX to CA4P. More importantly, Ps-DOX-CA4P (1:10) showed strong synergistic cytotoxicity (combination index CI = 0.31) against human nasopharyngeal epidermal carcinoma (KB) cells. Furthermore, Ps-DOX-CA4P accumulated remarkably in KB tissues xenografts in nude mice. Consistent with these observations, Ps-DOX-CA4P (1:10) achieved significant antitumor potency because of fast tumor vasculature disruption and sustained tumor cells proliferation inhibition in vivo. The overall findings indicate that co-delivery of an antiangiogenic drug and a chemotherapeutic agent in polymersomes is a potentially promising strategy for cancer therapy.
Zhaohui Tang - One of the best experts on this subject based on the ideXlab platform.
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Combretastatin A4 nanodrug induced mmp9 amplification boosts tumor selective release of doxorubicin prodrug
Advanced Materials, 2019Co-Authors: Zhaohui Tang, Xuesi Chen, Jian Jiang, Na ShenAbstract:Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes Combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.
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Combretastatin A4 nanodrug combined plerixafor for inhibiting tumor growth and metastasis simultaneously.
Biomaterials science, 2019Co-Authors: Jian Jiang, Wantong Song, Na Shen, Kazuo Sakurai, Zhaohui TangAbstract:Inhibition of tumor growth and metastasis simultaneously is an important issue for tumor therapy. The CXCR4/CXCL12 axis plays a crucial role in cancer metastasis, and the blocking of the CXCR4/CXCL12 axis is an effective way of inhibiting cancer metastasis. Combretastatin A4 nanodrug (CA4-NPs), a neogenesis blood vascular disrupting agent, can accumulate around blood vessels and disrupt tumor neogenesis of blood vessels more efficaciously than typical small molecular drug Combretastatin A4 phosphate (CA4P). However, in this work, we find that the CXCR4 expression is significantly enhanced in CA4-NPs-treated tumor tissues in a metastatic orthotopic 4T1 mammary adenocarcinoma mouse model. Considering that the overexpression of CXCR4 can promote tumor cell metastasis, a novel cooperative strategy that utilizes plerixafor (PLF, CXCR4 antagonist) with CA4-NPs for inhibiting tumor growth and metastasis simultaneously is developed. The combination of CA4-NPs (60 mg kg-1 on CA4 basis) + PLF shows remarkably enhanced antitumor efficacy. The tumor growth inhibition rate of the combination group reaches 91.3%, significantly higher than those of non-cooperative groups. In addition, the number of lung metastasis foci of the combination group is least among all groups. This cooperative strategy provides a useful method for inhibiting tumor growth and metastasis simultaneously, and gives the evidence to support the clinical use of the combination of vascular disruption agents and CXCR4 antagonists.
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co administration of Combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma
Acta Biomaterialia, 2019Co-Authors: Yalin Wang, Dawei Zhang, Wantong Song, Zhaohui Tang, Kazuo Sakurai, Guanyi Wang, Yingmin Liu, Ziling Liu, Xuesi ChenAbstract:Abstract Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/Combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg−1 plus sorafenib 30 mg·kg−1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment. Statement of Significance Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/Combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.
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an eximious and affordable gsh stimulus responsive poly α lipoic acid nanocarrier bonding Combretastatin A4 for tumor therapy
Biomaterials Science, 2019Co-Authors: Dawei Zhang, Zhaohui Tang, Na Shen, Zhilin Liu, Chenguang Yang, Xuesi ChenAbstract:Due to poor penetration of cytotoxic-drug-loaded-nanomedicines, more and more attention has been paid to nanodrugs of vascular disrupting agents (VDAs). However, traditional VDA nanodrugs lack tumor-selectivity, so new nano-carriers for tumor-selective CA4 delivery are urgently needed. Here, a novel PEGylated poly(alpha-lipoic acid) graft Combretastatin A4 (PALA-g-mPEG/CA4) nanoparticle with glutathione (GSH) stimulus responsive ability was prepared from alpha-lipoic acid in a simple approach, which can accumulate and release CA4 selectively in a tumor site. Furthermore, this simple system has potential application value for tumor-targeting delivery and GSH sensitive release of other drugs.
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correction an eximious and affordable gsh stimulus responsive poly α lipoic acid nanocarrier bonding Combretastatin A4 for tumor therapy
Biomaterials Science, 2019Co-Authors: Zhilin Liu, Dawei Zhang, Zhaohui Tang, Na Shen, Chenguang Yang, Xuesi ChenAbstract:Due to poor penetration of cytotoxic-drug-loaded-nanomedicines, more and more attention has been paid to nanodrugs of vascular disrupting agents (VDAs). However, traditional VDA nanodrugs lack tumor-selectivity, so new nano-carriers for tumor-selective CA4 delivery are urgently needed. Here, a novel PEGylated poly(alpha-lipoic acid) graft Combretastatin A4 (PALA-g-mPEG/CA4) nanoparticle with glutathione (GSH) stimulus responsive ability was prepared from alpha-lipoic acid in a simple approach, which can accumulate and release CA4 selectively in a tumor site. Furthermore, this simple system has potential application value for tumor-targeting delivery and GSH sensitive release of other drugs.
Jean-claude Florent - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of Combretastatin A4.
Bioorganic and Medicinal Chemistry, 2013Co-Authors: Renee Pontikis, Guy G Chabot, Lionel Quentin, Stéphane Bourg, Emmanuelle Devillers, Jean-claude FlorentAbstract:To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl Combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.
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Synthesis and structure-activity relationships of constrained heterocyclic analogues of Combretastatin A4.
ChemMedChem, 2011Co-Authors: Martin Arthuis, Renee Pontikis, Guy G Chabot, Johanne Seguin, Lionel Quentin, Stéphane Bourg, Luc Morin-allory, Jean-claude FlorentAbstract:A series of Combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.
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domino approach to 2 aroyltrimethoxyindoles as novel heterocyclic Combretastatin A4 analogues
European Journal of Medicinal Chemistry, 2011Co-Authors: Martin Arthuis, Renee Pontikis, Guy G Chabot, Lionel Quentin, Daniel Scherman, Jean-claude FlorentAbstract:Two series of 2-aroyltrimethoxyindoles were designed to investigate the effects of the replacement of the trimethoxyphenyl ring of phenstatin with a trimethoxyindole moiety. These compounds were efficiently prepared through a domino palladium-catalyzed sequence from 2-gem-dibromovinylanilines substituted by three methoxy groups and arylboronic acids under carbon monoxide atmosphere. These novel heterocyclic Combretastatin A4 analogues were evaluated for their cell growth inhibitory properties and their ability to inhibit the tubulin polymerization.
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Synthesis and biological evaluation of cis-locked vinylogous Combretastatin-A4 analogues: derivatives with a cyclopropyl-vinyl or a cyclopropyl-amide bridge.
Bioorganic and Medicinal Chemistry Letters, 2009Co-Authors: Julia Kaffy, Renee Pontikis, Sylviane Thoret, Luc Morin-allory, Alban Arrault, Joelle Dubois, Jean-claude FlorentAbstract:A series of novel Combretastatin A4 analogues, in which the cis-olefinic bridge is replaced by a cyclopropyl-vinyl or a cyclopropyl-amide moiety, were synthesized and evaluated for inhibition of tubulin polymerization and antiproliferative activity. The derivative 9a with a (cis,E)-cyclopropyl-vinyl unit is the most promising compound. As expected, molecular docking of 9a has shown that only one of the cis-cyclopropyl enantiomers is a good ligand for tubulin.
David J Chaplin - One of the best experts on this subject based on the ideXlab platform.
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A review and update of the current status of the vasculature-disabling agent Combretastatin-A4 phosphate (CA4P).
Expert opinion on investigational drugs, 2009Co-Authors: Dietmar W. Siemann, David J Chaplin, Patricia A WalickeAbstract:Vascular-disrupting strategies impair a tumor's blood vessel network, which is essential for tumor progression and metastasis. Vascular-disrupting agents (VDAs) cause a rapid and selective vascular shutdown in tumors to produce extensive secondary neoplastic cell death due to ischemia. A lead agent in this therapeutic strategy is the tubulin depolymerizing agent Combretastatin-A4 phosphate (CA4P). Used alone, CA4P induces extensive necrosis in a wide variety of preclinical cancer models and significant blood flow reductions in the patient tumors. Preclinical and clinical data further indicate that CA4P can effectively be combined with chemotherapy or radiotherapy. Finally, the potential of combining VDAs with antiangiogenic therapies has shown considerable promise in preclinical models and such combinations are now beginning to be evaluated in patients.
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Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial cadherin signaling
Journal of Clinical Investigation, 2005Co-Authors: Loic Vincent, Pouneh Kermani, Lauren M Young, Joseph Cheng, Koji Shido, Heidi Bompaisvincent, Daniel J Hicklin, Peter Bohlen, Fan Zhang, David J ChaplinAbstract:The molecular and cellular pathways that support the maintenance and stability of tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as Combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of tumor neovessels has opened up new avenues of research to identify factors that support tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of unstable nascent tumor neovessels by rapidly disrupting the molecular engagement of the endothelial cell–specific junctional molecule vascular endothelial-cadherin (VE-cadherin) in vitro and in vivo in mice. CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of VE-cadherin/β-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and tumor necrosis. Remarkably, stabilization of VE-cadherin signaling in endothelial cells with adenovirus E4 gene or ensheathment with smooth muscle cells confers resistance to CA4P. CA4P synergizes with low and nontoxic doses of neutralizing mAbs to VE-cadherin by blocking assembly of neovessels, thereby inhibiting tumor growth. These data suggest that the microtubule-targeting agent CA4P selectively induces regression of unstable tumor neovessels, in part through disruption of VE-cadherin signaling. Combined treatment with anti–VE-cadherin agents in conjunction with microtubule-disrupting agents provides a novel synergistic strategy to selectively disrupt assembly and induce regression of nascent tumor neovessels, with minimal toxicity and without affecting normal stabilized vasculature.
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Combretastatin A4 phosphate: background and current clinical status
Expert opinion on investigational drugs, 2004Co-Authors: Scott Young, David J ChaplinAbstract:Combretastatin A4 phosphate (CA4P) represents the lead compound in a group of novel tubulin depolymerising agents being developed as vascular targeting agents (VTAs). VTAs are drugs that induce rapid and selective vascular dysfunction in tumours. CA4P is a water-soluble prodrug of the cis-stilbene CA4 originally isolated from the tree Combretum caffrum. Preclinical studies have shown that CA4P induces blood flow reductions and subsequent tumour cell death in a variety of preclinical models. Moreover, this activity has been linked to its ability to rapidly alter the morphology of immature endothelial cells by disrupting their tubulin cytoskeleton. Phase I clinical trials have established a maximum tolerated dose in the range 60 – 68 mg/m2 and in addition have established that significant changes to tumour perfusion can be achieved across a wide range of doses. The dose-limiting toxicities include tumour pain, ataxia and cardiovascular changes. The maximum tolerated dose was independent of schedule, indicat...
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phase i trial of the antivascular agent Combretastatin A4 phosphate on a 5 day schedule to patients with cancer magnetic resonance imaging evidence for altered tumor blood flow
Journal of Clinical Oncology, 2003Co-Authors: James P Stevenson, Michael R.l. Stratford, Mark A Rosen, Maryann Gallagher, Daniel G Haller, David J Vaughn, Bruce J Giantonio, Ross Zimmer, William P Petros, David J ChaplinAbstract:Purpose: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. Patients and Methods: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving ≥ 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. Results: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea o...
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Schedule dependence of Combretastatin A4 phosphate in transplanted and spontaneous tumour models.
International Journal of Cancer, 2002Co-Authors: Sally A. Hill, David J Chaplin, Gemma Lewis, Gillian M. TozerAbstract:Tubulin depolymerizing drugs that selectively disrupt tumour-associated vasculature have recently been identified. The lead drug in this class, Combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. Previous studies have focussed on the effects of single drug doses and have demonstrated little or no retardation of tumour growth when CA4P is used alone, but significant benefit when it is combined with conventional treatment. We have investigated the effects of multiple daily or twice daily dosing with CA4P on the vascular function, cell survival and growth of syngeneic and spontaneous breast cancers in mice. In both transplanted and spontaneous tumours significant growth retardation is observed if CA4P is administered daily (10 doses × 50 mg/kg), whereas no significant effects are seen if the same total dose (500 mg/kg) is administered as a single bolus injection. This effect is attributed, at least in part, to anti-proliferative effects on the tumour and endothelial cells, which retard the revascularisation and repopulation of the tumour core that is initially necrosed by the drug treatment. Further investigation of dose scheduling showed that the initial anti-vascular effects of CA4P are enhanced by administering the drug in 2 equal doses separated between 2 and 6 hr. The twice daily dosing schedule (25 mg/kg twice a day) produced increased growth retardation compared to the 50 mg/kg once a day schedule in the transplanted CaNT tumour. It did not do so in the spontaneous T138 tumour model. These studies indicate that the potential anti-tumour activity of CA4P when used as a single agent in clinical trials may be enhanced when used in multiple dose schedules. © 2002 Wiley-Liss, Inc.