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Differentiating agents in pediatric malignancies: Retinoids in neuroblastoma

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Abstract

Retinoids are derivatives of vitamin A that include all-trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphologic differentiation of human neuroblastoma cell lines. Phase I trials have shown that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improves event-free survival in high-risk neuroblastoma. Because 4-HPR achieves multi-log cell kills in neuroblastoma cell lines that are resistant to ATRA and 13-cis-RA, a pediatric phase I trial is in progress to determine the maximum tolerated dose of 4-HPR, with a view toward giving 4-HPR after completion of myeloablative therapy and 13-cis-RA.

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References and Recommended Reading

  1. Sidell N, Altman A, Haussler MR, Seeger RC: Effects of retinoic acid (RA) on the growth and phenotypic expression of several human neuroblastoma cell lines. Exp Cell Res 1983, 148:21–30.

    Article  PubMed  CAS  Google Scholar 

  2. Prasad KN, Kumar S: Role of cyclic AMP in differentiation of human neuroblastoma cells in culture. Cancer 1975, 36:1338–1343.

    Article  PubMed  CAS  Google Scholar 

  3. Reynolds CP, Perez-Polo JR: Nerve growth factor induces neurite outgrowth in a clone derived from an NGF-insensitive human neuroblastoma cell line. Int J Dev Neurosci 1989, 7:125–132.

    Article  PubMed  CAS  Google Scholar 

  4. Reynolds CP, Maples J: Modulation of cell surface antigens accompanies morphological differentiation of human neuroblastoma cell lines. Prog Clin Biol Res 1985, 175:13–37.

    PubMed  CAS  Google Scholar 

  5. Tsokos M, Scarpa S, Ross RA, Triche TJ: Differentiation of human neuroblastoma recapitulates neural crest development: study of morphology, neurotransmitter enzymes, and extracellular matrix proteins. Am J Pathol 1987, 128:484–496.

    PubMed  CAS  Google Scholar 

  6. Kumar S, Steward JK, Waghe M, et al.: The administration of the nerve growth factor to children with widespread neuroblastoma. J Pediatr Surg 1970, 5:18–22.

    Article  PubMed  CAS  Google Scholar 

  7. Helson L, Helson C, Peterson RF, Das SK: A rationale for the treatment of metastatic neuroblastoma. J Natl Cancer Inst 1976, 57:727–729.

    PubMed  CAS  Google Scholar 

  8. Thiele CJ, Reynolds CP, Israel MA: Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature 1985, 313:404–406.

    Article  PubMed  CAS  Google Scholar 

  9. Reynolds CP, Kane DJ, Einhorn PA, et al.: Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 1991, 366:203–211.

    PubMed  CAS  Google Scholar 

  10. Linney E: Retinoic acid receptors: transcription factors modulating gene regulation, development, and differentiation. Curr Top Dev Biol 1992, 27:309–350.

    Article  PubMed  CAS  Google Scholar 

  11. Hashimoto Y, Shudo K: Retinoids and their nuclear receptors. Cell Biol Rev 1991, 25:209–230.

    Google Scholar 

  12. Li C, Einhorn PA, Reynolds CP: Expression of retinoic acid receptors alpha, beta, and gamma in human neuroblastoma cell lines. Prog Clin Biol Res 1994, 385:221–227.

    PubMed  CAS  Google Scholar 

  13. Cheung B, Hocker JE, Smith SA, et al.: Favorable prognostic significance of high-level retinoic acid receptor beta expression in neuroblastoma mediated by effects on cell cycle regulation. Oncogene 1998, 17:751–759.

    Article  PubMed  CAS  Google Scholar 

  14. Koeffler HP: Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood 1983, 62:709–721.

    PubMed  CAS  Google Scholar 

  15. Nilsson B: Probable in vivo induction of differentiation by retinoic acid of promyelocytes in acute promyelocytic leukaemia. Br J Haematol 1984, 57:365–371.

    PubMed  CAS  Google Scholar 

  16. Kessler JF, Jones SE, Levine N, et al.: Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides). Arch Dermatol 123:201–204.

  17. Lippman SM, Meyskens FL Jr.: Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Ann Intern Med 1987, 107:499–502.

    PubMed  CAS  Google Scholar 

  18. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al.: 13-cis-retinoic acid plus interferon-alpha 2a in locally advanced squamous cell carcinoma of the cervix. J Natl Cancer Inst 1993, 85:499–500.

    Article  PubMed  CAS  Google Scholar 

  19. Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990, 323:795–801.

    Article  PubMed  CAS  Google Scholar 

  20. Kraemer KH, DiGiovanna JJ, Moshell AN, et al.: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988, 318:1633–1637.

    Article  PubMed  CAS  Google Scholar 

  21. Finklestein JZ, Krailo MD, Lenarsky C, et al.: 13-cis-retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: report from the Children’s Cancer Study Group. Med Pediatr Oncol 1992, 20:307–311.

    Article  PubMed  CAS  Google Scholar 

  22. Villablanca JG, Khan AA, Avramis VI, et al.: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 1995, 13:894–901.

    PubMed  CAS  Google Scholar 

  23. Khan AA, Villablanca JG, Reynolds CP, Avramis VI: Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer Chemother Pharmacol 1996, 39:34–41.

    Article  PubMed  CAS  Google Scholar 

  24. Reynolds CP, Schindler PF, Jones DM, et al.: Comparison of 13-cis-retinoic acid to trans-retinoic acid using human neuroblastoma cell lines. Prog Clin Biol Res 1994, 385:237–244.

    PubMed  CAS  Google Scholar 

  25. Olson JA: Adverse effects of large doses of vitamin A and retinoids. Semin Oncol 1983, 10:290–293.

    PubMed  CAS  Google Scholar 

  26. Villablanca JG, Khan AA, Avramis VI, Reynolds CP: Hypercalcemia: a dose-limiting toxicity associated with 13-cis-retinoic acid. Am J Pediatr Hematol Oncol 1993, 15:410–415.

    PubMed  CAS  Google Scholar 

  27. Warrell RPJ, Frankel SR, Miller WHJ, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (alltrans-retinoic acid). N Engl J Med 1991, 324:1385–1393.

    Article  PubMed  Google Scholar 

  28. Chomienne C, Ballerini P, Balitrand N, et al.: All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship. Blood 1990, 76:1710–1717.

    PubMed  CAS  Google Scholar 

  29. Smith MA, Parkinson DR, Cheson BD, Friedman MA: Retinoids in cancer therapy. J Clin Oncol 1992, 10:839–864.

    PubMed  CAS  Google Scholar 

  30. Smith MA, Adamson PC, Balis FM, et al.: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 1992, 10:1666–1673.

    PubMed  CAS  Google Scholar 

  31. Adamson PC, Reaman G, Finklestein JZ, et al.: Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer. J Clin Oncol 1997, 15:3330–3337.

    PubMed  CAS  Google Scholar 

  32. Smith MA, Adamson PC, Balis FM, et al.: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 1992, 10:1666–1673.

    PubMed  CAS  Google Scholar 

  33. Matthay K, Villablanca JG, Seeger RC, et al.: Treatment of high risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 1999, 341:1165–1173. This CCG phase III randomized study demonstrated a significant increase in event-free survival for patients treated with myeloablative therapy (compared with intensive non-myeloablative chemotherapy) and for patients receiving 13-cis-retinoic acid after completion of cytotoxic therapy.

    Article  PubMed  CAS  Google Scholar 

  34. Ponzoni M, Bocca P, Chiesa V, et al.: Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. Cancer Res 1995, 55:853–861.

    PubMed  CAS  Google Scholar 

  35. Di Vinci A, Geido E, Infusini E, Giaretti W: Neuroblastoma cell apoptosis induced by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. Int J Cancer 1994, 59:422–426.

    Article  PubMed  Google Scholar 

  36. Mariotti A, Marcora E, Bunone G, et al.: N-(4-hydroxyphenyl) retinamide: a potent inducer of apoptosis in human neuroblastoma cells. J Natl Cancer Inst 1994, 86:1245–1247.

    Article  PubMed  CAS  Google Scholar 

  37. Reynolds CP, Melton LJ, Wang YL: N-(4-hydroxyphenyl) retinamide is highly active against retinoic acid resistant neuroblastoma cell lines. Proc Amer Assoc Cancer Res 1997, 38:25.

    Google Scholar 

  38. Maurer BJ, Metelitsa LS, Seeger RC, et al.: N-(4-hydroxyphenyl) retinamide increases ceramide and reactive oxygen species and induces mixed apoptosis/necrosis in neuroblastoma cell lines. J Natl Cancer Inst 1999, 91:1138–1146. This study demonstrated that, as had been reported for cervical carcinoma and leukemia cells, one mechanism of action by which 4-HPR is cytotoxic for neuroblastoma is via generation of reactive oxygen species. In addition, this paper shows a novel mechanism of action for 4-HPR that involves generation of large amounts of the pro-death lipid ceramide, which involves both apoptosis and necrosis and is effective in conditions of reduced oxygen.

    Article  PubMed  CAS  Google Scholar 

  39. Decensi A, Torrisi R, Polizzi A, et al.: Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl Cancer Inst 1994, 86:105–110.

    Article  PubMed  CAS  Google Scholar 

  40. Sani BP, Shealy YF, Hill DL: N-(4-hydroxyphenyl)retinamide: interactions with retinoid-binding proteins/receptors. Carcinogenesis 1995, 16:2531–2534.

    Article  PubMed  CAS  Google Scholar 

  41. Sheikh MS, Shao ZM, Li XS, et al.: N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis 1995, 16:2477–2486.

    Article  PubMed  CAS  Google Scholar 

  42. Delia D, Aiello A, Formelli F, et al.: Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. Blood 1995, 85:359–367.

    PubMed  CAS  Google Scholar 

  43. Delia D, Aiello A, Meroni L, et al.: Role of antioxidants and intracellular free radicals in retinamide-induced cell death. Carcinogenesis 1997, 18:943–948. See annotation below.

    Article  PubMed  CAS  Google Scholar 

  44. Oridate N, Suzuki S, Higuchi M, et al.: Involvement of reactive oxygen species in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells. J Natl Cancer Inst 1997, 89:1191–1198. These two papers show that one mechanism of action by which 4-HPR is cytotoxic for tumor cells is via the generation of reactive oxygen species.

    Article  PubMed  CAS  Google Scholar 

  45. Kalemkerian GP, Slusher R, Ramalingam S, et al.: Growth inhibition and induction of apoptosis by fenretinide in small-cell lung cancer cell lines. J Natl Cancer Inst 1995, 87:1674–1680.

    Article  PubMed  CAS  Google Scholar 

  46. Keshelava N, Seeger RC, Groshen S, Reynolds CP: Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 1998, 58:5396–5405.

    PubMed  CAS  Google Scholar 

  47. Lavie Y, Cao H, Volner A, et al.: Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem 1997, 272:1682–1687.

    Article  PubMed  CAS  Google Scholar 

  48. Lee L, Abe A, Shayman JA: Improved inhibitors of glucosylceramide synthase. J Biol Chem 1999, 274:14662–14669.

    Article  PubMed  CAS  Google Scholar 

  49. Maurer BJ, Cabot MC, Reynolds CP: Synergism of N-(4-hydroxyphenyl)retinamide cytotoxicity by modulators of ceramide metabolism in solid tumor cell lines. J Natl Cancer Inst 2000, in press.

  50. Bagniewski PG, Reid JM, Villablanca JG, et al.: A phase I pharmacokinetic study of fenretinide (HPR) in children with high-risk solid tumors. Proc Amer Assoc Cancer Res 1999, 40:92.

    Google Scholar 

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  1. Division of Hematology-Oncology, Children’s Hospital of Los Angeles and The University of Southern California School of Medicine, 4650 Sunset Boulevard, 90054-0700, Los Angeles, CA, USA

    C. Patrick Reynolds MD, PhD

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Reynolds, C.P. Differentiating agents in pediatric malignancies: Retinoids in neuroblastoma. Curr Oncol Rep 2, 511–518 (2000). https://doi.org/10.1007/s11912-000-0104-y

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