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Cytotoxic effects of antiproliferative agents on human retinal glial cells in vitro

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Abstract

Purpose: Proliferative vitreoretinopathy (PVR) is characterizedby the formation of cellular membranes on the detached retina and also in the vitreous. Glial cellscan be found in epiretinal and subretinal membranes from eyes with PVR, proliferative diabeticretinopathy (PDR), idiopathic macular pucker, uveitis and other diseases affecting theretina. Proliferation and contraction of glial cells appears to play a role in the pathogenesisof PVR. This study is designed to inspect the effectiveness of harringtonine, as well as colchicine,daunomycin and fluorouracil, against cellular proliferation of cultured human retinal glial cellsthat might be involved in the retinal and/or vitreous proliferation. Methods: Cultures of human retinal glial cells were preparedusing the enzyme digesting method. Cells that had been in culture for 2–5 passages were usedin this study. Harringtonine (0.063 μg/ml ∼ 2.0 μg/ml), colchicines(0.5 μg/ml ∼ 16.0 μg/ml), daunomycin (0.1 μg/ml ∼ 3.2 μg/ml) and 5-fluorouracil(0.5 μg/ml ∼ 16.0 μg/ml) were added to cultures of human retinal glial cellsand the proliferation rates of the cells were measured by the MTT method. Results: Harringtonine at the dosage of 0.063 μg/mlinduced suppression of cellular growth, but the changes were not statistically significant (p > 0.05).At a dosage ranging from 0.125 μg/ml to 2.0 μg/ml, harringtonine significantly suppressedcellular growth according to the test (p < 0.01). Likewise, other antiproliferativeagents inhibited cellular growth significantly at a dosage from 1.0 μg/ml to 16.0 μg/ml(colchicine), 0.2 μg/ml to 3.2 μg/ml (daunomycin) and 1.0 μg/ml to 16.0 μg/ml(5-fluorouracil), but not at 0.5 μg/ml (colchicine), 0.1 μg/ml (daunomycin) and0.5 μg/ml (5-fluorouracil). The ID50 were 0.33 μg/ml (harringtonine), 3.11 μg/ml (colchicine), 0.79 μg/ml (daunomycin) and 5.23 μg/ml (5-fluorouracil), respectively.Conclusions: Harringtonine was extremely effective ininhibiting human retinal glial cell proliferation, like other antiproliferative drugs such as colchicine,daunomycin and 5-fluorouracil. Harringtonine, therefore, may be a candidate for further studies regardingthe treatment of experimental PVR.

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References

  1. Machemer R, Laqua H. Pigment epithelial proliferation in retinal detachment: (massive periretinal proliferation). Am J Ophthalmol 1975; 80: 1–23.

    Google Scholar 

  2. Machemer R. Pathogenesis and classification of massive periretinal proliferation. Br J Ophthalmol 1978; 62: 737–747.

    Google Scholar 

  3. Mandelcorn MS, Machemer R, Fineberg E. Proliferation and metaplasia of intravitreal retinal pigment epithelial cell autotransplants. Am J Ophthalmol 1975; 80: 227–237.

    Google Scholar 

  4. Kampid A, Kenyon KR, Michels RG, Green WR, de la Cruz Z. Epiretinal and vitreous membranes: A comparative study of 56 cases. Arch Ophthalmol 1981; 99: 1445–1454.

    Google Scholar 

  5. Jerdan JS, Pepose JS, Michels RG, Hayashi H, Bustros SD, Sebag M, et al. Proliferative vitreoretinopathy membrane: An immunohistochemical study. Ophthalmology 1989; 96: 801–810.

    Google Scholar 

  6. Sternberg P, Machemer R. Subretinal proliferation. Am J Ophthalmol 1984; 98: 456–462.

    Google Scholar 

  7. Bringmann A, Pannicke T, Moll V, Milenkovic I, Faude F, Enzmann V, et al. Upregulation of P2X(7) receptor currents in Muller glial cells during proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci 2001; 42: 860–867.

    Google Scholar 

  8. Nork TM, Wallow IHL, Sramek SJ, Anderson G. Muller's cell involvement in proliferative diabetic retinopathy. Arch Ophthalmol 1987; 105: 1424–1429.

    Google Scholar 

  9. Foos RY, Kreiger AE, Mofsinger K. Pathogenic study following vitrectomy for proliferative diabetic retinopathy. Retina 1985; 5: 101–106.

    Google Scholar 

  10. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Nakamura M. New insights into the pathophysiology of diabetic retinopathy: potential cell-specific therapeutic targets. Diabetes Technol Ther 2000; 2: 601–608.

    Google Scholar 

  11. Noble KG, Carr RE. Idiopathic preretinal gliosis. Ophthalmology 1982; 89: 521–525.

    Google Scholar 

  12. Chan C-C, Palestine AJ, Kuwabara T, Nussenblatt RB. Immunopathologic study of Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1988; 105: 607–611.

    Google Scholar 

  13. Reale E, Groos S, Luciano L, Eckardt C, Eckardt U. Membrana limitans interna and epiretinal membrane lying on macular holes. Some morphological observations. Ital J Anat Embryol 2001; 106: 509–515.

    Google Scholar 

  14. DeJuan E, Gridz DC, Machemer R. Ultrastructural characteristics of proliferative tissue in retinopathy of prematurity. Am J Ophthalmol 1987; 104: 149–156.

    Google Scholar 

  15. Smiddy WE, Green WR, Michels RG, de la Cruz Z. Ultrastructural studies of vitreomacular traction syndrome. Am J Ophthalmol 1989; 107: 177–185.

    Google Scholar 

  16. Kono T, Kohno T, Inomata H. Epiretinal membrane formation: light and electron microscopic study in an experimental rabbit model. Arch Ophthalmol 1995; 113: 359–364.

    Google Scholar 

  17. Michels RG. Surgery of retinal detachment with proliferative vitreoretinopathy. Retina 1984; 4: 61–83.

    Google Scholar 

  18. Glaser BM, Cardon A, Biscoe B. Proliferative vitreoretinopathy. The mechanism of development of vitreoretinal traction. Ophthalmology 1987; 94: 327–332.

    Google Scholar 

  19. Blumenkranz MS, Hernandez E, Ophir A. 5–Fluorouracil: New applications in complicated retinal detachment for an established antimetabolite. Ophthalmology 1984; 91: 122–130.

    Google Scholar 

  20. Rubsamen PE, Davis PA, Hernandez E, O'Grady GE, Cousins SW. Prevention of experimental proliferative vitreoretinapathy with a biodegradable intravitreal implant for the sustained release of fluorouracil. Arch Ophthalmol 1994; 112: 407–413.

    Google Scholar 

  21. Lemor M, Yei JH, Glaser BM. Oral colchicine for the treatment of experimental traction retinal detachment. Arch Ophthalmol 1986; 104: 1226–1229.

    Google Scholar 

  22. Wiedemann P, Lemmen K, Schmiedl R, Heimann K. Intraocular daunomycin for the treatment and prophylaxis of traumatic proliferative vitreoretinopathy. Am J Ophthalmol 1987; 104: 10–14.

    Google Scholar 

  23. Steinhorst UH, Chen EP, Hatchell DL, Samsa GP, Salloupis PT, Westendorf J, et al. Aclacinomycin A in the treatment of experimental proliferative vitreoretinopthy. Invest Ophthalmol Vis Sci 1993; 34: 1753–1760.

    Google Scholar 

  24. Lemor M, Bustros S, Glaser BM. Low-dose colchicine inhibits astrocyte, fibroblast, and retinal pigment epithelial cell migration and proliferation. Arch Ophthalmol 1986; 104: 1223–1225.

    Google Scholar 

  25. Koutsandrea CN, Miceli MV, Peyman GA, Farahat HG, Niesman MR. Ciprofloxacin and dexamethasone inhibit the proliferation of human retinal pigment epithelial cells in culture. Curr Eye Res 1991; 10: 249–258.

    Google Scholar 

  26. Mojon D, Boscoboinik D, Haas A, Bohnke M, Azzi A. Vitamin E inhibits retinal pigment epithelium cell proliferation in vitro. Ophthalmic Res 1994; 26: 304–309.

    Google Scholar 

  27. Puro DG, Mano T, Chan C-C, Fukuda M, Shimada H. Thrombin stimulates the proliferation of human retinal glial cells. Graefe's Arch Clin Exp Ophthalmol 1990; 228: 169–173.

    Google Scholar 

  28. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.

    Google Scholar 

  29. Eng LF, DeArmond SJ. Immunochemistry of the glial fibrillary acidic protein. Prog Neuropathol 1983; 5: 19–39.

    Google Scholar 

  30. Guerin CJ, Wolfshagen RW, Eifring DE. Immunocytochemical identification of retinal glia as a component of human epiretinal membranes. Invest Ophthalmol Vis Sci 1990; 31: 1483–1487.

    Google Scholar 

  31. Lewis GP, Matsumoto B, Fisher SK. Changes in the organization and expression of cytoskeletal proteins during retinal degeneration induced by retinal detachment. Invest Ophthalmol Vis Sci 1995; 36: 2404–2416.

    Google Scholar 

  32. Cook B, Lewis GP, Fisher SK, Adler R. Apoptotic photoreceptor degeneration in experimental retinal detachment. Invest Ophthalmol Vis Sci 1995; 36: 990–996.

    Google Scholar 

  33. Verdoorn C, Lavakette RD, Dalma-Weizhausz J, Orn GM, Sorgente N, Ryan SJ. Cellular migration, proliferation, and contraction. An in vitro approach to a clinical problemproliferative vitreoretinopathy. Arch Ophthalmol 1986; 104: 1216–1219.

    Google Scholar 

  34. Tano Y, Sugita G, Abrams G, Machemer R. Inhibition of intraocular proliferations with intravitreal corticosteriods. Am J Ophthalmol 1980; 89: 131–136.

    Google Scholar 

  35. Feldman EJ, Arlin Z, Ahmed T. Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia. Leukemia 1992; 6: 1189–1191.

    Google Scholar 

  36. Feldman EJ, Seiter KP, Ahmed T. Homoharringtonine in patients with melodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemia. Leukemia 1996; 10: 40–42.

    Google Scholar 

  37. Kantarjian HM, Talpaz M, Smith TL. Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. J Clin Oncol 2000; 18: 3513–3521.

    Google Scholar 

  38. O'Dwyer PJ, King SA, Hoth DF, Suffness M, Leyand-Jones B. Homoharringtonine-perspectives on an active new natural product. J Clin Oncol 1986; 4: 1563–1568.

    Google Scholar 

  39. Zeng SQ, Hu CZ, Lu YS, Tian XH. Ocular toxicity study of intravitreal harringtonine. Chinese J Ocular Fundus Dis 1990; 6: 138–141.

    Google Scholar 

  40. Myers CE, Corden B, Gianni L. Anti-tumor antibiotics. I. Anthracyclines. In: Chabner BA, Pinedi HM, eds. The Cancer Pharmacology Annual 2. Amsterdam: Elsevier, 1984, pp. 66–79.

    Google Scholar 

  41. Kirmani M, Santana M, Sorgente N, Bekhor C, Patterson R, Tran T, et al. Antiproliferative drugs in the treatment of experimental proliferative vitreoretinopathy. Retina 1983; 3: 269–272.

    Google Scholar 

  42. Wiedemann P, Leimung C, Hilgers RD, Heimann K. Daunomycin and silicone oil for the treatment of proliferative vitreoretinopathy. Graefe's Arch Clin Exp Ophthalmol 1991; 229: 150–152.

    Google Scholar 

  43. Sanatana M, Wiedemann P, Kirmani M. Daunomycin in the treatment of periodical proliferative vitreoretinopathy: Retinal toxicity of intravitreal daunomycin in the rabbit. Graefes Arch Clin Exp Ophthalmol 1984; 221: 210–213.

    Google Scholar 

  44. Wiedemann P, Sorgente N, Bekhor C, Patterson R, Tran T, Ryan SJ. Daunomycin in the treatment of experimental proliferative vitreoretinopathy. Effective doses in vitro and in vivo. Invest Ophthalmol Vis Sci 1985; 26: 719–725.

    Google Scholar 

  45. Weller M, Heimann K, Wiedemann P. Cytotoxic effects of daunomycin on retinal pigment epithelium in vitro. Graefe's Arch Clin Exp Ophthalmol 1987; 225: 235–238.

    Google Scholar 

  46. Blumenkranz MS, Ophir A, Claflin AJ, Hajek A. Fluorouracil for the treatment of massive periretinal proliferation. Am J Ophthalmol 1982; 94: 458–467.

    Google Scholar 

  47. Assil KK, Weinreb RN. Multivesicular liposomes: Sustained release of the antimetabolite cytarabine in the eye. Arch Ophthalmol 1987; 105: 400–403.

    Google Scholar 

  48. Barza M, Stuart M, Szoka F. Effect of size and lipid composition on the pharmacokinetics of intravitreal liposones. Invest Ophthalmol Vis Sci 1987; 28: 893–900.

    Google Scholar 

  49. Lewis H, Schwartz S, Lee D. The use of bioerodible polymer and 5–fluorouracil in the treatment of experimental proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci 1991; 32(suppl): 1047.

    Google Scholar 

  50. Asaria RH, Kon CH, Bunce C, Charteris DG, Wong D, Khaw PT, et al. Adjuvant 5–fluorouracil and heparin prevents proliferative vitreoretinopathy: Results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001; 108: 1179–1183.

    Google Scholar 

  51. Hatchell DL, McAdoo T, Sheta S, King RT, Bartolome JV. Quantification of cellular proliferation in experimental proliferative vitreoretinopathy. Arch Ophthalmol 1988; 106: 641–672.

    Google Scholar 

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  1. Department of Ophthalmology, Changzheng Hospital, 415 Fengyang Road, Shanghai, 200003, China

    JiPing Cai, RuiLi Wei, XiaoYe Ma, Huang Zhu & You Li

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Cai, J., Wei, R., Ma, X. et al. Cytotoxic effects of antiproliferative agents on human retinal glial cells in vitro . Int Ophthalmol 24, 225–231 (2001). https://doi.org/10.1023/A:1022509614815

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