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. 1994 May;93(5):1981–1986. doi: 10.1172/JCI117190

Antiproliferative effect of retinoid compounds on Kaposi's sarcoma cells.

J Corbeil 1, E Rapaport 1, D D Richman 1, D J Looney 1
PMCID: PMC294306  PMID: 8182129

Abstract

A panel of retinoid compounds (tretinoin, isotretinoin, acitretin, and RO13-1470) were tested for inhibitory activity against Kaposi's sarcoma cell (KSC) cultures in vitro. Tretinoin was found to be the most effective retinoid tested, inhibiting the growth of KSC in vitro while having no effect on the expression of interleukin-6 and basic fibroblast growth factor, two important cytokines involved in KSC growth. Tretinoin also did not appear to downregulate the expression of receptors for these two cytokines. At low concentrations (10(-9) M), acitretin and tretinoin selectively inhibited growth of early passage KSC. At higher concentrations (10(-6)-10(-5) M), retinoid treatment induced a pattern of DNA degradation and morphological changes in KSC characteristic of apoptosis (programmed cell death). The inhibitory activity of tretinoin on KSC growth was decreased if human serum (but not fetal calf serum) was present in the growth medium, and partially restored by removal of serum lipids. These data suggest that retinoids possess potential as therapeutic agents in Kaposi's sarcoma.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bollag W., Peck R., Frey J. R. Inhibition of proliferation by retinoids, cytokines and their combination in four human transformed epithelial cell lines. Cancer Lett. 1992 Feb 29;62(2):167–172. doi: 10.1016/0304-3835(92)90188-2. [DOI] [PubMed] [Google Scholar]
  2. Bonhomme L., Fredj G., Averous S., Szekely A. M., Ecstein E., Trumbic B., Meyer P., Lang J. M., Misset J. L., Jasmin C. Topical treatment of epidemic Kaposi's sarcoma with all-trans-retinoic acid. Ann Oncol. 1991 Mar;2(3):234–235. doi: 10.1093/oxfordjournals.annonc.a057916. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Corbeil J., Evans L. A., Vasak E., Cooper D. A., Penny R. Culture and properties of cells derived from Kaposi sarcoma. J Immunol. 1991 May 1;146(9):2972–2976. [PubMed] [Google Scholar]
  5. Drew W. L., Mills J., Hauer L. B., Miner R. C., Rutherford G. W. Declining prevalence of Kaposi's sarcoma in homosexual AIDS patients paralleled by fall in cytomegalovirus transmission. Lancet. 1988 Jan 2;1(8575-6):66–66. doi: 10.1016/s0140-6736(88)91053-7. [DOI] [PubMed] [Google Scholar]
  6. Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990 May 3;345(6270):84–86. doi: 10.1038/345084a0. [DOI] [PubMed] [Google Scholar]
  7. Ensoli B., Nakamura S., Salahuddin S. Z., Biberfeld P., Larsson L., Beaver B., Wong-Staal F., Gallo R. C. AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science. 1989 Jan 13;243(4888):223–226. doi: 10.1126/science.2643161. [DOI] [PubMed] [Google Scholar]
  8. Epstein J. B., Scully C. Intralesional vinblastine for oral Kaposi sarcoma in HIV infection. Lancet. 1989 Nov 4;2(8671):1100–1101. doi: 10.1016/s0140-6736(89)91114-8. [DOI] [PubMed] [Google Scholar]
  9. Geara F., Le Bourgeois J. P., Piedbois P., Pavlovitch J. M., Mazeron J. J. Radiotherapy in the management of cutaneous epidemic Kaposi's sarcoma. Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1517–1522. doi: 10.1016/0360-3016(91)90327-z. [DOI] [PubMed] [Google Scholar]
  10. Honda M., Kitamura K., Mizutani Y., Oishi M., Arai M., Okura T., Igarahi K., Yasukawa K., Hirano T., Kishimoto T. Quantitative analysis of serum IL-6 and its correlation with increased levels of serum IL-2R in HIV-induced diseases. J Immunol. 1990 Dec 15;145(12):4059–4064. [PubMed] [Google Scholar]
  11. Kahn J. O., Kaplan L. D., Volberding P. A., Ziegler J. L., Crowe S., Saks S. R., Abrams D. I. Intralesional recombinant tumor necrosis factor-alpha for AIDS-associated Kaposi's sarcoma: a randomized, double-blind trial. J Acquir Immune Defic Syndr. 1989;2(3):217–223. [PubMed] [Google Scholar]
  12. Kanai M., Raz A., Goodman D. S. Retinol-binding protein: the transport protein for vitamin A in human plasma. J Clin Invest. 1968 Sep;47(9):2025–2044. doi: 10.1172/JCI105889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kovacs J. A., Deyton L., Davey R., Falloon J., Zunich K., Lee D., Metcalf J. A., Bigley J. W., Sawyer L. A., Zoon K. C. Combined zidovudine and interferon-alpha therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS) Ann Intern Med. 1989 Aug 15;111(4):280–287. doi: 10.7326/0003-4819-111-4-280. [DOI] [PubMed] [Google Scholar]
  14. Krown S. E., Gold J. W., Niedzwiecki D., Bundow D., Flomenberg N., Gansbacher B., Brew B. J. Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS) Ann Intern Med. 1990 Jun 1;112(11):812–821. doi: 10.7326/0003-4819-112-11-812. [DOI] [PubMed] [Google Scholar]
  15. Lane H. C., Falloon J., Walker R. E., Deyton L., Kovacs J. A., Masur H., Banks S., Kirk L. E., Baseler M. W., Salzman N. P. Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. A phase II randomized, placebo-controlled trial. Ann Intern Med. 1989 Jul 1;111(1):41–50. doi: 10.7326/0003-4819-111-1-41. [DOI] [PubMed] [Google Scholar]
  16. Le-Ruppert K., Masters J. R., Knuechel R., Seegers S., Tainsky M. A., Hofstaedter F., Buettner R. The effect of retinoic acid on chemosensitivity of PA-1 human teratocarcinoma cells and its modulation by an activated N-ras oncogene. Int J Cancer. 1992 Jun 19;51(4):646–651. doi: 10.1002/ijc.2910510423. [DOI] [PubMed] [Google Scholar]
  17. Levin A. A., Sturzenbecker L. J., Kazmer S., Bosakowski T., Huselton C., Allenby G., Speck J., Kratzeisen C., Rosenberger M., Lovey A. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. doi: 10.1038/355359a0. [DOI] [PubMed] [Google Scholar]
  18. Longo D. L., Steis R. G., Lane H. C., Lotze M. T., Rosenberg S. A., Preble O., Masur H., Rook A. H., Fauci A. S., Jacob J. Malignancies in the AIDS patient: natural history, treatment strategies, and preliminary results. Ann N Y Acad Sci. 1984;437:421–430. doi: 10.1111/j.1749-6632.1984.tb37163.x. [DOI] [PubMed] [Google Scholar]
  19. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  20. McKenzie R., Travis W. D., Dolan S. A., Pittaluga S., Feuerstein I. M., Shelhamer J., Yarchoan R., Masur H. The causes of death in patients with human immunodeficiency virus infection: a clinical and pathologic study with emphasis on the role of pulmonary diseases. Medicine (Baltimore) 1991 Sep;70(5):326–343. doi: 10.1097/00005792-199109000-00004. [DOI] [PubMed] [Google Scholar]
  21. Michaeli J., Rifkind R. A., Marks P. A. Differentiating agents in cancer therapy. Cancer Chemother Biol Response Modif. 1992;13:286–307. [PubMed] [Google Scholar]
  22. Miles S. A., Martínez-Maza O., Rezai A., Magpantay L., Kishimoto T., Nakamura S., Radka S. F., Linsley P. S. Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells. Science. 1992 Mar 13;255(5050):1432–1434. doi: 10.1126/science.1542793. [DOI] [PubMed] [Google Scholar]
  23. Miles S. A., Rezai A. R., Salazar-González J. F., Vander Meyden M., Stevens R. H., Logan D. M., Mitsuyasu R. T., Taga T., Hirano T., Kishimoto T. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068–4072. doi: 10.1073/pnas.87.11.4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miles S. A., Wang H. J., Cortes E., Carden J., Marcus S., Mitsuyasu R. T. Beta-interferon therapy in patients with poor-prognosis Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). A phase II trial with preliminary evidence of antiviral activity and low incidence of opportunistic infections. Ann Intern Med. 1990 Apr 15;112(8):582–589. doi: 10.7326/0003-4819-112-8-582. [DOI] [PubMed] [Google Scholar]
  25. Nair B. C., DeVico A. L., Nakamura S., Copeland T. D., Chen Y., Patel A., O'Neil T., Oroszlan S., Gallo R. C., Sarngadharan M. G. Identification of a major growth factor for AIDS-Kaposi's sarcoma cells as oncostatin M. Science. 1992 Mar 13;255(5050):1430–1432. doi: 10.1126/science.1542792. [DOI] [PubMed] [Google Scholar]
  26. Nakamura S., Salahuddin S. Z., Biberfeld P., Ensoli B., Markham P. D., Wong-Staal F., Gallo R. C. Kaposi's sarcoma cells: long-term culture with growth factor from retrovirus-infected CD4+ T cells. Science. 1988 Oct 21;242(4877):426–430. doi: 10.1126/science.3262925. [DOI] [PubMed] [Google Scholar]
  27. Niedt G. W., Schinella R. A. Acquired immunodeficiency syndrome. Clinicopathologic study of 56 autopsies. Arch Pathol Lab Med. 1985 Aug;109(8):727–734. [PubMed] [Google Scholar]
  28. Peterson P. A. Characteristics of a vitamin A-transporting protein complex occurring in human serum. J Biol Chem. 1971 Jan 10;246(1):34–43. [PubMed] [Google Scholar]
  29. Rabkin C. S., Biggar R. J., Horm J. W. Increasing incidence of cancers associated with the human immunodeficiency virus epidemic. Int J Cancer. 1991 Mar 12;47(5):692–696. doi: 10.1002/ijc.2910470511. [DOI] [PubMed] [Google Scholar]
  30. Rizzino A. Appearance of high affinity receptors for type beta transforming growth factor during differentiation of murine embryonal carcinoma cells. Cancer Res. 1987 Aug 15;47(16):4386–4390. [PubMed] [Google Scholar]
  31. Roth W. K., Werner S., Schirren C. G., Hofschneider P. H. Depletion of PDGF from serum inhibits growth of AIDS-related and sporadic Kaposi's sarcoma cells in culture. Oncogene. 1989 Apr;4(4):483–487. [PubMed] [Google Scholar]
  32. Schofield P. N., Granerus M., Lee A., Ektröm T. J., Engström W. Concentration-dependent modulation of basic fibroblast growth factor action on multiplication and locomotion of human teratocarcinoma cells. FEBS Lett. 1992 Feb 24;298(2-3):154–158. doi: 10.1016/0014-5793(92)80044-h. [DOI] [PubMed] [Google Scholar]
  33. Sidell N., Taga T., Hirano T., Kishimoto T., Saxon A. Retinoic acid-induced growth inhibition of a human myeloma cell line via down-regulation of IL-6 receptors. J Immunol. 1991 Jun 1;146(11):3809–3814. [PubMed] [Google Scholar]
  34. Siegenthaler G., Saurat J. H., Ponec M. Terminal differentiation in cultured human keratinocytes is associated with increased levels of cellular retinoic acid-binding protein. Exp Cell Res. 1988 Sep;178(1):114–126. doi: 10.1016/0014-4827(88)90383-7. [DOI] [PubMed] [Google Scholar]
  35. Smith M. A., Parkinson D. R., Cheson B. D., Friedman M. A. Retinoids in cancer therapy. J Clin Oncol. 1992 May;10(5):839–864. doi: 10.1200/JCO.1992.10.5.839. [DOI] [PubMed] [Google Scholar]
  36. Stürzl M., Roth W. K., Brockmeyer N. H., Zietz C., Speiser B., Hofschneider P. H. Expression of platelet-derived growth factor and its receptor in AIDS-related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor maintenance. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7046–7050. doi: 10.1073/pnas.89.15.7046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tallman M. S., Wiernik P. H. Retinoids in cancer treatment. J Clin Pharmacol. 1992 Oct;32(10):868–888. doi: 10.1002/j.1552-4604.1992.tb04633.x. [DOI] [PubMed] [Google Scholar]
  38. Telford W. G., King L. E., Fraker P. J. Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry. 1992;13(2):137–143. doi: 10.1002/cyto.990130205. [DOI] [PubMed] [Google Scholar]

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