Skip to main content
SpringerLink
Log in

Risks and Benefits of Retinoids in the Chemoprevention of Cancer

  • Review Article
  • Risk-Benefit Assessment
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

Chemoprevention of cancer is a new branch of clinical research; it may be defined as the reduction of cancer incidence by pharmacological means through the suppression of established malignant cell clones or through alteration in growth and progression of premalignant cell populations. In the last few years, this area of research has progressed dramatically from preclinical studies to phase I, II and III clinical trials.

Among the various chemical or natural compounds used as chemopreventive agents, retinoids appear to be one of the most promising groups of agents. Analyses of preclinical and clinical studies have shown retinoids to be active in reversing skin and oral precancer, in preventing primary skin cancer, superficial bladder cancer, and second primary tumours associated with head and neck and lung cancers. Preclinical studies have shown evidence of the activity of fenretinide in breast cancer. Preliminary clinical data seem to show a protective effect of fenretinide against ovarian cancer.

Current evidence therefore suggests that chemoprevention of cancer with retinoids is a promising path.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sporn MB, Dunlop NM, Newton DL, et al. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976; 35: 1332–8

    PubMed  CAS  Google Scholar 

  2. Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc 1979; 38: 2528–34

    PubMed  CAS  Google Scholar 

  3. Spandidos DA, Lamothe A, Field JK. Multiple transcriptional activation of cellular oncogenes in human head and neck solid tumours. Anticancer Res 1985; 5: 221–4

    PubMed  CAS  Google Scholar 

  4. Vialet J, Minna JD. Dominant oncogenes and tumor suppressor genes in the pathogenesis of lung cancer. Am J Respir Cell Mol Biol 1990; 2: 225–32

    Google Scholar 

  5. Rodenhuis S. Oncogenes and human lung cancer. Cancer Treat Res 1989; 45: 89–106

    Article  PubMed  CAS  Google Scholar 

  6. De Vries N, De Flora S. N-acetyl-L-cysteine. J Cell Biochem 1993; 17F Suppl.: 270–7

    Article  Google Scholar 

  7. Lippman SM, Lee JS, Lotan R, et al. Biomarkers as intermediate endpoints in chemoprevention trials. J Natl Cancer Inst 1990; 82: 555–60

    Article  PubMed  CAS  Google Scholar 

  8. Benner SE, Lippman SM, Hong WK. Chemoprevention strategies for lung and upper aerodigestive tract cancer. Cancer Res 1992; 52 Suppl.: 2758S–63S

    PubMed  CAS  Google Scholar 

  9. Blaner WS. Biochemistry and pharmacology of retinoids. In: Hong WK, Lotan R, editors. Retinoids in oncology. New York: Marcel Dekker Inc., 1993: 1–42

    Google Scholar 

  10. Blomhoff R, Holte K, Naess L, et al. Newly administered [3H]retinol is transferred from hepatocytes to stellate cells in liver for storage. Exp Cell Res 1984; 150: 186–93

    Article  PubMed  CAS  Google Scholar 

  11. Bershad S, Rubinstein A, Paterniti Jr JA, et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985; 313: 981–5

    Article  PubMed  CAS  Google Scholar 

  12. Dimery IW. Clinical toxicity of retinoids. In: Hong WK, Lotan R, editors. Retinoids in oncology. New York: Marcel Dekker Inc, 1993: 127–45

    Google Scholar 

  13. Rotmensz N, De Palo G, Formelli F, et al. Long term tolerability of fenretinide (4-HPR) in breast cancer patients. Eur J Cancer 1991; 27: 1127–31

    Article  PubMed  CAS  Google Scholar 

  14. Pizzichetta M, Rossi R, Costa A, et al. Lipoproteins in fenretinide (4-HPR) treated patients. Diabetes Nutr Metab 1992; 5: 71–2

    Google Scholar 

  15. Costa A, Malone W, Perloff M, et al. Tolerability of the synthetic retinoid fenretinide (HPR). Eur J Cancer Clin Oncol 1989; 25: 805–8

    Article  PubMed  CAS  Google Scholar 

  16. Kaiser-Kupfer MI, Peck GL, Caruso RC. Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Ophthalmol 1986; 104: 69–70

    Article  PubMed  CAS  Google Scholar 

  17. Modiano MR, Dalton WS, Lippman SM, et al. Ocular toxic effects of fenretinide. J Natl Cancer Inst 1990; 82: 1063

    Article  PubMed  CAS  Google Scholar 

  18. Formelli F, Carsana R, Costa A. N-(4-hydroxyphenyl)retinamide (4-HPR) lowers plasma retinol levels in rats. Med Sci Res 1987; 15: 843

    CAS  Google Scholar 

  19. Formelli F, Carsana R, Costa A, et al. Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients. Cancer Res 1989; 48: 6149–52

    Google Scholar 

  20. Peng YM, Dalton WS, Albert DS, et al. Pharmacokinetics of N-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentration in cancer patients. Int J Cancer 1989; 43: 22–6

    Article  PubMed  CAS  Google Scholar 

  21. Dimitrov NV, Meyer CJ, Perloff M, et al. Alteration of retinol-binding protein concentrations by the synthetic retinoid fenretinide in healthy human subjects. Am J Clin Nutr 1990; 51: 1082–7

    PubMed  CAS  Google Scholar 

  22. Formelli F, Clerici M, Campa T, et al. Five year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 1993; 11: 2036–42

    PubMed  CAS  Google Scholar 

  23. Flanagan JL, Willhite CC, Ferm VH. Comparative teratogenic activity of cancer chemopreventive retinoidal benzoic acid congeners (arotinoids). J Natl Cancer Inst 1987; 78: 533–8

    PubMed  CAS  Google Scholar 

  24. Dai WG, La Braico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26: 560–99

    Article  Google Scholar 

  25. Expert panel to review the safety and toxicity of 4-hydroxyphenyl-retinamide. Bethesda, Md.: National Institutes of Health, 1991: Sept 5

  26. Bollag W. Vitamin A and retinoids: from nutrition to pharmaco-therapy in dermatology and oncology. Lancet 1983; i: 860–3

    Article  Google Scholar 

  27. Klingman AM, Thorne EG. Topical therapy of actinic keratosis with tretinoin. In: Marks R, editors. Retinoids in cutaneous malignancy. Cambridge, Ma.: Blackwell Scientific Publications, 1991: 66–73

    Google Scholar 

  28. Moriarty M, Dunn J, Darragh A, et al. Etretinate in treatment of actinic keratosis: a double blind crossover study. Lancet 1982; i: 364–5

    Article  Google Scholar 

  29. Watson AB. Preventive effect of etretinate therapy on multiple actinic keratoses. Cancer Detect Prev 1986; 9: 161–5

    PubMed  CAS  Google Scholar 

  30. Tangrea JA, Edwards BK, Taylor PR, et al. Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. J Natl Cancer Inst 1992; 84: 328–32

    Article  PubMed  CAS  Google Scholar 

  31. Nava M, Fabrizio T, Arioli N, et al. Chemoprevention of basal cell carcinoma by prolonged administration of the synthetic retinoid fenretinide (4-HPR). In: De Palo G, Sporn M, Veronesi U, editors. Progress and perspectives in chemoprevention of cancer. Vol. 79. New York: Serono Symposia Publication from Raven Press, 1992: 161–70

    Google Scholar 

  32. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986; 315: 1501–5

    Article  PubMed  CAS  Google Scholar 

  33. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993; 328: 15–20

    Article  PubMed  CAS  Google Scholar 

  34. Chiesa F, Tradati N, Marazza M, et al. Prevention of local relapses and new localizations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR): preliminary results. Oral Oncol Eur J Cancer 1992; 28B: 97–102

    Article  CAS  Google Scholar 

  35. 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 

  36. Bolla M, Lefur R, Ton Van J, et al. Prevention of second primary tumors with etretinate in squamous cell carcinoma of oral cavity and Oropharynx. Results of a multicentric double-blind randomized study. Cancer Res 1994; 54: 854–6

    Google Scholar 

  37. Arnold A, Johnstone B, Stoskopf B, et al. Recruitment for an efficacy study in chemoprevention: the Concerned Smoker Study. Prev Med 1989; 18: 700–10

    Article  PubMed  CAS  Google Scholar 

  38. Lee JS, Lippman SM, Benner SE, et al. Randomized placebo-controlled trial of isotretinoin in the chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994; 12: 937–45

    PubMed  CAS  Google Scholar 

  39. Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993; 11: 1216–22

    PubMed  CAS  Google Scholar 

  40. Alfthan O, Tarkkanen J, Gröhn P, et al. Tigason (etretinate) in prevention of recurrence of superficial bladder tumors. Eur Urol 1983; 9: 6–9

    PubMed  CAS  Google Scholar 

  41. Studer UE, Biedermann C, Chollet D, et al. Prevention of recurrent superficial bladder tumors by oral etretinate: preliminary results of a randomized, double-blind multicenter trial in Switzerland. J Urol 1984; 131: 47–9

    PubMed  CAS  Google Scholar 

  42. Meyskens FL, Surwit E, Moon TE, et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst 1994; 86: 539–43

    Article  PubMed  Google Scholar 

  43. Veronesi U, De Palo G, Costa A, et al. Chemoprevention of breast cancer with retinoids. Monogr J Natl Cancer Inst 1992; 12: 93–7

    Google Scholar 

  44. 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: 1633–7

    Article  PubMed  CAS  Google Scholar 

  45. Chiesa F, Tradati N, Marazza M, et al. Fenretinide (4-HPR) in chemoprevention of oral leukoplakia. J Cell Biochem 1993; 17F Suppl.: 255–61

    Article  CAS  Google Scholar 

  46. De Palo G, Veronesi U, Marubini E, et al. Controlled clinical trials with fenretinide in breast cancer, basal cell carcinoma and oral leukoplakia. J Cell Biochem 1995; 22 Suppl.: 11

    Article  Google Scholar 

  47. Mathé G, Gouveia J, Hercend T, et al. Correlation between precancerous bronchial metaplasia and cigarette consumption, and preliminary results of retinoid treatment. Cancer Detect Prev 1982; 5: 461–6

    PubMed  Google Scholar 

  48. Saccomanno G, Moran P, Schmidt R, et al. Effects of 13-cis-retinoids on premalignant and malignant cells of lung origin. Acta Cytol 1982; 26: 79–85

    Google Scholar 

  49. Browman G, Arnold A, Levine MN, et al. Use of screening phase data to evaluate observer variation of sputum cytodiagnosis as an outcome measure in a chemoprevention trial. Cancer Res 1990; 50: 1216–9

    PubMed  CAS  Google Scholar 

  50. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–35

    Article  Google Scholar 

  51. Moon RC, McCormick DL, Becci PJ, et al. Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse. Carcinogenesis 1982; 3: 1469–72

    Article  PubMed  CAS  Google Scholar 

  52. McCormick AM, Patel M. Metabolism of 4-hydroxyphenyl retinamide to retinoic acid in vivo and in cultured bladder carcinoma cells. Fed Proc 1985; 44: 1672

    Google Scholar 

  53. Decensi A, Bruno S, Giaretti W, et al. Activity of 4-HPR in superficial bladder cancer using DNA flow cytometry as an intermediate endpoint. J Cell Biochem 1992; 161 Suppl.: 139–47

    Article  Google Scholar 

  54. Surwit EA, Graham V, Droegemueller W, et al. Evaluation of topically applied trans-retinoic acid in the treatment of cervical intraepithelial lesions. Am J Obstet Gynecol 1982; 143: 821–3

    PubMed  CAS  Google Scholar 

  55. Weiner SA, Surwit EA, Graham VE, et al. A phase I trial of topically applied trans-retinoic acid in cervical dysplasia. Invest New Drugs 1986; 4: 241–4

    Article  PubMed  CAS  Google Scholar 

  56. Graham V, Surwit ES, Weiner S, et al. Phase II trial of β-all-trans-retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap. West J Med 1986; 145: 192–5

    PubMed  CAS  Google Scholar 

  57. Moon RC, Thompson HJ, Becci PJ, et al. N-(4-hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res 1979; 39: 1339–46

    PubMed  CAS  Google Scholar 

  58. Moon RC, Pritchard JF, Mehta RG, et al. Suppression of rat mammary cancer development by N-(4-hydroxyphenyl)-retinamide (4-HPR) following surgical removal of first palpable tumor. Carcinogenesis 1989; 10: 1645–9

    Article  PubMed  CAS  Google Scholar 

  59. McCormick DL, Mehta RG, Thompson CA. Enhanced inhibition of mammary carcinogenesis by combined treatment with N-(4-hydroxyphenyl)retinamide and ovariectomy. Cancer Res 1982; 42: 508–12

    PubMed  CAS  Google Scholar 

  60. Dowlatshahi K, Mehta RG, Thomas CF, et al. Therapeutic effect of N-(4-hydroxyphenyl)retinamide on N-methyl-N-nitrosourea-induced rat mammary cancer. Cancer Lett 1989; 47: 187–92

    Article  PubMed  CAS  Google Scholar 

  61. Ratko TA, Detrisac DJ, Dinger NM. Chemopreventive efficacy of combined retinoid and tamoxifen treatment following surgical excision of a primary mammary cancer in female rats. Cancer Res 1989; 49: 4472–6

    PubMed  CAS  Google Scholar 

  62. Torrisi R, Pansa F, Orengo M, et al. The synthetic retinoid fenretinide lowers plasma insulin-like growth factor levels in breast cancer patients. Cancer Res 1993; 53: 4769–71

    PubMed  CAS  Google Scholar 

  63. De Palo G, Costa A, Formelli F, et al. Chemoprevention of breast cancer. In Vivo 1993; 7: 577–80

    PubMed  Google Scholar 

  64. Costa A, Formelli F, Chiesa F, et al. Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide. Cancer Res 1994; 54: 2032S–7S

    PubMed  CAS  Google Scholar 

  65. Formelli F, Cleris L. Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Cancer Res 1993; 53: 5374–6

    PubMed  CAS  Google Scholar 

  66. De Palo G, Veronesi U, Camerini T, et al. Can fenretinide protect women against ovarian cancer? J Nat Cancer Inst 1995; 87: 146–7

    Article  PubMed  Google Scholar 

  67. Warrel RP, de The H, Wang Zy, et al. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177–89

    Article  Google Scholar 

  68. Lippman SM, Parkinson DR, Itri LM, et al. 13-cis-retinoic acid and interferon-alpha-2a. Effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 1992; 84: 235–40

    Article  PubMed  CAS  Google Scholar 

  69. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al. 13-cis-retinoic acid plus interferon-alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 1992; 84: 241–5

    Article  PubMed  CAS  Google Scholar 

  70. Lippman SM, Kessler JF, Meyskens Jr FL. Retinoids as preventive and therapeutic anticancer agents. Cancer Treat Rep 1987; 71: 391–405

    PubMed  CAS  Google Scholar 

  71. Boyd AS. An overview of the retinoids. Am J Med 1989; 86: 568–74

    Article  PubMed  CAS  Google Scholar 

  72. Lippman SM, Meyskens Jr FM. Results of the use of vitamin A and retinoids in cutaneous malignancies. Pharmacol Ther 1989; 40: 107–22

    Article  PubMed  CAS  Google Scholar 

  73. Darmon M. Retinoic acid in skin and epithelia. Dev Biol 1991; 2: 219–28

    Google Scholar 

  74. Marks R, editor. Retinoids in cutaneous malignancy. Cambridge, MA.: Blackwell Scientific Publication, 1991

    Google Scholar 

  75. Lippman SM, Hong WK. Cancer chemoprevention. J Clin Oncol 1994; 12: 851–73

    PubMed  CAS  Google Scholar 

  76. Hong WK, Itri LM. Retinoids and human cancer. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. 2nd ed. New York: Raven Press, 1994; 15: 597–624

    Google Scholar 

  77. Kelloff GJ, Crowell JA, Boone CW, et al. Strategy and planning for chemopreventive drug development: clinical development plans. J Cell Biochem 1994; 20: 55–299

    Article  CAS  Google Scholar 

  78. Pastorino U, Hong WK, editors. Chemo and immuno prevention of cancer. Stuttgart: George Thieme Verlag, 1991

    Google Scholar 

  79. De Palo G, Sporn N, Veronesi U, editors. Progress and perspectives in chemoprevention of cancer. Vol 79. New York: Serono Symposia Publication from Raven Press, 1992

    Google Scholar 

  80. Hong WK, Lotan R, editors. Retinoids in oncology. New York: Marcel Dekker Inc, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istituto Nazionale Tumori, Milan, Italy

    Giuseppe De Palo & Franca Formelli

Authors
  1. Giuseppe De Palo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franca Formelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Palo, G., Formelli, F. Risks and Benefits of Retinoids in the Chemoprevention of Cancer. Drug-Safety 13, 245–256 (1995). https://doi.org/10.2165/00002018-199513040-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199513040-00004

Keywords

Search

Navigation