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Headway and Hurdles in the Clinical Development of Dietary Phytochemicals for Cancer Therapy and Prevention: Lessons Learned from Vitamin A Derivatives

  • Review Article
  • Theme: Natural Products Drug Discovery in Cancer Prevention
  • Published:
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Abstract

Accumulating epidemiologic and preclinical evidence support the pharmacologic use of a variety of dietary chemicals for the prevention and treatment of cancer. However, it will be challenging to translate these findings into routine clinical practice since phytochemicals have pleiotropic biological activities that have to be balanced for optimal efficacy without unacceptable and potentially unanticipated toxicities. Correctly matching patient populations and settings with optimal, natural product-based phytochemical therapies will require a greater understanding of the specific mechanisms underlying the efficacy, toxicity, and resistance of each agent in a variety of normal, premalignant, and malignant settings. This, in turn, necessitates continued commitment from the basic research community to guide carefully designed and informed clinical trials. The most developed class of anticancer phytochemicals consists of the derivatives of vitamin A called retinoids. Unlike other natural product chemicals currently under study, the retinoids have been extensively tested in humans. Over 30 years of clinical investigation has resulted in several disappointments, but there were some spectacular successes where certain retinoid-based protocols are now FDA-approved standard of care therapies to treat specific malignancies. Furthermore, retinoids are one of the most evaluated pharmacologic agents in the ultra-challenging setting of interventional cancer prevention. This review will summarize the development of retinoids in cancer therapy and prevention with an emphasis on currently proposed mechanisms mediating their efficacy, toxicity, and resistance.

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REFERENCES

  1. Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011;3:385–428.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Tang XH, Gudas LJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011;6:345–64.

    Article  CAS  PubMed  Google Scholar 

  3. Niles RM. Signaling pathways in retinoid chemoprevention and treatment of cancer. Mutat Res. 2004;555:81–96.

    Article  CAS  PubMed  Google Scholar 

  4. Duong V, Rochette-Egly C. The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta. 1812;2011:1023–31.

    Google Scholar 

  5. Al M, Alvarez S, Shankaranarayanan P, Lera AR, Bourguet W, Gronemeyer H. Retinoid receptors and therapeutic applications of RAR/RXR modulators. Curr Top Med Chem. 2012;12:505–27.

    Article  Google Scholar 

  6. Barnard JH, Collings JC, Whiting A, Przyborski SA, Marder TB. Synthetic retinoids: structure-activity relationships. Chemistry. 2009;15:11430–42.

    Article  CAS  PubMed  Google Scholar 

  7. Harrison EH. Mechanisms of digestion and absorption of dietary vitamin A. Annu Rev Nutr. 2005;25:87–103.

    Article  CAS  PubMed  Google Scholar 

  8. Theodosiou M, Laudet V, Schubert M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci. 2010;67:1423–45.

    Article  CAS  PubMed  Google Scholar 

  9. D’Ambrosio DN, Clugston RD, Blaner WS. Vitamin A metabolism: an update. Nutrients. 2011;3:63–103.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Napoli JL. Physiological insights into all-trans-retinoic acid biosynthesis. Biochim Biophys Acta. 1821;2012:152–67.

    Google Scholar 

  11. Zanotti G, Berni R. Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin. Vitam Horm. 2004;69:271–95.

    Article  CAS  PubMed  Google Scholar 

  12. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science. 2007;315(5813):820–5.

    Article  CAS  PubMed  Google Scholar 

  13. Noy N. Retinoid-binding proteins: mediators of retinoid action. Biochem J. 2000;348:481–95.

    Article  CAS  PubMed  Google Scholar 

  14. Ross AC, Zolfaghari R. Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr. 2011;31:65–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. J Neurobiol. 2006;66:606–30.

    Article  CAS  PubMed  Google Scholar 

  16. Wolbach SB, Howe PR. Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med. 1925;42:753–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Hong WK. Retinoids and human cancer. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. New York: Raven; 1994. p. 597–658.

    Google Scholar 

  18. Moon RC, Mehta RG, Rao KJ. Retinoids and cancer in experimental animals. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. New York: Raven; 1994. p. 573–95.

    Google Scholar 

  19. Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer. 2007;7:357–69.

    Article  CAS  PubMed  Google Scholar 

  20. Freemantle SJ, Spinella MJ, Dmitrovsky E. Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene. 2003;22:7305–15.

    Article  CAS  PubMed  Google Scholar 

  21. Lippman SM, Hawk ET. Cancer prevention: from 1727 to milestones of the past 100 years. Cancer Res. 2009;69:5269–84.

    Article  CAS  PubMed  Google Scholar 

  22. Petrie K, Zelent A, Waxman S. Differentiation therapy of acute myeloid leukemia: past, present and future. Curr Opin Hematol. 2009;16:84–91.

    Article  CAS  PubMed  Google Scholar 

  23. Camacho LH. Clinical applications of retinoids in cancer medicine. J Biol Regul Homeost Agents. 2003;17(1):98–114.

    CAS  PubMed  Google Scholar 

  24. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev. 2006;4, CD001829.

    PubMed  Google Scholar 

  25. Fritz H, Kennedy D, Fergusson D, Fernandes R, Doucette S, Cooley K, et al. Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis. PLoS One. 2011;6:e21107.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Feng L, Wang Z. Clinical trials in chemoprevention of head and neck cancers. Rev Recent Clin Trials. 2012;7:249–54.

    Article  PubMed  Google Scholar 

  27. Goralczyk R. Beta-carotene and lung cancer in smokers: review of hypotheses and status of research. Nutr Cancer. 2009;61:767–74.

    Article  CAS  PubMed  Google Scholar 

  28. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, et al. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev. 2006;58:712–25.

    Article  CAS  PubMed  Google Scholar 

  29. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, et al. International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev. 2006;58:760–72.

    Article  PubMed  Google Scholar 

  30. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43:1773–808.

    Article  CAS  PubMed  Google Scholar 

  31. Freemantle SJ, Kerley JS, Olsen SL, Gross RH, Spinella MJ. Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma. Oncogene. 2002;21:2880–9.

    Article  CAS  PubMed  Google Scholar 

  32. Delacroix L, Moutier E, Altobelli G, Legras S, Poch O, Choukrallah MA, et al. Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol. 2010;30:231–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol. 2011;12:R2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Perissi V, Rosenfeld MG. Controlling nuclear receptors: the circular logic of cofactor cycles. Nat Rev Mol Cell Biol. 2005;6:542–54.

    Article  CAS  PubMed  Google Scholar 

  35. Lonard DM, O’Malley BW. Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nat Rev Endocrinol. 2012;8:598–604.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Chen W, Roeder RG. Mediator-dependent nuclear receptor function. Semin Cell Dev Biol. 2011;22:749–58.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Gurevich I, Flores AM, Aneskievich BJ. Corepressors of agonist-bound nuclear receptors. Toxicol Appl Pharmacol. 2007;223:288–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Kerley JS, Olsen SL, Freemantle SJ, Spinella MJ. Transcriptional activation of the nuclear receptor corepressor RIP140 by retinoic acid: a potential negative-feedback regulatory mechanism. Biochem Biophys Res Commun. 2001;285:969–75.

    Article  CAS  PubMed  Google Scholar 

  39. White KA, Yore MM, Warburton SL, Vaseva AV, Rieder E, Freemantle SJ, et al. Negative feedback at the level of nuclear receptor coregulation. Self-limitation of retinoid signaling by RIP140. J Biol Chem. 2003;278:43889–92.

    Article  CAS  PubMed  Google Scholar 

  40. Heim KC, Gamsby JJ, Hever MP, Freemantle SJ, Loros JJ, Dunlap JC, et al. Retinoic acid mediates long-paced oscillations in retinoid receptor activity: evidence for a potential role for RIP140. PLoS One. 2009;4:e7639.

    Article  PubMed Central  PubMed  Google Scholar 

  41. White KA, Yore MM, Deng D, Spinella MJ. Limiting effects of RIP140 in estrogen signaling: potential mediation of anti-estrogenic effects of retinoic acid. J Biol Chem. 2005;280:7829–35.

    Article  CAS  PubMed  Google Scholar 

  42. Heim KC, White KA, Deng D, Tomlinson CR, Moore JH, Freemantle SJ, et al. Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells. Mol Cancer. 2007;6:57.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Kashyap V, Laursen KB, Brenet F, Viale AJ, Scandura JM, Gudas LJ. RARγ is essential for retinoic acid induced chromatin remodeling and transcriptional activation in embryonic stem cells. J Cell Sci. 2013;126:999–1008.

    Article  CAS  PubMed  Google Scholar 

  44. Lee ER, Murdoch FE, Fritsch MK. High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid. Stem Cells. 2007;25:2191–9.

    Article  CAS  PubMed  Google Scholar 

  45. Gudas LJ. Retinoids induce stem cell differentiation via epigenetic changes. Semin Cell Dev Biol. 2013;24:701–5.

    Article  CAS  PubMed  Google Scholar 

  46. Morey L, Pascual G, Cozzuto L, Roma G, Wutz A, Benitah SA, et al. Nonoverlapping functions of the polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell. 2012;10:47–62.

    Article  CAS  PubMed  Google Scholar 

  47. Mendoza-Parra MA, Gronemeyer H. Genome-wide studies of nuclear receptors in cell fate decisions. Semin Cell Dev Biol. 2013:706–15.

  48. Stallings RL, Foley NH, Bray IM, Das S, Buckley PG. MicroRNA and DNA methylation alterations mediating retinoic acid induced neuroblastoma cell differentiation. Semin Cancer Biol. 2011;21:283–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Annibali D, Gioia U, Savino M, Laneve P, Caffarelli E, Nasi S. A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2. PLoS One. 2012;7:e40269.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Connolly RM, Nguyen NK, Sukumar S. Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin Cancer Res. 2013;19:1651–9.

    Article  CAS  PubMed  Google Scholar 

  51. Bushue N, Wan YJ. Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev. 2010;62:1285–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Soprano DR, Teets BW, Soprano KJ. Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells. Vitam Horm. 2007;75:69–95.

    Article  CAS  PubMed  Google Scholar 

  53. Spinella MJ, Kerley JS, White KA, Curtin JC. Retinoid target gene activation during induced tumor cell differentiation: human embryonal carcinoma as a model. J Nutr. 2003;133:273S–6.

    PubMed  Google Scholar 

  54. McBurney MW. P19 embryonal carcinoma cells. Int J Dev Biol. 1993;37:135–40.

    CAS  PubMed  Google Scholar 

  55. Andrews PW. Teratocarcinomas and human embryology: pluripotent human EC cell lines. APMIS. 1998;106:158–67.

    Article  CAS  PubMed  Google Scholar 

  56. Rochette-Egly C, Chambon P. F9 embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling. Histol Histopathol. 2001;16:909–22.

    CAS  PubMed  Google Scholar 

  57. Giuliano CJ, Kerley-Hamilton JS, Bee T, Freemantle SJ, Manickaratnam R, Dmitrovsky E, et al. Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005;1731:48–56.

    Article  CAS  PubMed  Google Scholar 

  58. Spinella MJ, Freemantle SJ, Sekula D, Chang JH, Christie AJ, Dmitrovsky E. Retinoic acid promotes ubiquitination and proteolysis of cyclin D1 during induced tumor cell differentiation. J Biol Chem. 1999;274:22013–8.

    Article  CAS  PubMed  Google Scholar 

  59. Snow GE, Kasper AC, Busch AM, Schwarz E, Ewings KE, Bee T, et al. Wnt pathway reprogramming during human embryonal carcinoma differentiation and potential for therapeutic targeting. BMC Cancer. 2009;9:383.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Curtin JC, Dragnev KH, Sekula D, Christie AJ, Dmitrovsky E, Spinella MJ. Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function. Oncogene. 2001;20:2559–69.

    Article  CAS  PubMed  Google Scholar 

  61. Tapia N, Schöler HR. p53 connects tumorigenesis and reprogramming to pluripotency. J Exp Med. 2010;207:2045–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Houldsworth J, Heath SC, Bosl GJ, Studer L, Chaganti RS. Expression profiling of lineage differentiation in pluripotential human embryonal carcinoma cells. Cell Growth Differ. 2002;13:257–64.

    CAS  PubMed  Google Scholar 

  63. Langston AW, Gudas LJ. Identification of a retinoic acid responsive enhancer 3′ of the murine homeobox gene Hox-1.6. Mech Dev. 1992;38:217–27.

    Article  CAS  PubMed  Google Scholar 

  64. Hosler BA, LaRosa GJ, Grippo JF, Gudas LJ. Expression of REX-1, a gene containing zinc finger motifs, is rapidly reduced by retinoic acid in F9 teratocarcinoma cells. Mol Cell Biol. 1989;9:5623–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, et al. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res. 2006;66:820–7.

    Article  CAS  PubMed  Google Scholar 

  66. Giuliano CJ, Freemantle SJ, Spinella MJ. Testicular germ cell tumors: a paradigm for the successful treatment of solid tumor stem cells. Curr Cancer Ther Rev. 2006;2:255–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Gu P, LeMenuet D, Chung AC, Mancini M, Wheeler DA, Cooney AJ. Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation. Mol Cell Biol. 2005;25:8507–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Al Tanoury Z, Piskunov A, Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res. 2013;54:1761–75.

    Article  CAS  PubMed  Google Scholar 

  69. Wang J, Yen A. A MAPK-positive feedback mechanism for BLR1 signaling propels retinoic acid-triggered differentiation and cell cycle arrest. J Biol Chem. 2008;283:4375–86.

    Article  CAS  PubMed  Google Scholar 

  70. Persaud SD, Lin YW, Wu CY, Kagechika H, Wei LN. Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal. 2013;25:19–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell. 2007;129:723–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol. 2003;10:820–5.

    Article  CAS  PubMed  Google Scholar 

  73. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.

    Article  CAS  PubMed  Google Scholar 

  74. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol. 2009;27:1007–13.

    Article  CAS  PubMed  Google Scholar 

  75. Masetti R, Biagi C, Zama D, Vendemini F, Martoni A, Morello W, et al. Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. Adv Ther. 2012;29:747–62.

    Article  CAS  PubMed  Google Scholar 

  76. Quéreux G, Saint-Jean M, Peuvrel L, Brocard A, Knol AC, Dréno B. Bexarotene in cutaneous T-cell lymphoma: third retrospective study of long-term cohort and review of the literature. Expert Opin Pharmacother. 2013;14:1711–21.

    Article  PubMed  Google Scholar 

  77. Dedicoat M, Vaithilingum M, Newton R. Treatment of Kaposi’s sarcoma in HIV-1 infected individuals with emphasis on resource poor settings. Cochrane Database Syst Rev. 2003;3, CD003256.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Bhutani T, Koo J. A review of the chemopreventative effects of oral retinoids for internal neoplasms. J Drugs Dermatol. 2011;10:1292–8.

    CAS  PubMed  Google Scholar 

  80. Veronesi U, Mariani L, Decensi A, Formelli F, Camerini T, Miceli R, et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann Oncol. 2006;17:1065–71.

    Article  CAS  PubMed  Google Scholar 

  81. Cazzaniga M, Varricchio C, Montefrancesco C, Feroce I, Guerrieri-Gonzaga A. Fenretinide (4-HPR): a preventive chance for women at genetic and familial risk? J Biomed Biotechnol. 2012:172897.

  82. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988;318:1633–7.

    Article  CAS  PubMed  Google Scholar 

  83. Moon TE, Levine N, Cartmel B, Bangert JL, Rodney S, Dong Q, et al. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev. 1997;6:949–56.

    CAS  PubMed  Google Scholar 

  84. Marquez C, Bair SM, Smithberger E, Cherpelis BS, Glass LF. Systemic retinoids for chemoprevention of non-melanoma skin cancer in high-risk patients. J Drugs Dermatol. 2010;9:753–8.

    PubMed  Google Scholar 

  85. Alfthan O, Tarkkanen J, Gröhn P, Heinonen E, Pyrhönen S, Säilä K. Tigason (etretinate) in prevention of recurrence of superficial bladder tumors. A double-blind clinical trial. Eur Urol. 1983;9:6–9.

    CAS  PubMed  Google Scholar 

  86. Studer UE, Jenzer S, Biedermann C, Chollet D, Kraft R, von Toggenburg H, et al. Adjuvant treatment with a vitamin A analogue (etretinate) after transurethral resection of superficial bladder tumors. Final analysis of a prospective, randomized multicenter trial in Switzerland. Eur Urol. 1995;28:284–90.

    CAS  PubMed  Google Scholar 

  87. Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340:1046–7.

    Article  CAS  PubMed  Google Scholar 

  88. Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986;315:1501–5.

    Article  CAS  PubMed  Google Scholar 

  89. Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, 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  CAS  PubMed  Google Scholar 

  90. 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. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029–35.

    Article  Google Scholar 

  91. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–5.

    Article  CAS  PubMed  Google Scholar 

  92. Sun SY, Lotan R. Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol. 2002;41(1):41–55.

    Article  PubMed  Google Scholar 

  93. Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, et al. Bexarotene and erlotinib for aerodigestive tract cancer. J Clin Oncol. 2005;23:8757–64.

    Article  CAS  PubMed  Google Scholar 

  94. Dragnev KH, Ma T, Cyrus J, Galimberti F, Memoli V, Busch AM, et al. Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models. Cancer Prev Res. 2011;4:818–28.

    Article  CAS  Google Scholar 

  95. Hildebrandt MA, Lippman SM, Etzel CJ, Kim E, Lee JJ, Khuri FR, et al. Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin Cancer Res. 2012;18:3705–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Lee JJ, Wu X, Hildebrandt MA, Yang H, Khuri FR, Kim E, et al. Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients. Cancer Prev Res. 2011;4:185–93.

    Article  CAS  Google Scholar 

  97. Blumenschein Jr GR, Khuri FR, von Pawel J, Gatzemeier U, Miller Jr WH, Jotte RM, et al. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008;26:1879–85.

    Article  CAS  PubMed  Google Scholar 

  98. Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, et al. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naïve patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008;26:1886–92.

    Article  CAS  PubMed  Google Scholar 

  99. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein Jr GR, Tsao A, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1:44–53.

    Article  CAS  PubMed  Google Scholar 

  100. Gold KA, Kim ES, Wistuba II, Hong WK. Personalizing lung cancer prevention through a reverse migration strategy. Top Curr Chem. 2013;329:221–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

Work cited from our laboratory was supported in part by the National Institutes of Health, National Cancer Institute grants R01-CA104312 and R21-CA124817, the Department of Defense (DOD) grant PR093629 and a grant from the Lance Armstrong Foundation.

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  1. Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, 7650 Remsen, Hanover, New Hampshire, 03755, USA

    Christina Y. Yim, Pingping Mao & Michael J. Spinella

  2. Norris Cotton Cancer Center, Lebanon, New Hampshire, USA

    Michael J. Spinella

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  1. Christina Y. Yim
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Correspondence to Michael J. Spinella.

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Guest Editors: Ah-Ng Tony Kong and Chi Chen

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Yim, C.Y., Mao, P. & Spinella, M.J. Headway and Hurdles in the Clinical Development of Dietary Phytochemicals for Cancer Therapy and Prevention: Lessons Learned from Vitamin A Derivatives. AAPS J 16, 281–288 (2014). https://doi.org/10.1208/s12248-014-9562-2

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