Combretastatin A-4, an agent that displays selective toxicity towards tumour vasculature

Dj, Chaplin; Prise, S.; Tozer, G. M.; Pettit, George W; Dark, Graham

doi:10.1016/s0959-8049(97)84574-1

Cited by 4 publications

(3 citation statements)

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“…However, it is important to differentiate between the toxicity profiles of CA-4 after acute (single dose) and prolonged treatment regimes. Thus the maximum-tolerated single dose of CA-4P in mice has been defined as Ͼ1000 mg/kg 22,23 and several reports 24,25 have described anti-tumor effects after the administration of 100 mg/kg, ie, at Ͻ1/10th maximum-tolerated dose. In contrast, our own unpublished work and other studies 26 have shown that systemic toxicity results from repeated intraperitoneal injections of 25 and 50 mg/kg/12 hours in adult mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Griggs

Skepper

Smith

et al. 2002

The American Journal of Pathology

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Retinal neovascularization occurs in a variety of diseases including diabetic retinopathy, the most common cause of blindness in the developed world. There is accordingly considerable incentive to develop drugs that target the aberrant angiogenesis associated with these conditions. Previous studies have shown that a number of anti-angiogenic agents can inhibit retinal neovascularization in a well-characterized murine model of ischemia-induced proliferative retinopathy. Combretastatin-A4 (CA-4) is an anti-vascular tubulin-binding agent currently undergoing clinical evaluation for the treatment of solid tumors. We have recently shown that CA-4 is not tumor-specific but elicits anti-vascular effects in nonneoplastic angiogenic vessels. In this study we have examined the capacity of CA-4 to inhibit retinal neovascularization in vivo. CA-4 caused a dose-dependent inhibition of neovascularization with no apparent side effects. The absence of vascular abnormalities or remnants of disrupted neovessels in retinas of CA-4-treated mice suggests an anti-angiogenic mechanism in this model, in contrast to the anti-vascular effects observed against established tumor vessels. Importantly, histological and immunohistochemical analyses indicated that CA-4 permitted the development of normal retinal vasculature while inhibiting aberrant neovascularization. These data are consistent with CA-4 eliciting tissue-dependent anti-angiogenic effects and suggest that CA-4 has potential in the treatment of nonneoplastic diseases with an angiogenic component.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Griggs

Skepper

Smith

et al. 2002

The American Journal of Pathology

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“…For example, lipophilic prodrug strategies can be used for achieving sustained drug release in the vitreous with the formation of crystalline drug precipitates, 3,4 and hydrophilic strategies can be utilized for reaching adequate solubility. 5 Changing a drug's lipophilicity can impact its intravitreal clearance; in general, a high octanol−water distribution coefficient and hydrogen donor capacity will increase a compound's intravitreal clearance. 6 Another attractive, yet poorly utilized, approach is to design prodrugs with high binding to melanin, which might result in prolonged drug retention in the posterior eye.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Some of these properties, such as solubility, permeability, and vitreal retention, can be altered with a prodrug approach by chemically modifying an existing drug. For example, lipophilic prodrug strategies can be used for achieving sustained drug release in the vitreous with the formation of crystalline drug precipitates, , and hydrophilic strategies can be utilized for reaching adequate solubility . Changing a drug’s lipophilicity can impact its intravitreal clearance; in general, a high octanol–water distribution coefficient and hydrogen donor capacity will increase a compound’s intravitreal clearance .…”

Section: Introductionmentioning

confidence: 99%

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

et al. 2020

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Because of poor ocular drug bioavailability, intravitreal injections have become the gold standard for drug delivery to the posterior eye. The prodrug approach can be used for optimizing the biopharmaceutical properties of intravitreal drugs. The preclinical screening of prodrugs' properties, such as hydrolysis and bioconversion, should be conducted in a resource-efficient way for an extensive set of synthesized compounds with validated methods. Our objective was to explore cassette dosing in in vitro prodrug hydrolysis and bioconversion studies in buffer, vitreous, and retinal pigment epithelium (RPE) homogenate for rapid medium-throughput screening. Moreover, our aim was to correlate the prodrug structure with hydrolytic behavior. We synthesized 18 novel ganciclovir prodrugs and first studied their hydrolysis in aqueous buffer and porcine vitreous in vitro with cassette dosing for 35 h. A method for vitreous homogenate pH equilibration to a physiological level by using buffer and incubation under 5% carbon dioxide was validated. The hydrolysis of the prodrugs was evaluated in porcine RPE homogenate in vitro with cassette dosing, and five prodrugs were assayed individually to examine their bioconversion into ganciclovir in RPE after 2 h. Lastly, the prodrugs' binding to melanin was studied in vitro. The prodrugs showed a wide spectrum of hydrolysis rates, ranging from a few percentages to 100% in the vitreous and RPE; in general, hydrolysis in RPE was faster than in vitreous. Prodrugs with long carbon chains and disubstitution showed lability in the tissue homogenates, whereas prodrugs with branched carbon chains and aromatic groups were stable. All five prodrugs chosen for the bioconversion study in RPE were hydrolyzed into ganciclovir, and their hydrolytic behavior matched results from the cassette mix experiment, supporting the cassette mix approach for hydrolysis and bioconversion studies. None of the prodrugs bound highly to melanin (<50% bound). In conclusion, cassette dosing proved useful for the rapid screening of prodrug hydrolysis and bioconversion properties. Analyzing several compounds simultaneously can complicate the analytics, and thus, choosing the compounds of the cassette mix should be done carefully to avoid mutual interference of the compounds with the results. The methodology and results of the work are applicable in ocular drug research and prodrug design.

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Injectable Hydrogel–Microsphere Construct with Sequential Degradation for Locally Synergistic Chemotherapy

Zheng

Cheng

Chen

et al. 2017

ACS Appl. Mater. Interfaces

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In recent years, in situ chemotherapy mediated by biodegradable polymer platforms has attracted increased attention. Herein, an advanced drug delivery system, combretastatin A-4 (CA4) and docetaxel (DTX)-loaded microsphere embedded in injectable thermosensitive polypeptide hydrogel (i.e., hydrogel-microsphere (Gel-MP) construct), was reported for sequential release of drugs with different mechanisms to treat osteosarcoma synergistically. The Gel-MP construct showed sequential biodegradability and excellent biocompatibility. CA4 was preferentially released from hydrogel with faster degradation to disturb the vascular structure of the tumor and reduce the exchange of nutrients between the tumor and surrounding tissues, which created interstitial space in the tissue for DTX penetration to inhibit tumor cell proliferation. The in vivo treatment with Gel/CA4-MP/DTX efficiently suppressed the growth of mouse K7 osteosarcoma compared to other formulations. More importantly, by systematical study of histopathology and immunohistochemistry, the Gel-MP construct can significantly upregulate antiproliferation effect and reduce toxicity of drugs. Therefore, this injectable and locally sequential delivery system has a bright prospect in clinical application of in situ synergistic chemotherapy.

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Combretastatin A-4, an agent that displays selective toxicity towards tumour vasculature

Cited by 4 publications

References 0 publications

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

Injectable Hydrogel–Microsphere Construct with Sequential Degradation for Locally Synergistic Chemotherapy

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