Preventive Versus Treatment Effect of Ag3340, a Potent Matrix Metalloproteinase Inhibitor in a Rat Model of Choroidal Neovascularization

Bradey, Mohammed El; Cheng, Lingyun; Bartsch, Dirk-Uwe; Appelt, Krzystof; Rodanant, Nuttawut; Bergeron–Lynn, Germaine; Freeman, William R.

doi:10.1089/1080768041223657

Cited by 29 publications

(21 citation statements)

References 29 publications

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“…The increased expression of MMP-3 following PDT should be regarded as a negative effect, because many malignant tumors spread through the increase of MMP-3 production [41]. Inhibitors of MMPs, like prinomastat, were found to be active in the earliest stages of experimental choroidal neovascularization, and it was suggested to be used in combination with photodynamic therapy to inhibit the recurrence of choroidal neovascularization from temporarily closed new vessels [42]. The administration of prinomastat significantly improved the PDT-mediated tumor response.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo matrix metalloproteinase expression after photodynamic therapy with a liposomal formulation of aminolevulinic acid and its methyl ester

Osiecka

Jurczyszyn

Symonowicz

et al. 2010

Cellular and Molecular Biology Letters

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colony stimulating factor; HNSCC -head and neck squamous cell carcinoma; IL-1 -interleukin-1; met-ALA -methyl ester of aminolevulinic acid; MMPs -matrix metalloproteinases; m-THPC -meso-tetra(hydroxyphenyl)chlorine; PDT -photodynamic therapy; PPIX -protoporphyrin IX; ROS -reactive oxygen species, TIMPs -tissue inhibitors of matrix metalloproteinases; VEGF -vascular endothelial growth factor Abstract: Photodynamic therapy (PDT) is a well-known method for the treatment of malignant tumors, and its principles have been well established over the past 30 years. This therapy involves the application of a chemical called a photosensitizer and its subsequent excitation with light at the appropriate wavelength and energy. Topical photodynamic therapy with aminolevulinic acid (5-ALA) is an alternative therapy for many malignant processes, including nonmelanoma skin cancers such as basal-cell carcinoma (BCC). Our novel approach for this study was to use a liposomal formulation of 5-ALA and its methyl ester (commercially available as metvix) both in vitro and in vivo, and to check whether the liposome-entrapped precursors of photosensitizers can induce the expression of metalloproteinases (MMPs) in animal tumor cells and in other tissues from tumor-bearing rats and in selected cell lines in vitro. We also checked whether the application of tissue inhibitors of matrix metalloproteinases Unauthenticated Download Date | 5/11/18 3:12 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 631(TIMPs) has any effect on MMPs in the above-mentioned experimental models, and if they can cause complete inhibition of MMP expression. Immunohistochemical studies revealed that after the PDT, the intensity of expression of MMPs in healthy animals was very low and seen in single cells only. After the PDT in tumor-bearing rats, MMP-3 was expressed in the tumor cells with the highest intensity of staining in the tissues directly adjacent to the tumors, while MMP-2 and -9 were not found. In the control groups, there was no observed expression of MMPs. In vitro studies showed that MMP-3 was expressed in MCF-7 cells after PDT, but MMP-9 was not observed and MMP-2 was only seen in single cases. Our studies confirmed that the application of an MMP-3 inhibitor may block an induction of MMP-3 expression which had previously been initiated by PDT. The preliminary data obtained from cancer patients revealed that new precursors are effective in terms of PDT, and that using MMP inhibitors should be considered as a potential enhancing factor in clinical PDT.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo matrix metalloproteinase expression after photodynamic therapy with a liposomal formulation of aminolevulinic acid and its methyl ester

Osiecka

Jurczyszyn

Symonowicz

et al. 2010

Cellular and Molecular Biology Letters

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“…However, by week 3, the risk associated with SI was not yet significant, since the differences observed in the percentage of CNV development between the two groups were related only to the higher number of burns that had associated hemorrhage in the L + SI group. The presence of blood increased the angiogenic response, probably because of rupture of BM, and more cytokines derived from platelets could facilitate CNV development [18,19] .…”

Section: Discussionmentioning

confidence: 99%

Development of Laser-Induced Choroidal Neovascularization in Rats after Retinal Damage by Sodium Iodate Injection

García‐Layana

Vásquez²,

Salinas-Alamán³

et al. 2009

Ophthalmic Res

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Purpose: To determine the role of the retinal pigment epithelium (RPE) in the development of laser-induced choroidal neovascularization (CNV) by selective damage with sodium iodate (SI). Methods: In group 1, diode laser photocoagulation was applied to the right eye of Long-Evans rats (n = 11). In group 2 (n = 11), SI was administered intravenously at a dose of 40 mg/kg of body weight 2 days after photocoagulation. In group 3 (n = 10), SI was injected 2 days before laser was applied. In group 4 (n = 10), SI was injected immediately after photocoagulation. Results: CNV ingrowth developed in 42 of 93 burns (45%) of the laser group and in 46 of 75 burns (61%) when SI was administered 2 days after laser (p = 0.036). No CNV developed in the other groups. Conclusions: The angiogenic effect of the RPE is essential during the first hours after the onset of the laser-induced CNV process. When the RPE was damaged before or at the time of photocoagulation, CNV was not induced. These results suggest that RPE integrity is a decisive element in CNV formation.

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“…Recently, several anti-angiogenic agents, including TNP-470, irsogladine and anecortave acetate, have been investigated to verify their potential for clinical use as a new drug for CNV. 9,11,14,[24][25][26] FMPA is a synthetic analog of MPA. It has been widely used as a therapeutic agent for breast and endometrium cancers without unacceptable side effects, and synthesized in order to enhance its anti-tumor and anti-angiogenic activities by fluorinating MPA.…”

Section: Discussionmentioning

confidence: 99%

“…The laser-induced CNV model in rats has been widely used for study of CNV. [10][11][12][24][25][26][27] The essential process of CNV formation in this model, including the break-up of the basement membrane, the migration and proliferation of vascular endothelial cells and the tubular formation, is similar to the naturally-occurring process. In this study, FMPA inhibited the incidence of CNV formation by subconjunctival injection, and it was thus thought that FMPA might be useful drug for treating CNV.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Laser-Induced Choroidal Neovascularization by Subconjunctival Injection of 9.ALPHA.-Fluoromedroxyprogesterone Acetate (FMPA), an Anti-angiogenic Agent, in Rats

Murata

Yamaji

Uchida

et al. 2006

Biological & Pharmaceutical Bulletin

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Age-related macular degeneration (AMD) is the primary cause of severe vision loss in old age patients in developed countries and exudative (wet) AMD is characterized by choroidal neovascularization (CNV).1,2) Surgical therapy or photocoagulation therapy has been performed to treat CNV, [3][4][5][6][7][8] but these therapies affect not only the CNV itself but also the healthy retina. Therefore drug therapy for CNV with minimal damage to the healthy retina is under investigation and many anti-angiogenic agents have been evaluated.9-16) Angiogenesis is an important process by which new blood vessels are formed from preexisting microvessels in many diseases such as cancer, diabetic retinopathy, and exudative AMD.17) It has been reported that anecortave acetate, an angiostatic steroid, is clinically efficacious for improving vision in patients with exudative AMD.14) Betamethasone is a corticosteroid with anti-inflammatory and immunosuppressive abilities, and it has been reported that betamethasone shows anti-angiogenic activities in some experimental studies. [18][19][20] We synthesized 9a-fluoromedroxyprogesterone acetate (FMPA) in order to explore a more potent anti-angiogenic agent than medroxyprogesterone acetate (MPA), 21) which has been widely used as a therapeutic agent for breast and endometrium cancers. FMPA showed 100-times greater antiangiogenic activity than MPA in the chorioallantoic membrane (CAM) assay system 21) and showed a 7-fold stronger anti-angiogenic effect than MPA in the rabbit corneal assay system. 22) FMPA inhibited the activity of plasminogen activator (PA), an important protease playing an essential role in the process of angiogenesis, in bovine endothelial cells. 23) In the mouse dorsal air sac method, FMPA inhibited the mouse sarcoma 180 cell-induced angiogenesis by oral administration. 23) These results indicate that FMPA may be useful for the treatment of diseases associated with angiogenesis. However, there has been no study of the effect of FMPA on CNV. Therefore, in this study, we examined the effect of FMPA on laser-induced CNV in rats, and also the effects of anecortave acetate and betamethasone as positive controls on laser-induced CNV in rats. In addition, we also examined the effect of FMPA on the retinal function by electro retinogram (ERG) to confirm whether or not FMPA had retinal toxicity. MATERIALS AND METHODSAnimals Male 8-week-old Brown Norway (BN) rats from Charles River Japan were used. These rats were housed under standard pathogen-free conditions in constant periods of 12-h light/dark (23°C) and were allowed access to food and water ad libitum. All experiments proceeded in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.Chemicals FMPA was synthesized in our laboratory as reported previously.21) The structure of FMPA is shown in Fig. 1. Anecortave acetate was synthesized in our laboratory. 9a a-Fluoromedroxyprogesterone acetate (FMPA) is a synthetic analog of medroxyprogesterone acetate (MPA). FMPA exhibited more potent anti...

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Preventive Versus Treatment Effect of Ag3340, a Potent Matrix Metalloproteinase Inhibitor in a Rat Model of Choroidal Neovascularization

Cited by 29 publications

References 29 publications

In vitro and in vivo matrix metalloproteinase expression after photodynamic therapy with a liposomal formulation of aminolevulinic acid and its methyl ester

In vitro and in vivo matrix metalloproteinase expression after photodynamic therapy with a liposomal formulation of aminolevulinic acid and its methyl ester

Development of Laser-Induced Choroidal Neovascularization in Rats after Retinal Damage by Sodium Iodate Injection

Suppression of Laser-Induced Choroidal Neovascularization by Subconjunctival Injection of 9.ALPHA.-Fluoromedroxyprogesterone Acetate (FMPA), an Anti-angiogenic Agent, in Rats

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