9-cis-Retinoic Acid Treatment Increases Serum Concentrations of α-Tocopherol in Former Smokers

Purpose: Low serum concentrations of antioxidants may be associated with an increased risk of cancer. Based on the accumulated evidence, we hypothesized that retinoids would elevate serum α-tocopherol. This study was designed to determine whether 9-cis-retinoic acid (9-cis-RA), the most common chemopreventive agent, could alter serum α-tocopherol in former smokers. Because hyperlipidemia is a known side effect of retinoids, we also evaluated the association between serum α-tocopherol and lipids in the same population. Experimental Design: Subjects who had stopped smoking at least 12 months before the study were randomly assigned to receive oral 9-cis-RA or placebo daily for 3 months. Clinical information and blood samples were obtained monthly; serum α-tocopherol concentrations were measured by high-performance liquid chromatography and lipid levels by enzymatic assays before treatment and every month during the treatment. Results: Of the 149 subjects in the study, 113 completed 3 months of treatment and provided samples for evaluation of serum α-tocopherol. Serum α-tocopherol levels in the 9-cis-RA group (n = 52) were higher after treatment (r = 0.445, P < 0.01) than before. The incidences of grade ≥2 hypertriglyceridemia and hypercholesterolemia were higher in the 9-cis-RA group than in the placebo group (P = 0.0005 and P = 0.01, respectively), but there were no serious complications related to hyperlipidemia. Conclusions: Treatment of former smokers with 9-cis-RA significantly increased their serum α-tocopherol levels, and this could be a benefit. In addition, serum α-tocopherol could serve as a biomarker for 9-cis-RA treatment.

[1]  A. Beharka,et al.  Recent developments in vitamin E and immune response. , 2009, Nutrition reviews.

[2]  S. V. Kandarkar,et al.  Role of vitamins C and E as chemopreventive agents in the hamster cheek pouch treated with the oral carcinogen-DMBA. , 2008, Oral diseases.

[3]  J. Auwerx,et al.  Ligand‐dependent contribution of RXRβ to cholesterol homeostasis in Sertoli cells , 2004, EMBO reports.

[4]  S. Gangemi,et al.  Correlation between Serum Retinol and α-Tocopherol Levels in Centenarians , 2003 .

[5]  G. Omenn,et al.  The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[6]  S. DeKosky,et al.  22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion* , 2003, The Journal of Biological Chemistry.

[7]  C. Abnet,et al.  Prospective study of serum vitamin E levels and esophageal and gastric cancers. , 2003, Journal of the National Cancer Institute.

[8]  J. Cerhan,et al.  Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Diane D. Liu,et al.  Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial. , 2003, Journal of the National Cancer Institute.

[10]  A. Trichopoulou,et al.  Plasma retinol and tocopherol levels in relation to demographic, lifestyle and nutritional factors of plant origin in Greece , 2003, British Journal of Nutrition.

[11]  R. Chandraratna,et al.  Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents. , 2001, Biochemical pharmacology.

[12]  S. Lippman,et al.  Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. , 2001, Journal of the National Cancer Institute.

[13]  S. D. Vriese,et al.  Oxidative stability of low density lipoproteins and vitamin E levels increase in maternal blood during normal pregnancy , 2001, Lipids.

[14]  Alan C. Wilson,et al.  Correlates of Serum α- and γ-Tocopherol in the Women's Health Initiative , 2001 .

[15]  K I Bland,et al.  Clinical highlights from the National Cancer Data Base, 2000 , 2000, CA: a cancer journal for clinicians.

[16]  D. Albanes,et al.  Serum α-Tocopherol and Subsequent Risk of Lung Cancer Among Male Smokers , 1999 .

[17]  R. D'Agostino,et al.  Alpha-tocopherol dietary supplement decreases titers of antibody against 5-hydroxymethyl-2'-deoxyuridine (HMdU). , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[18]  D. Albanes,et al.  The effects of supplementation with α‐tocopherol and β‐carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial , 1999 .

[19]  G. Murphy,et al.  Clinical highlights from the National Cancer Data Base, 1999 , 1999, CA: a cancer journal for clinicians.

[20]  Jacques Ferlay,et al.  Estimates of the worldwide incidence of 25 major cancers in 1990 , 1999, International journal of cancer.

[21]  M. Russell,et al.  Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. , 1999, Journal of the National Cancer Institute.

[22]  T. Kooistra,et al.  Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids. , 1998, The Journal of clinical investigation.

[23]  R. Mensink,et al.  Maternal and neonatal plasma antioxidant levels in normal pregnancy, and the relationship with fatty acid unsaturation , 1998, British Journal of Nutrition.

[24]  S. Ripatti,et al.  Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. , 1998, Journal of the National Cancer Institute.

[25]  H. DeLuca,et al.  Effects of retinoic acid (all-trans and 9-cis) on tumor progression in small-cell lung carcinoma. , 1998, Biochemical and biophysical research communications.

[26]  M. Sporn,et al.  Recent advances in chemoprevention of cancer. , 1997, Science.

[27]  V. Steele,et al.  Prevention by retinoids of azoxymethane-induced tumors and aberrant crypt foci and their modulation of cell proliferation in the colon of rats. , 1997, Carcinogenesis.

[28]  B. Lacarelle,et al.  In vitro metabolism of three major isomers of retinoic acid in rats. Intersex and interstrain comparison. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[29]  N. Weigel,et al.  1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. , 1997, Endocrinology.

[30]  R. Maestro,et al.  All‐TRANS, 13‐CIS and 9‐CIS retinoic acids induce a fully reversible growth inhibition in HNSCC cell lines: Implications for in vivo retinoic acid use , 1997, International journal of cancer.

[31]  J. Palmgren,et al.  Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. , 1996, Journal of the National Cancer Institute.

[32]  G. Omenn,et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. , 1996, The New England journal of medicine.

[33]  A. Collins,et al.  Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. , 1996, Cancer research.

[34]  M. Kris,et al.  Initial clinical trial of the retinoid receptor pan agonist 9-cis retinoic acid. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  J. Schwartz,et al.  Vitamin E inhibits experimental carcinogenesis and tumour angiogenesis. , 1996, European journal of cancer. Part B, Oral oncology.

[36]  S. Lippman,et al.  Phase I trial of 9-cis retinoic acid in adults with solid tumors. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  M. Sporn,et al.  Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid. , 1996, Journal of the National Cancer Institute.

[38]  B. Poch,et al.  Vitamin E prevents exercise-induced DNA damage. , 1995, Mutation research.

[39]  M. Rubin,et al.  9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein. , 1994, Cancer research.

[40]  M. Sporn,et al.  Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. , 1994, Cancer research.

[41]  S. Lippman,et al.  Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  J. Hendriks,et al.  Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[43]  C. Vigo‐Pelfrey.  Membrane Lipid Oxidation , 1990 .

[44]  M. Kodama.  [Role of active oxygen species in carcinogenesis]. , 1988, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[45]  N. Lowe,et al.  New retinoids for dermatologic diseases. Uses and toxicity. , 1988, Dermatologic clinics.

[46]  W. R. Bruce,et al.  A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. , 1988, Cancer research.

[47]  W. Hong,et al.  13-cis-retinoic acid in the treatment of oral leukoplakia. , 1986, The New England journal of medicine.

[48]  N. Le,et al.  Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. , 1985, New England Journal of Medicine.

[49]  A. Wellstein,et al.  The efficacy of 9-cis retinoic acid in experimental models of cancer , 2005, Breast Cancer Research and Treatment.

[50]  R. Russell,et al.  Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes. , 2003, The Journal of nutrition.

[51]  R. Lotan,et al.  Retinoids and their receptors in cancer development and chemoprevention. , 2002, Critical reviews in oncology/hematology.

[52]  S. Ripatti,et al.  Prostate Cancer and Supplementation With -Tocopherol and -Carotene: Incidence and Mortality in a Controlled Trial , 1998 .

[53]  N. Weigel,et al.  1 , 25-Dihydroxyvitamin D 3 and 9-cis-Retinoic Acid Act Synergistically to Inhibit the Growth of LNCaP Prostate Cells and Cause Accumulation of Cells in G 1 * , 1997 .

[54]  A. Anagnostou,et al.  dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. , 1997, Nutrition and cancer.

[55]  M. Traber,et al.  Vitamin E in humans: demand and delivery. , 1996, Annual review of nutrition.

[56]  M. Boehm,et al.  Retinoid-induced hypertriglyceridemia in rats is mediated by retinoic acid receptors. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[57]  D. Albanes,et al.  The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. , 1994, The New England journal of medicine.

[58]  S. Lippman,et al.  Reduction in oral mucosa micronuclei frequency following alpha-tocopherol treatment of oral leukoplakia. , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[59]  P. Engstrom,et al.  Chemoprevention of cancer. , 1994, Current problems in cancer.

[60]  G. Shklar,et al.  Prevention by vitamin E of experimental oral carcinogenesis. , 1987, Journal of the National Cancer Institute.