Dear
Some studies have shown that reduced retinol serum level was associated with higher incidence of some cancers like lung cancer. Is vitamin A a cure or a cause?
Read this article
http://www.ncbi.nlm.nih.gov/pubmed/25879031 OR
Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins
You may find an answer in the following paper:
Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins
Elena Doldo, Gaetana Costanza, Sara Agostinelli, Chiara Tarquini, Amedeo Ferlosio, Gaetano Arcuri, Daniela Passeri, Maria Giovanna Scioli, and Augusto Orlandi
BioMed Research International
Volume 2015 (2015), Article ID 624627, 14 pages
http://dx.doi.org/10.1155/2015/624627
Vitamin A is good for one's overal general health just like many other vitamins. Although some papers suggest deficiency of Vitamin A may be associated with a higher incidence of a particular malignancy, Vitamin A in itself is not a treatment for cancer.
Effect of Vit A on cancer may depend on tissue, dose, duration of dosing, concomitant drugs or conditions,...
Rinsho Ketsueki. 1994 Jun;35(6):598-602.
[A case of acute promyelocytic leukemia (APL) with myeloblastoma in the oral
cavity developing after receiving all-trans retinoic acid (ATRA)].
[Article in Japanese]
Izumi T(1), Hatake K, Imagawa S, Yoshikda M, Ohta M, Sasaki R, Miwa A, Suda T,
Sakamoto S, Miura Y.
Author information:
(1)Division of Hematology, Medicine, Jichi Medical School.
A 44-year-old woman was diagnosed as having acute promyelocytic leukemia (APL) in
April 1988. On her first admission, chromosomal translocation (15; 17), +8, and
+12 was detected. When she was readmitted to our hospital with the second relapse
in May 1990, t(3; 13) and +8 was detected, instead of t(15;17). Complete
remission was re-achieved with VP-16, MIT, and BHAC, but the third relapse
occurred in September 1990. After obtaining informed consent, she was given
etretinate 40 mg per day orally for 17 days, without any effect on leukemia. She
was then given all-trans retinoic acid (ATRA) 60 mg per day orally for 29 days.
Although a mild granulocytic recovery was observed, no sufficient hematological
recovery was obtained (minor response). Besides common side effects of ATRA, such
as dry skin and hypertriglycedemia, she had a myeloblastoma in the oral cavity,
but it is unknown whether the symptom was a complication of ATRA therapy or not.
PMID: 8078196 [PubMed - indexed for MEDLINE]
J Am Acad Dermatol. 1992 Dec;27(6 Pt 2):S34-7.
Retinoids for the future: oncology.
DiGiovanna JJ(1).
Author information:
(1)Dermatology Branch, National Cancer Institute, National Institutes of Health,
Bethesda, MD 20892.
A major incentive for the development of the synthetic retinoids has been their
potential for the treatment and prevention of cancer. Early studies demonstrated
that treatment with isotretinoin or etretinate alone could result in the
regression of some existing skin cancers. However, even at high doses the
response rates were poor. Greater efficacy has been observed with retinoids used
in the prevention of cancer of the skin and oral cavity in high-risk patients.
The potential for retinoids as chemopreventive agents is being further explored
as selected retinoids are being targeted to specific malignancies, such as
fenretinide for breast cancer chemoprevention. The effectiveness of tretinoin as
a treatment for promyelocytic leukemia has raised enthusiasm for retinoids as
cancer therapeutic agents. Furthermore, evidence of synergy between the retinoids
and a variety of cytokines as enhances of differentiation chart a bright future
for retinoids in oncology.
PMID: 1460123 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst. 1979 Jun;62(6):1435-8.
Vitamin A and lung cancer.
Mettlin C, Graham S, Swanson M.
Retrospective dietary and smoking data were gathered by interview of 292 white
male patients with lung cancer and 801 control patients with nonrespiratory,
nonneoplastic diseases at Roswell Park Memorial Institute, Buffalo, New York. A
computed index of vitamin A intake was used to differentiate lung cancer patients
from controls. Lung cancer patients had lower values than did controls. The
reduced relative risk (RR) of lung cancer associated with vitamin A was most
evident among men who smoked heavily. For them, a dose-response relationship
increasing to an RR of 2.4 for low values of the index was observed. Frequency of
daily milk drinking was lower among patients with lung cancer. Lower RR was found
among the men who smoked heavily and frequently consumed carrots. These findings
are consistent with evidence from animal studies on inhibition of tumor incidence
by retinoids and with previous findings in prospective and retrospective
epidemiologic studies.
PMID: 286115 [PubMed - indexed for MEDLINE]
PMID 7427541, Br Med J, 1980.
Prog Food Nutr Sci. 1985;9(3-4):283-341.
Diet, nutrition, and cancer.
Palmer S.
Evidence pertaining to the role of dietary factors in carcinogenesis comes from
both epidemiological studies and laboratory experiments. In 1982, the Committee
on Diet, Nutrition, and Cancer of the National Research Council conducted a
comprehensive evaluation of this evidence. That assessment as well as recent
epidemiological and laboratory investigations suggest that a high fat diet is
associated with increased susceptibility to cancer of different sites,
particularly the breast and colon, and to a lesser extent, the prostate. Current
data permit no definitive conclusions about other dietary macroconstituents
including cholesterol, total caloric intake, protein, carbohydrates and total
dietary fiber. Specific components of fiber, however, may have a protective
effect against colon cancer. In epidemiological studies, frequent consumption of
certain fruits and vegetables, especially citrus fruits and carotene-rich and
cruciferous vegetables, is associated with a lower incidence of cancers at
various sites. The specific components responsible for these effects are not
clearly identified, although the epidemiological evidence appears to be most
consistent for a protective effect of carotene on lung cancer and less so for
vitamins A and C and various cancer sites. The laboratory evidence is most
consistent for vitamin A deficiency and enhanced tumorigenesis, and for the
ability of various nonnutritive components in cruciferous vegetables to block
in-vivo carcinogenesis. The data for minerals and carcinogenesis are extremely
limited, although preliminary evidence from both epidemiological and laboratory
studies suggests that selenium may protect against overall cancer risk. Frequent
consumption of cured, pickled, or smoked foods, possibly because they may contain
nitrosamines or polycyclic aromatic hydrocarbons, appears to increase the risk of
esophageal or stomach cancer, however, the specific causative agents in these
foods are not clearly identified. Excessive alcohol consumption among smokers
appears to be associated with an elevated risk of cancers of the oral cavity,
esophagus, larynx, and respiratory tract. The mechanisms of action of dietary
factors on carcinogenesis are poorly understood. The NRC committee, and more
recently, the National Cancer Institute and the American Cancer Society have
proposed interim dietary guidelines to lower the risk of cancer. These guidelines
are consistent with general dietary recommendations proposed by U.S. government
agencies for maintenance of good health.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 3010379 [PubMed - indexed for MEDLINE]
N Engl J Med. 1984 Feb 16;310(7):430-4.
Relation of serum vitamins A and E and carotenoids to the risk of cancer.
Willett WC, Polk BF, Underwood BA, Stampfer MJ, Pressel S, Rosner B, Taylor JO,
Schneider K, Hames CG.
Epidemiologic studies suggest that low carotene intake and low levels of serum
retinol may be associated with an increased risk of cancer. Likewise, in some
animal studies vitamin E has been associated with a reduced rate of induced
cancers. Therefore, we measured retinol, retinol-binding protein, vitamin E
(alpha-tocopherol), and total carotenoids in serum collected in 1973 from 111
participants in the Hypertension Detection and Follow-up Program who were free of
cancer at the time but were diagnosed as having cancer during the subsequent five
years. These measurements were compared with those in 210 controls who were
matched for age, sex, race, and time of blood collection, and who remained free
of cancer. Mean values for retinol were similar for cases and controls (67.3 and
68.7 micrograms per deciliter, respectively [95 per cent confidence limits for
case-control difference, -6.7 to 3.5]). Values were also similar for
retinol-binding protein (6.01 and 5.94 mg per deciliter [-0.42 to 0.56]), and
carotenoids (114.5 and 111.6 micrograms per deciliter [-9.1 to 15.9]). The mean
base-line retinol level in the 18 subjects with subsequent lung cancer was higher
than that in their matched controls (79.0 vs. 71.4 micrograms per deciliter, -4.9
to 19.7). Serum vitamin E levels were somewhat lower in subjects who later had
cancer than in controls (1.16 and 1.26 mg per deciliter, -0.22 to 0.02), in part
because of the confounding effect of serum cholesterol levels (when adjusted for
lipid levels, the case-control difference was -0.05 mg per deciliter; -0.17 to
0.07). These data do not support hypotheses relating intake or serum levels of
antioxidant vitamins to a reduced cancer risk.
PMID: 6537988 [PubMed - indexed for MEDLINE]
Nutr Cancer. 1987;9(2-3):109-21.
Dietary vitamin A and lung cancer: results of a case-control study among chemical
workers.
Bond GG, Thompson FE, Cook RR.
A nested case-control study conducted among a cohort of chemical manufacturing
employees provided an opportunity to test the hypothesis that lung cancer risk is
inversely related to dietary intake of vitamin A. Eligible for study were 308
former male employees who had died of lung cancer between 1940 and 1980. Two
control groups, one a decedent and the other a "living" series, were individually
matched to the cases one-for-one. Interviews were completed with 734 subjects or
their next-of-kin and included a food frequency list. A vitamin A index was
developed for each subject based on the frequency of consumption of 29 food
items. After adjustment for a number of potentially confounding variables (e.g.,
smoking, educational level, and use of vitamin supplements), there was evidence
that vitamin A intake was inversely associated with lung cancer risk. The effect
was most pronounced in the comparisons with the "living" controls and appeared
strongest among cigarette smokers. Subjects in the lowest tertile of vitamin A
intake had approximately twice the risk of lung cancer as those in the highest.
Analyses of an index of carotenoids and of individual food items suggested that
plant sources of vitamin A may play a more important role in producing the effect
than do animal sources.
PMID: 3562289 [PubMed - indexed for MEDLINE]
Am J Clin Nutr. 2013 Aug;98(2):488-93. doi: 10.3945/ajcn.113.062778. Epub 2013
Jun 26.
Metabolomic profile of response to supplementation with β-carotene in the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Mondul AM(1), Sampson JN, Moore SC, Weinstein SJ, Evans AM, Karoly ED, Virtamo J,
Albanes D.
Author information:
(1)Nutritional Epidemiology Branch and the Biostatistics Branch, Division of
Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of
Health and Human Services, Bethesda, MD, USA.
BACKGROUND: Two chemoprevention trials found that supplementation with β-carotene
increased the risk of lung cancer and overall mortality. The biologic basis of
these findings remains poorly understood.
OBJECTIVE: The objective was to compare the on-study change in metabolomic
profiles of men randomly assigned to receive or not receive β-carotene
supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC)
Study.
DESIGN: The ATBC Study was a randomized, double-blind, placebo-controlled,
primary cancer prevention trial; participants were Finnish male smokers assigned
to 1 of 4 intervention groups: 1) α-tocopherol, 2) β-carotene, 3) both, or 4)
placebo. Fifty participants with both baseline and follow-up fasting serum
samples were randomly selected from each of these groups. Metabolomic profiling
was conducted by mass spectrometry. The association between change in each
metabolite over time and trial assignment (β-carotene or no β-carotene) was
estimated by linear regression.
RESULTS: We measured 489 metabolites, and 17 changed significantly (P < 0.05) in
response to β-carotene supplementation. More of these 17 metabolites were of
xenobiotic origin than would be expected by chance (9 of 60, or 15%; P =
0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a
marker of glycemic control (β = -0.379, P = 0.0071).
CONCLUSIONS: Male smokers supplemented with β-carotene developed metabolomic
profiles consistent with the induction of cytochrome P450 enzymes, the primary
metabolizers of xenobiotics in humans. These findings may shed light on the
increased mortality associated with β-carotene supplementation in the ATBC Study
and suggest the need to explore potential interactions between medication use and
dietary supplements, particularly among smokers. This trial was registered at
clinicaltrials.gov as NCT00342992.
PMCID: PMC3712556
PMID: 23803886 [PubMed - indexed for MEDLINE]
Am J Clin Nutr. 2012 Nov;96(5):1204S-6S. doi: 10.3945/ajcn.112.034868. Epub 2012
Oct 10.
A global clinical view on vitamin A and carotenoids.
Sommer A(1), Vyas KS.
Author information:
(1)Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21209, USA.
The clinical importance of vitamin A as an essential nutrient has become
increasingly clear. Adequate vitamin A is required for normal organogenesis,
immune competence, tissue differentiation, and the visual cycle. Deficiency,
which is widespread throughout the developing world, is responsible for a million
or more instances of unnecessary death and blindness each year. β-Carotene is an
important, but insufficient, source of vitamin A among poor populations, which
accounts for the widespread nature of vitamin A deficiency. It has only recently
become apparent that the bioconversion of traditional dietary sources of
β-carotene to vitamin A is much less efficient than previously supposed. The
other major carotenoids, particularly lycopene, lutein, and zeaxanthin, have been
found to have important biological properties, including antioxidant and
photoprotective activity, and high intake has been linked in observational
studies with reduced risk of a number of chronic diseases. But, to date, no
clinical trials have proven the clinical value of ingested carotenoids
individually or in combination, in either physiologic or pharmacologic doses,
with the excepton of the provitamin A activity of carotene. Indeed, several
trials have suggested an increased risk of lung cancer among high-risk
individuals (smokers and asbestos workers) who were given high doses of
β-carotene alone or in combination with other antioxidants. Much more evidence is
needed before commonly encountered claims of the value of ingesting high doses of
non-provitamin A carotenoids are validated.
PMID: 23053551 [PubMed - indexed for MEDLINE]
Cancer Epidemiol Biomarkers Prev. 2011 Apr;20(4):672-8. doi:
10.1158/1055-9965.EPI-10-1166. Epub 2011 Feb 18.
Increased risk of lung cancer in men with tuberculosis in the alpha-tocopherol,
beta-carotene cancer prevention study.
Shiels MS(1), Albanes D, Virtamo J, Engels EA.
Author information:
(1)Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, 6120 Executive Blvd, EPS 7059, Rockville, MD
20852, USA. [email protected]
BACKGROUND: Lung cancer and tuberculosis cause significant morbidity and
mortality worldwide. Tuberculosis may increase lung cancer risk through
substantial and prolonged pulmonary inflammation. However, prospective data on
tuberculosis and lung cancer risk are limited.
METHODS: Our study included 29,133 Finnish male smokers followed prospectively in
the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2005). Lung
cancers were identified through linkage with the Finnish Cancer Registry, and
hospital-treated tuberculosis cases were ascertained from the National Hospital
Discharge Register. We assessed the association between tuberculosis and lung
cancer risk with proportional hazards regression models, adjusting for age and
cigarette smoking.
RESULTS: Forty-four lung cancer cases occurred among 273 men with tuberculosis
(incidence rate = 1,786 per 100,000 person-years). Tuberculosis was associated
with a two-fold elevation in lung cancer risk (HR = 1.97; 95% CI = 1.46-2.65)
with significant associations observed for both incident (HR = 2.05; 95% CI =
1.42-2.96) and prevalent tuberculosis (HR = 1.82; 95% CI = 1.09-3.02). Lung
cancer risk was greatest in the 2-year window after tuberculosis diagnosis (HR =
5.01; 95% CI = 2.96-8.48) but remained elevated at longer latencies (HR = 1.53;
95% CI = 1.07-2.20). Though tuberculosis was associated with an increased risk of
squamous cell carcinoma (HR = 3.71), adenocarcinoma (HR = 1.71), small cell
carcinoma (HR = 1.72), and lung cancer of other (HR = 1.23) and unknown
histologies (HR = 1.35), only the association for squamous cell carcinoma was
statistically significant.
CONCLUSIONS: Tuberculosis is associated with increased lung cancer risk in male
smokers.
IMPACT: Our results add to the growing body of evidence implicating chronic
inflammation and pulmonary scarring in the etiology of lung cancer.
PMCID: PMC3076700
PMID: 21335509 [PubMed - indexed
Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2202-6. doi:
10.1158/1055-9965.EPI-09-0013.
Dietary supplement use and prostate cancer risk in the Carotene and Retinol
Efficacy Trial.
Neuhouser ML(1), Barnett MJ, Kristal AR, Ambrosone CB, King IB, Thornquist M,
Goodman GG.
Author information:
(1)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,
Seattle, WA 98109-1024, USA. [email protected]
We investigated dietary supplement use and prostate cancer risk in the Carotene
and Retinol Efficacy Trial (CARET). CARET was a randomized, double-blinded,
placebo-controlled trial testing a daily dose of 30 mg beta-carotene + 25,000 IU
retinyl palmitate for lung cancer prevention (1985-1996; active follow-up
occurred through 2005). Secondary outcomes, including prostate cancer, were also
assessed. Participants were queried about dietary supplements, health history,
family history of cancer, smoking, and lifestyle habits. Cox proportional hazards
regression estimated multivariate-adjusted relative risk [and 95% confidence
intervals (95% CI)] of prostate cancer for dietary supplement users and nonusers
with or without the high-dose CARET vitamins during the intervention and
postintervention phases. After an average of 11 years of follow-up, 890 prostate
cancer cases were reported. Neither the CARET nor other supplements were
associated with total prostate cancer risk. For aggressive prostate cancer, men
in the CARET intervention arm who used additional supplements had a relative risk
for aggressive prostate cancer (Gleason >or=7 or stage III/IV) of 1.52 (95% CI,
1.03-2.24; P < 0.05), relative to all others. These associations disappeared in
the postintervention period (0.75; 95% CI, 0.51-1.09). Conversely, there was no
association of CARET + other supplements with nonaggressive disease, relative to
all others. There was no effect modification by smoking or time on CARET
intervention in any analyses. CARET only included smokers, so findings reported
here may not apply to nonsmokers. Our results are consistent with other studies
suggesting that dietary supplements may influence prostate cancer risk.
PMCID: PMC2733330
PMID: 19661078 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst. 2006 Apr 5;98(7):441-50.
Randomized phase III trial of low-dose isotretinoin for prevention of second
primary tumors in stage I and II head and neck cancer patients.
Khuri FR(1), Lee JJ, Lippman SM, Kim ES, Cooper JS, Benner SE, Winn R, Pajak TF,
Williams B, Shenouda G, Hodson I, Fu K, Shin DM, Vokes EE, Feng L, Goepfert H,
Hong WK.
Author information:
(1)Winship Cancer Institute/Emory University School of Medicine, Atlanta, GA
30322, USA. [email protected]
Comment in
J Natl Cancer Inst. 2006 Apr 5;98(7):426-7.
BACKGROUND: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A
derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical
and clinical studies of high-dose isotretinoin in patients with head and neck
squamous cell cancer (HNSCC) have produced encouraging results. We conducted a
phase III randomized trial of low-dose isotretinoin versus placebo in early-stage
HNSCC patients to assess its effect on second primary tumor incidence and
survival.
METHODS: We randomly assigned 1190 patients who had been treated for stage I or
II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3
years. The patients were monitored for up to 4 more years. Survival was analyzed
by the Kaplan-Meier method, and Cox proportional hazards models were used for
multivariable survival analysis. All statistical tests were two-sided.
RESULTS: Isotretinoin did not statistically significantly reduce the rate of
second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] =
0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared
with placebo in patients with early-stage HNSCC. Current smokers had a higher
rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to
2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of
death from any cause for current smokers versus never smokers was 2.51 (95% CI =
1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI =
1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung
(31%), oral cavity (17%), larynx (8%), and pharynx (5%).
CONCLUSIONS: Low-dose isotretinoin was not effective in reducing the rate of
second primary tumors or death or smoking-related disease. Smoking statistically
significantly increased the rate of second primary tumors and death. Ongoing
trials are testing higher doses of isotretinoin as part of combination
bioadjuvant therapeutic methods for patients with locally advanced HNSCC.
PMID: 16595780 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst. 2004 Dec 1;96(23):1743-50.
The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and
cardiovascular disease mortality during 6-year follow-up after stopping
beta-carotene and retinol supplements.
Goodman GE(1), Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn GS,
Valanis B, Williams JH Jr.
Author information:
(1)Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Bldg. M,
M1-B514, Seattle, WA 98109, USA. [email protected]
Comment in
J Natl Cancer Inst. 2004 Dec 1;96(23):1729-31.
BACKGROUND: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the
effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the
incidence of lung cancer, other cancers, and death in 18,314 participants who
were at high risk for lung cancer because of a history of smoking or asbestos
exposure. CARET was stopped ahead of schedule in January 1996 because
participants who were randomly assigned to receive the active intervention were
found to have a 28% increase in incidence of lung cancer, a 17% increase in
incidence of death and a higher rate of cardiovascular disease mortality compared
with participants in the placebo group.
METHODS: After the intervention ended, CARET participants returned the study
vitamins to their study center and provided a final blood sample. They continue
to be followed annually by telephone and mail self-report. Self-reported cancer
endpoints were confirmed by review of pathology reports, and death endpoints were
confirmed by review of death certificates. All statistical tests were two-sided.
RESULTS: With follow-up through December 31, 2001, the post-intervention relative
risks of lung cancer and all-cause mortality for the active intervention group
compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to
1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk
curves for lung cancer incidence and all-cause mortality indicated that relative
risks remained above 1.0 throughout the post-intervention follow-up. By contrast,
the relative risk of cardiovascular disease mortality decreased rapidly to 1.0
after the intervention was stopped. During the post-intervention phase, females
had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36),
cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause
mortality (1.37 versus 0.98; P = .001) than males.
CONCLUSIONS: The previously reported adverse effects of beta-carotene and retinyl
palmitate on lung cancer incidence and all-cause mortality in cigarette smokers
and individuals with occupational exposure to asbestos persisted after drug
administration was stopped although they are no longer statistically significant.
Planned subgroup analyses suggest that the excess risks of lung cancer were
restricted primarily to females, and cardiovascular disease mortality primarily
to females and to former smokers.
PMID: 15572756 [PubMed - indexed for MEDLINE]
Int J Oncol. 2003 Dec;23(6):1607-13.
Surrogate end-point biomarker analysis in a retinol chemoprevention trial in
current and former smokers with bronchial dysplasia.
Lam S(1), Xu X, Parker-Klein H, Le Riche JC, Macaulay C, Guillaud M, Coldman A,
Gazdar A, Lotan R.
Author information:
(1)Department of Respiratory Therapy, British Columbia Cancer Agency, Vancouver,
British Columbia V5Z 3J5, Canada. [email protected]
Epidemiological studies suggested that vitamin A may be protective against lung
cancer, however, recent chemoprevention trials with beta-carotene, a precursor of
vitamin A, demonstrated enhancement of lung carcinogenesis among smokers. Whether
vitamin A is beneficial or harmful in chemoprevention of lung cancer in smokers
has not been resolved. This study was designed to determine the effect of retinol
alone in current and former smokers using bronchial dysplasia, nuclear
morphometry and retinoic acid receptor-beta (RAR-beta) mRNA expression as
surrogate end-point biomarkers (SEBs). Eighty-one current or former smokers with
a smoking history of >/=30 pack-years were randomized to receive either placebo
or retinol (50,000 IU per day) for six months. Fluorescence bronchoscopy was
performed prior to treatment to localize areas suggestive of dysplasia. At least
4 bronchial biopsies were taken per subject including at least two biopsies from
apparently normal areas. The same areas were precisely re-biopsied after 6
months. Any new areas suggestive of dysplasia were also biopsied. Changes in the
SEBs were assessed before and after treatment. At baseline, the frequency of
biopsies negative for RAR-beta expression was: normal (23%), hyperplasia (28%),
metaplasia (41%), mild dysplasia (41%), and moderate/severe dysplasia (44%).
There was no significant difference in the regression rate between the retinol
and placebo groups using histopathology and nuclear morphometry as SEBs. The
likelihood of regression was found to be lower in those who continued to smoke
during the study (OR=1.86 for those smoking >10 cigarettes per day, p=0.084 to
OR=0.95, p=0.26 for those smoking 20+ per day compared to ex-smokers). Retinol
was not effective in the up-regulation of RAR-beta in lesions with bronchial
dysplasia. We postulate that the lack of effect of retinol on RAR-beta expression
among individuals who continued to smoke while taking retinol may be due to
suppressive effect of tobacco smoke constituents on RAR-beta expression and/or
altered cellular metabolism of retinol to retinoic acid and its isomers.
PMID: 14612933 [PubMed - indexed for MEDLINE
Cancer Res. 2001 Feb 15;61(4):1457-63.
Randomized trial of supplemental beta-carotene to prevent second head and neck
cancer.
Mayne ST(1), Cartmel B, Baum M, Shor-Posner G, Fallon BG, Briskin K, Bean J,
Zheng T, Cooper D, Friedman C, Goodwin WJ Jr.
Author information:
(1)Department of Epidemiology, Yale University School of Medicine, New Haven,
Connecticut 06520-8034, USA. [email protected]
Beta-carotene has established efficacy in animal models of oral carcinogenesis
and has been shown to regress oral precancerous lesions in humans. The purpose of
this study was to see whether these effects extended to the prevention of
oral/pharyngeal/laryngeal (head and neck) cancer in humans. The subject
population for this randomized, placebo-controlled, double-blinded clinical trial
included 264 patients who had been curatively treated for a recent early-stage
squamous cell carcinoma of the oral cavity, pharynx, or larynx. Patients were
assigned randomly to receive 50 mg of beta-carotene per day or placebo and were
followed for up to 90 months for the development of second primary tumors and
local recurrences. After a median follow-up of 51 months, there was no difference
between the two groups in the time to failure [second primary tumors plus local
recurrences: relative risk (RR), 0.90; 95% confidence interval (CI), 0.56-1.45].
In site-specific analyses, supplemental beta-carotene had no significant effect
on second head and neck cancer (RR, 0.69; 95% CI, 0.39-1.25) or lung cancer (RR,
1.44; 95% CI, 0.62-3.39). Total mortality was not significantly affected by this
intervention (RR, 0.86; 95% CI, 0.52-1.42). Whereas none of the effects were
statistically significant, the point estimates suggested a possible decrease in
second head and neck cancer risk but a possible increase in lung cancer risk.
These effects are consistent with the effects observed in trials using
intermediate end point biological markers in humans, in which beta-carotene has
established efficacy in oral precancerous lesions but has no effect or slightly
worsens sputum cytology, and in animal carcinogenicity studies, in which
beta-carotene has established efficacy in buccal pouch carcinogenesis in hamsters
but not in animal models of respiratory tract/lung carcinogenesis, with some
suggestions of tumor-promoting effects in respiratory tract/lung. If our results
are replicated by other ongoing/completed trials, this suggests a critical need
for mechanistic studies addressing differential responses in one epithelial site
(head and neck) versus another (lung).
PMID: 11245451 [PubMed - indexed for MEDLINE]
Cancer Causes Control. 2000 Aug;11(7):617-26.
Effects of beta-carotene supplementation on cancer incidence by baseline
characteristics in the Physicians' Health Study (United States).
Cook NR(1), Le IM, Manson JE, Buring JE, Hennekens CH.
Author information:
(1)Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
OBJECTIVES: The Physicians' Health Study (PHS) was a randomized trial of
beta-carotene (50 mg, alternate days) and aspirin in primary prevention of cancer
and cardiovascular disease among 22,071 US male physicians. This report updates
results for beta-carotene and examines effect modification by baseline
characteristics.
METHODS: Beta-carotene's effect on cancer over nearly 13 years was examined
overall and within subgroups defined by baseline characteristics using
proportional-hazards models.
RESULTS: 2667 incident cancers were confirmed, with 1117 prostate, 267 colon, and
178 lung cancers. There were no significant differences with supplementation in
total (relative risk (RR) = 1.0, 95% confidence interval (CI) = 0.9-1.0);
prostate (RR = 1.0, 95% CI = 0.9-1.1); colon (RR = 0.9, 95% CI = 0.7-1.2); or
lung (RR = 0.9, 95% CI = 0.7-1.2) cancer, and no differences over time. In
subgroup analyses, total cancer was modestly reduced with supplementation among
those aged 70+ years (RR = 0.8, 95% CI = 0.7-1.0), daily drinkers of alcohol (RR
= 0.9, 95% CI = 0.8-1.0), and those in the highest BMI quartile (RR = 0.9, 95% CI
= 0.7-1.0). Prostate cancer was reduced with supplementation among those in the
highest BMI quartile (RR = 0.8, 95% CI = 0.6-1.0), and colon cancer was reduced
among daily drinkers of alcohol (RR = 0.5, 95% CI = 0.3-0.8).
CONCLUSIONS: The PHS found no overall effect of beta-carotene on total cancer, or
the three most common site-specific cancers. The possibility of risk reduction
within specific subgroups remains.
PMID: 10977106 [PubMed - indexed for MEDLINE]
Cancer. 1999 Nov 1;86(9):1783-92.
Beta-carotene supplementation for patients with low baseline levels and decreased
risks of total and prostate carcinoma.
Cook NR(1), Stampfer MJ, Ma J, Manson JE, Sacks FM, Buring JE, Hennekens CH.
Author information:
(1)Division of Preventive Medicine, Department of Medicine, Brigham and Women's
Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
Comment in
Cancer. 1999 Nov 1;86(9):1629-31.
BACKGROUND: The Physicians' Health Study was a randomized, double-blind,
placebo-controlled trial using a 2x2 factorial design including supplementation
with beta-carotene (50 mg every other day) in the primary prevention of cancer
among 22,071 U.S. male physicians ages 40-84 years at randomization. Before
randomization, the authors collected baseline blood specimens to determine
whether any benefit was greater among or confined to those with low baseline
levels of beta-carotene.
METHODS: Baseline blood samples were collected from 14,916 participants. These
samples were assayed, according to a nested case-control design, from 1439 men
subsequently diagnosed with cancer over 12 years of follow-up (631 with prostate
carcinoma) and 2204 controls matched by age and smoking habits.
RESULTS: Men in the lowest quartile for plasma beta-carotene at baseline had a
marginally significant (P = 0.07) increased risk of cancer compared with those in
the highest quartile (relative risk [RR] = 1.30, 95% confidence interval [CI],
0.98-1.74). Men in the lowest quartile assigned at random to beta-carotene
supplementation had a possible but nonsignificant decrease in overall cancer risk
(RR = 0.83, 95% CI, 0.63-1.09) compared with those assigned to placebo. This was
primarily due to a significant reduction in the risk of prostate carcinoma (RR =
0.68, 95% CI, 0. 46-0.99) in this group. After the first 2 years of follow-up
were excluded, the results were virtually unchanged.
CONCLUSIONS: These prespecified subgroup analyses appeared to support the idea
that beta-carotene supplementation may reduce risk of prostate carcinoma among
those with low baseline levels. Further follow-up of this population will help
determine whether these findings are valid.
PMID: 10547552 [PubMed - indexed for MEDLINE]
Am J Clin Nutr. 1995 Dec;62(6 Suppl):1431S-1438S.
Beta-Carotene, vitamin A, and lung cancer chemoprevention: results of an
intermediate endpoint study.
McLarty JW(1), Holiday DB, Girard WM, Yanagihara RH, Kummet TD, Greenberg SD.
Author information:
(1)Department of Epidemiology/Biomathematics, University of Texas Health Center
at Tyler 75710, USA.
A randomized, placebo-controlled clinical trial of beta-carotene and retinol was
conducted with 755 former asbestos workers as study subjects. The targeted
endpoint for the intervention study was a reduction in the incidence and
prevalence of sputum atypia. The dosage of 50 mg beta-carotene/d and 25,000 IU
retinol/d on alternate days resulted significant increases in serum
concentrations of both agents with no clinically significant toxicity. Skin
yellowing was observed in approximately 35% of patients and may have contributed
adversely to protocol adherence. Baseline analysis revealed that smoking and
drinking were associated with lower concentrations of serum beta-carotene, even
after dietary carotene intake was adjusted for (P < 0.0001). Baseline
concentrations of retinol were apparently lowered by smoking (P < 0.002) and
increased by drinking (P < 0.0001). Drinking and smoking also were significantly
related to lower beta-carotene concentrations after supplementation (P < 0.001).
No significant reduction in sputum atypia was observed after treatment.
PMID: 7495244 [PubMed - indexed for MEDLINE]
Cancer Res. 1994 Apr 1;54(7 Suppl):2025s-2028s.
Retinoid chemoprevention studies in upper aerodigestive tract and lung
carcinogenesis.
Lippman SM(1), Benner SE, Hong WK.
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.
D. Anderson Cancer Center, Houston 77030.
Chemoprevention is a clinical strategy to block or reverse carcinogenesis before
the development of invasive cancer. Studies of chemoprevention in the lungs and
upper aerodigestive tract have relied on the field carcinogenesis hypothesis,
which predicts that diffuse epithelial injury will result from exposure of that
epithelium to carcinogens. This hypothesis is supported by the frequent
occurrence of multiple primary tumors within the exposed field. In addition, the
understanding of carcinogenesis as a multistep process supports the use of
interventions in damaged epithelium before the development of clinically invasive
cancer. Current efforts are focused on applying to chemoprevention studies the
increasing knowledge of the molecular events in carcinogenesis. In our program,
clinical trials in lung and head and neck chemoprevention have focused on
individuals with evidence of field carcinogenesis, i.e., a history of previous
epithelial cancer or the presence of premalignant lesions. These trials include
studies to develop clinically applicable intermediate markers of carcinogenesis
and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin
in preventing second primary tumors following head and neck or lung cancers.
PMID: 8137332 [PubMed - indexed for MEDLINE]
Anticancer Drugs. 1991 Feb;2(1):79-86.
CARET, the beta-carotene and retinol efficacy trial to prevent lung cancer in
asbestos-exposed workers and in smokers.
Omenn GS(1), Goodman G, Grizzle J, Thornquist M, Rosenstock L, Barnhart S,
Anderson G, Balmes J, Cherniack M, Cone J, et al.
Author information:
(1)Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
CARET is a two-armed, double-blind, randomized chemo-prevention trial to test the
hypothesis that oral administration of beta-carotene 30 mg/day plus retinyl
palmitate 25,000 IU/day will decrease the incidence of lung cancer in high-risk
populations: heavy smokers and asbestos-exposed workers who have smoked. The
agents combine anti-oxidant and nuclear tumor suppressor mechanisms. Fastidious
monitoring for possible side effects is facilitated by inclusion of a Vanguard
population. As of 31 December 1990, 6,105 participants of the 18,000 needed have
been randomized in the trial. Efficacy results are expected in 1999.
PMID: 1958856 [PubMed - indexed for MEDLINE]
N Engl J Med. 1990 Sep 20;323(12):795-801.
Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma
of the head and neck.
Hong WK(1), Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer
AM, Lotan R, Peters LJ, et al.
Author information:
(1)Department of Medical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030.
Comment in
N Engl J Med. 1990 Sep 20;323(12):825-7.
BACKGROUND: Patients with head-and-neck cancers who are free of disease after
local therapy remain at high risk for both recurrent and second primary tumors.
Retinoids have proved efficacious in the treatment of premalignant oral lesions
and are promising agents for the prevention of epithelial carcinogenesis.
METHODS: We prospectively studied 103 patients who were disease-free after
primary treatment for squamous-cell cancers of the larynx, pharynx, or oral
cavity. After completion of surgery or radiotherapy (or both), these patients
were randomly assigned to receive either isotretinoin (13-cis-retinoic acid) (50
to 100 mg per square meter of body-surface area per day) or placebo, to be taken
daily for 12 months.
RESULTS: There were no significant differences between the two groups in the
number of local, regional, or distant recurrences of the primary cancers.
However, the isotretinoin group had significantly fewer second primary tumors.
After a median follow-up of 32 months, only 2 patients (4 percent) in the
isotretinoin group had second primary tumors, as compared with 12 (24 percent) in
the placebo group (P = 0.005). Multiple second primary tumors occurred in four
patients, all of whom were in the placebo group. Of the 14 second cancers, 13 (93
percent) occurred in the head and neck, esophagus, or lung.
CONCLUSIONS: Daily treatment with high doses of isotretinoin is effective in
preventing second primary tumors in patients who have been treated for
squamous-cell carcinoma of the head and neck, although it does not prevent
recurrences of the original tumor.
PMID: 2202902 [PubMed - indexed for MEDLINE]
Mol Aspects Med. 2015 Feb;41:1-115. doi: 10.1016/j.mam.2014.12.003. Epub 2014 Dec
25.
Retinoic acid receptors: from molecular mechanisms to cancer therapy.
di Masi A(1), Leboffe L(1), De Marinis E(2), Pagano F(2), Cicconi L(3),
Rochette-Egly C(4), Lo-Coco F(5), Ascenzi P(6), Nervi C(7).
Author information:
(1)Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma
I-00146, Italy. (2)Department of Medical and Surgical Sciences and
Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79,
Latina I-04100. (3)Department of Biomedicine and Prevention, University of Roma
"Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of
Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142,
Italy. (4)Department of Functional Genomics and Cancer, IGBMC, CNRS UMR 7104 -
Inserm U 964, University of Strasbourg, 1 rue Laurent Fries, BP10142, Illkirch
Cedex F-67404, France. Electronic address: [email protected]. (5)Department of
Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1,
Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation,
Via Ardeatina, 306, Roma I-00142, Italy. Electronic address:
[email protected]. (6)Interdepartmental Laboratory for Electron
Microscopy, Roma Tre University, Via della Vasca Navale 79, Roma I-00146, Italy.
Electronic address: [email protected]. (7)Department of Medical and Surgical
Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della
Repubblica 79, Latina I-04100. Electronic address: [email protected].
Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A,
induces a spectrum of pleiotropic effects in cell growth and differentiation that
are relevant for embryonic development and adult physiology. The RA activity is
mediated primarily by members of the retinoic acid receptor (RAR) subfamily,
namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily
of transcription factors. RARs form heterodimers with members of the retinoid X
receptor (RXR) subfamily and act as ligand-regulated transcription factors
through binding specific RA response elements (RAREs) located in target genes
promoters. RARs also have non-genomic effects and activate kinase signaling
pathways, which fine-tune the transcription of the RA target genes. The
disruption of RA signaling pathways is thought to underlie the etiology of a
number of hematological and non-hematological malignancies, including leukemias,
skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer,
prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer,
glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are
employed as potential chemotherapeutic or chemopreventive agents because of their
differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In
humans, retinoids reverse premalignant epithelial lesions, induce the
differentiation of myeloid normal and leukemic cells, and prevent lung, liver,
and breast cancer. Here, we provide an overview of the biochemical and molecular
mechanisms that regulate the RA and retinoid signaling pathways. Moreover,
mechanisms through which deregulation of RA signaling pathways ultimately impact
on cancer are examined. Finally, the therapeutic effects of retinoids are
reported.
Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID: 25543955 [PubMed - indexed for MEDLINE]
Br J Cancer. 2014 Nov 25;111(11):2163-71. doi: 10.1038/bjc.2014.365. Epub 2014
Oct 14.
Association of serum α-tocopherol, β-carotene, and retinol with liver cancer
incidence and chronic liver disease mortality.
Lai GY(1), Weinstein SJ(2), Albanes D(2), Taylor PR(3), Virtamo J(4), McGlynn
KA(5), Freedman ND(2).
Author information:
(1)1] Cancer Prevention Fellowship Program, Division of Cancer Prevention,
National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, USA [2]
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, 9609 Medical Center Drive, Room 6E316, Bethesda, MD
20892, USA. (2)Nutritional Epidemiology Branch, Division of Cancer Epidemiology
and Genetics, National Cancer Institute, 9609 Medical Center Drive, Room 6E316,
Bethesda, MD 20892, USA. (3)Genetic Epidemiology Branch, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive,
Bethesda, MD 20892, USA. (4)Department of Chronic Disease Prevention, National
Institute for Health and Welfare, Helsinki, Finland. (5)Hormonal and Reproductive
Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National
Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, USA.
BACKGROUND: Micronutrients may influence the development or progression of liver
cancer and liver disease. We evaluated the association of serum α-tocopherol,
β-carotene, and retinol with incident liver cancer and chronic liver disease
(CLD) mortality in a prospective cohort of middle-aged Finnish male smokers.
METHODS: Baseline and 3-year follow-up serum were available from 29,046 and
22,805 men, respectively. After 24 years of follow-up, 208 men were diagnosed
with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence
intervals were calculated for highest vs lowest quartiles from multivariate
proportional hazards models.
RESULTS: Higher β-carotene and retinol levels were associated with less liver
cancer (β-carotene: 0.35, 0.22-0.55, P-trend 1.4 micromol/L predict normal dark adaptation 95%
of the time. Other causes of abnormal dark adaptation include zinc and protein
deficiencies. Stable isotopes of vitamin A and isotope-dilution techniques were
used recently to evaluate body stores of vitamin A and the efficacy of vitamin A
intervention programs in field settings and are being used to determine the
vitamin A equivalences of dietary carotenoids. Vitamin A toxicity was described
in patients taking large doses of vitamin A and in patients with type I
hyperlipidemias and alcoholic liver disease. Conversely, tissue retinoic acid
deficiency was described in alcoholic rats as a result of hepatic vitamin A
mobilization, impaired oxidation of retinaldehyde, and increased destruction of
retinoic acid by P450 enzymes. Abnormal oxidation products of carotenoids can
cause toxicity in animal models and may have caused the increased incidence of
lung cancer seen in 2 epidemiologic studies of the effects of high-dose
beta-carotene supplementation. Major issues that remain to be studied include the
efficiency of conversion of carotenoids in whole foods to vitamin A by using a
variety of foods in various field settings and whether intraluminal factors (eg,
parasitism) and vitamin A status affect this conversion. In addition, the
biological activity of carotenoid metabolites should be better understood,
particularly their effects on retinoid signaling.
PMID: 10731492 [PubMed - indexed for MEDLINE]
Am J Clin Nutr. 1999 Jun;69(6):1071-85.
Alcohol, vitamin A, and beta-carotene: adverse interactions, including
hepatotoxicity and carcinogenicity.
Leo MA(1), Lieber CS.
Author information:
(1)Section of Liver Disease and Nutrition, the Alcohol Research and Treatment
Center, Bronx VA Medical Center and Mount Sinai School of Medicine, NY 10468,
USA.
Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their
corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism
have been described in hepatic microsomes that involve, in part, cytochrome
P450s, which can also metabolize various drugs. In view of these overlapping
metabolic pathways, it is not surprising that multiple interactions between
retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol,
drugs, or both, results not only in decreased dietary intake of retinoids and
carotenoids, but also accelerates the breakdown of retinol through
cross-induction of degradative enzymes. There is also competition between ethanol
and retinoic acid precursors. Depletion ensues, with associated hepatic and
extrahepatic pathology, including carcinogenesis and contribution to fetal
defects. Correction of deficiency through vitamin A supplementation has been
advocated. It is, however, complicated by the intrinsic hepatotoxicity of
retinol, which is potentiated by concomitant alcohol consumption. By contrast,
beta-carotene, a precursor of vitamin A, was considered innocuous until recently,
when it was found to also interact with ethanol, which interferes with its
conversion to retinol. Furthermore, the combination of beta-carotene with ethanol
results in hepatotoxicity. Moreover, in smokers who also consume alcohol,
beta-carotene supplementation promotes pulmonary cancer and, possibly,
cardiovascular complications. Experimentally, beta-carotene toxicity was
exacerbated when administered as part of beadlets. Thus ethanol, while promoting
a deficiency of vitamin A also enhances its toxicity as well as that of
beta-carotene. This narrowing of the therapeutic window for retinol and
beta-carotene must be taken into account when formulating treatments aimed at
correcting vitamin A deficiency, especially in drinking populations.
PMID: 10357725 [PubMed - indexed for MEDLINE]
Am J Clin Nutr. 1987 Apr;45(4):704-16.
Recommended dietary intakes (RDI) of vitamin A in humans.
Olson JA.
Mean and median dietary intakes of vitamin A in the US are approximately 1000 and
624 retinol equivalents, respectively. In this paper a satisfactory vitamin A
status is defined as a total-body pool that provides adequate vitamin A to meet
all known physiological needs and a reserve for 4 mo on low intakes or during
stress. Mean dietary intakes required to maintain an adequate body pool (ie, 20
micrograms vitamin A/g liver [0.07 mumol/g]) in reference 76-kg men and 62-kg
women are 506 and 413 micrograms retinol, respectively. Recommended dietary
intakes (RDI) for nearly all reference men and women are 700 micrograms and 600
micrograms, respectively. Vitamin A needs in infants, children, the elderly, and
pregnant and lactating women are quantified. The toxicity of vitamin A in early
pregnancy, for which a safe intake level is not known, is stressed. On many
grounds these suggested lower RDI values are preferable to the 1980 RDA values.
PMID: 3565297 [PubMed - indexed for MEDLINE]
J Cancer Res Clin Oncol. 1991;117(2):156-62.
Laboratory evaluation during high-dose vitamin A administration: a randomized
study on lung cancer patients after surgical resection.
Infante M(1), Pastorino U, Chiesa G, Bera E, Pisani P, Valente M, Ravasi G.
Author information:
(1)Department of Thoracic Surgery, Istituto Nazionale Tumori, Milan, Italy.
The laboratory findings in patients receiving high-dose vitamin A as adjuvant
treatment for stage I lung cancer are here reported. A group of 283 patients were
randomized to either treatment with retinyl palmitate (300,000 IU daily for 12
months) or standard follow-up, and are now evaluable after a median observation
period of 28 months. At regular intervals, all the patients underwent a physical
examination, chest roentgenogram, blood chemistries, haematological assays,
hepatic and renal function tests and determinations of serum triglycerides and
cholesterol. Serum transaminase abnormalities were of similar magnitude in cases
and controls, while gamma-glutamyltransferase levels were abnormally elevated in
69% of the treated patients compared to 39% of controls (mean values 149 vs 57
IU/l at 24 months, P less than 0.05). Serum triglyceride concentrations over 150
mg/dl were seen in 74% of treated patients compared to 43% of controls at 12
months, the average concentration was 283 mg/dl compared to 179 mg/dl (P less
than 0.05). Cholesterol levels showed a modest, non-significant rise with time in
both groups, and there was no other laboratory evidence of toxicity attributable
to vitamin A. Serum retinol and retinol-binding protein, assessed on a limited
sample of patients, were higher in the treatment arm (P less than 0.05) at 12
months. In our experience 300,000 IU/day of retinyl palmitate can be administered
as a possible chemopreventive agent with reasonable safety for up to 2 years.
PMID: 1672530 [PubMed - indexed for MEDLINE]
Med Toxicol Adverse Drug Exp. 1988 Jul-Aug;3(4):273-88.
Adverse effects of retinoids.
David M(1), Hodak E, Lowe NJ.
Author information:
(1)Department of Dermatology, Beilinson Medical Center, Sackler Medical School,
Tel Aviv University, Israel.
Oral retinoids, synthetic derivatives of vitamin A, have been used in the
treatment of various dermatoses over the last decade. The most useful drugs have
been isotretinoin (13-cis-retinoic acid) for nodulocystic acne and etretinate for
psoriasis vulgaris. Retinoids are also effective in the treatment of
papulosquamous dermatoses other than psoriasis (i.e. inherited disorders of
keratinisation), cutaneous T-cell lymphoma and in chemotherapy and
chemoprevention of cancer. However, systemic administration of these compounds is
frequently associated with mucocutaneous side effects, liver toxicity and
abnormalities of serum lipid profiles, which might be related to an increased
risk of coronary heart disease. Of particular concern is the teratogenic effect
of all retinoids, which limits their use in women of child-bearing potential.
Chronic toxicities from long term therapy with retinoids may result in skeletal
abnormalities, usually mimicking diffuse idiopathic hyperostosis syndrome.
Furthermore, the chronic use of retinoids in children may inhibit their growth
due to premature epiphyseal closure. In contrast to other side effects of
retinoids which are dose dependent and reversible upon withdrawal of the drug, it
seems unlikely that bone abnormalities will resolve after discontinuation of the
medication. In view of the wide spectrum of toxicities, treatment with retinoids
requires appropriate selection of patients, careful consideration of the benefit
to risk ratio for each individual, periodic monitoring of clinical response and
laboratory tests. Clinicians should use special management techniques in order to
prevent or minimize slide effects. Extensive investigations are currently being
conducted in an attempt to develop new retinoids which will improve the
therapeutic efficacy and reduce unwanted reactions.
PMID: 3054426 [PubMed - indexed for MEDLINE]
Urol Clin North Am. 2002 Feb;29(1):157-68.
Chemoprevention of bladder cancer.
Kamat AM(1), Lamm DL.
Author information:
(1)Department of Urology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
The data presented herein, although highly supportive for a protective role of
various nutrients against bladder cancer, are far from definitive. Many
authorities question the validity of current recommendations for nutritional
chemoprevention against bladder cancer. The reason for the wide variations
reported in epidemiologic studies lies in the nature of observational studies.
Dietary studies are limited in their conclusions because the protection afforded
by the consumption of a particular nutrient may be multifactorial, with different
components of the food exerting potential chemopreventive effects. Furthermore,
measuring levels of nutrients in the food intake of populations is confounded by
factors that might affect these levels and also the incidence of cancer. For
example, vitamin A can come from animal or vegetarian sources. Because animal fat
has been identified as a potential carcinogen in man, depending on the source of
the vitamin, varying levels of protection might be deduced. In addition,
chemoprevention studies using dietary supplements are expected to have mild
effects, and large studies would be required to confirm statistical significance.
Even with agents such as intravesical chemotherapy, only half the studies achieve
statistical significance [29]. Prospective randomized trials with a large sample
size, longer follow-up, and an extended duration of treatment are needed to
clarify the association between micronutrients and cancer protection. With these
caveats in mind, several recommendations can be made. Simple measures, such as
drinking more fluids (especially water), can have a profound impact on the
incidence of bladder cancer. Vitamins are being extensively studied in
chemopreventive trials for different cancers. There is strong evidence for a
chemoprotective effect of vitamin A in bladder cancer. The authors recommend
32,000 IU/day of vitamin A initially, with lower doses (24,000 IU) for persons
less than 50 kg. Because liver toxicity is a possibility with long-term
administration, the dose should be decreased to 16,000 IU after 3 years. High
doses of beta-carotene should be avoided based on a large clinical trial
reporting a 25% increase in the number of cases of prostate cancer and a
statistically significant increase in the incidence of lung cancer. Vitamin B6
has been studied in several clinical trials in bladder cancer. The US-based
Veterans Administration cooperative study found benefit for vitamin B6 when given
as a single agent. Data for vitamins C and E are insufficient to recommend either
agent as stand-alone treatment. Nonetheless, each of these vitamins is known to
have beneficial effects, including improved function of the immune system. It is
possible that only a small percentage of patients with bladder cancer respond to
vitamins B6, C, or E, yet each is safe, nontoxic, and inexpensive. In an effort
to pool the efficacy of individual agents and to increase the power of study, the
authors evaluated the combination of vitamins A, B6, C, and E in a double-blind
trial. The observed 50% 5-year reduction in tumor recurrence was highly
significant and greater than would be expected for any of the individual
ingredients and suggests that combinations of nutritional agents may be most
appropriate. A large-volume study along similar lines is being conducted. Among
the numerous other compounds and dietary substances purported to have
chemopreventive effect, soybeans, garlic, and green tea stand out as having the
greatest promise and can freely be recommended to patients. For synthetically
synthesized agents such as celecoxib, piroxicam, or DFMO, recommendations must be
deferred until the results of clinical trials are conclusively in favor of their
use. Many of the dietary factors found to be protective against bladder cancer
are being investigated in other cancers and are beneficial to general health.
Although naturally occurring nutrients are ideal, especially because the delicate
balance of various micronutrients might be impossible to synthesize in the
laboratory, the general population finds it easier to take vitamin supplements.
Unfortunately, dietary changes such as decreasing fat and increasing fruit and
vegetable intake are more difficult to initiate. There is a mistaken notion that
simply because an agent is naturally occurring, it cannot be as beneficial as
taking a substance synthesized in the laboratory. Even in a high-risk group such
as nuclear-bomb survivors in Japan, high consumption of vegetables and fruit is
protective against bladder cancer [44]. Encouraging patients to follow an
essentially healthy food habit lifestyle will be a significant contribution in
the fight against cancer.
PMID: 12109342 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol. 2003 May;40(5):293-301.
Pharmacology of all-trans-retinoic acid in children with acute promyelocytic
leukemia.
Lanvers C(1), Reinhardt D, Dübbers A, Wagner-Bohn A, Creutzig U, Ritter J, Boos
J.
Author information:
(1)University Children's Hospital Muenster, Department of Pediatric Hematology
and Oncology, Albert-Schweitzer-Str. 33, Germany.
Comment in
Pediatr Blood Cancer. 2004 Apr;42(4):392-3.
BACKGROUND: Due to severe side effects in virtually all children treated with a
standard dose of 45 mg/m(2)/day all-trans-retinoic acid (ATRA) for acute
promyelocytic leukemia (APL) the AML-BFM study group reduced the dosage to 25
mg/m(2)/day. For the lack of data on the use of ATRA at this dosage in children
with APL, the study group further decided to evaluate the pharmacokinetics and
metabolism of ATRA in children.
PROCEDURE: Twenty-three pharmacokinetic and metabolic profiles of ATRA were
studied in 14 children (aged 0.9-18.4 years) with APL. Eleven plasma samples were
collected over a period of 8 hr and analyzed for ATRA and its metabolites by
high-performance liquid chromatography.
RESULTS: Peak plasma concentrations of ATRA were characterized by wide
interpatient variability (range: 28.6-513.0 nM). Compared to adults the same
metabolic pathways were observed in children. Even though peak plasma
concentrations were in the lower range of those considered effective in vitro,
ATRA side effects, notably neurotoxicity, still required dose reduction,
treatment break, or drug withdrawal in eight patients. In this small number of
patients, neurotoxicity could not be related to age or any specific level of ATRA
or metabolites in the plasma. Plasma concentrations of vitamin A, however, were
significantly higher in those patients, who developed signs of neurotoxicity (P =
0.03, Mann-Whitney Rank Sum test).
CONCLUSIONS: Considering the low plasma concentrations and the persistence of
toxicity in spite of dose reduction intermittent dosing schedules might be
considered as an alternative to further dose reduction of ATRA in the treatment
of APL especially in children, who might be at risk of ATRA-induced
neurotoxicity.
Copyright 2003 Wiley-Liss, Inc.
PMID: 12652617 [PubMed - indexed for MEDLINE]
Alcohol Clin Exp Res. 2005 Jul;29(7):1317-20.
Mechanisms in alcohol-associated carcinogenesis.
Homann N(1), Seitz HK, Wang XD, Yokoyama A, Singletary KW, Ishii H.
Author information:
(1)Medical University of Schleswig-Holstein, Lübeck, Germany.
This review represents an overview on some aspects of pathogenetic mechanisms in alcohol-associated carcinogenesis and is based on presentations held on the symposium “Mechanisms in alcohol-associated carcinogenesis” at the 2004 ISBRA Meeting in Heidelberg/Mannheim, Germany. The chairs were Nils Homann and Hiromasa Ishii. The presentations were (1) Genetic polymorphisms of alcohol and aldehyde dehydrogenases, mean corpuscular volume and cancer risk of the upper aerodigestive tract in Japanese by Akira Yokoyama; (2) Retinoids, alcohol and carcinogenesis by Xiang-Dong Wang; (3) Bacterial ethanol metabolism and cancer by Nils Homann; (4) The role of ethanol metabolism in alcohol-associated carcinogenesis by Helmut K. Seitz; (5) Alcohol and breast cancer: potential mechanisms by Keith W. Singletary.
PMID: 16088994 [PubMed - indexed for MEDLINE]
Biochemistry. 2007 Apr 17;46(15):4449-58. Epub 2007 Mar 23.
Delivery of retinoid-based therapies to target tissues.
Moise AR(1), Noy N, Palczewski K, Blaner WS.
Author information:
(1)Department of Pharmacology, School of Medicine, Case Western Reserve
University, Cleveland, Ohio 44106-4965, USA. [email protected]
Through its various metabolites, vitamin A controls essential physiological
functions. Both naturally occurring metabolites and novel retinoid analogues have
shown effectiveness in many clinical settings that include skin diseases and
cancer, and in animal models of human conditions affecting vision. In this
review, we analyze several potential retinoid-based therapies from the point of
view of drug metabolism and transport to target tissues. We focus on the
endogenous factors that affect the absorption, transport, and metabolism of
retinoids by taking into account data obtained from the analysis of animal models
that lack the enzymes or proteins involved in the storage and absorption of
retinoids. We also discuss findings of toxicity associated with retinoids in an
effort to improve the outcome of retinoid-based therapies. In this context, we
review evidence that esterification of retinol and retinol-based drugs within
target tissues provides one of the most efficient means to improve the absorption
and to reduce the toxicity associated with pharmacological doses of retinoids.
Future retinoid-based therapeutic strategies could involve targeted delivery
mechanisms leading to lower toxicity and improved effectiveness of retinoids.
PMCID: PMC2562735
PMID: 17378589 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2010 Jul 20;28(21):3463-71. doi: 10.1200/JCO.2009.26.6452. Epub
2010 Jun 14.
Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on
paclitaxel and cisplatin as first-line treatment in patients with advanced
non-small-cell lung cancer.
Arrieta O(1), González-De la Rosa CH, Aréchaga-Ocampo E, Villanueva-Rodríguez G,
Cerón-Lizárraga TL, Martínez-Barrera L, Vázquez-Manríquez ME, Ríos-Trejo MA,
Alvarez-Avitia MA, Hernández-Pedro N, Rojas-Marín C, De la Garza J.
Author information:
(1)Instituto Nacional de Cancerología, Universidad Autónoma Metropolitana, Mexico
City, Mexico. [email protected]
PURPOSE: This randomized phase II trial evaluated whether the combination of
cisplatin and paclitaxel (PC) plus all-trans retinoic acid (ATRA) increases
response rate (RR) and progression-free survival (PFS) in patients with advanced
non-small-cell lung cancer (NSCLC) with an acceptable toxicity profile and its
association with the expression of retinoic acid receptor beta 2 (RAR-beta2) as a
response biomarker.
PATIENTS AND METHODS: Patients with stages IIIB with pleural effusion and IV
NSCLC were included to receive PC, and randomly assigned to receive ATRA 20
mg/m(2)/d (RA/PC) or placebo (P/PC) 1 week before treatment until two cycles were
completed. RAR-beta2 expression was analyzed in tumor and adjacent lung tissue.
RESULTS: One hundred seven patients were included, 55 in the P/PC group and 52 in
the RA/PC group. RR for RA/PC was 55.8% (95% CI, 46.6% to 64.9%) and for P/PC,
25.4% (95% CI, 21.3 to 29.5%; P = .001). The RA/PC group had a longer median PFS
(8.9 v 6.0 months; P = .008). Multivariate analysis of PFS showed significant
differences for the RA/PC group (hazard ratio, 0.62; 95% CI, 0.4 to 0.95). No
significant differences in toxicity grade 3/4 were found between groups, except
for hypertriglyceridemia (10% v 0%) in RA/PC (P = .05). Immunohistochemistry and
reverse-transcriptase polymerase chain reaction assays showed expression of
RAR-beta2 in normal tissues of all tumor samples, but only 10% of samples in the
tumor tissue.
CONCLUSION: Adding ATRA to chemotherapy could increase RR and PFS in patients
with advanced NSCLC with an acceptable toxicity profile. A phase III clinical
trial is warranted to confirm these findings.
PMID: 20547984 [PubMed - indexed for MEDLINE]
Breast. 2011 Oct;20 Suppl 3:S36-41. doi: 10.1016/S0960-9776(11)70292-2.
The science behind vitamins and natural compounds for breast cancer prevention.
Getting the most prevention out of it.
Lazzeroni M(1), Gandini S, Puntoni M, Bonanni B, Gennari A, DeCensi A.
Author information:
(1)Division of Cancer Prevention and Genetics, European Institute of Oncology,
Milan, Italy.
This review highlights the role of vitamins and natural compounds in breast
cancer prevention, with a particular focus on Vitamin D. In the last decades,
both encouraging and discouraging results about the association between
antioxidant supplementation and cancer have been reported to public and
scientific community. Their safe and favorable toxicity profile makes them
suitable to be investigated in a preventive setting. However, a recent large
meta-analysis showed that treatment with beta carotene, vitamin A, and vitamin E
may increase mortality, whereas the potential roles of vitamin C and selenium on
mortality need further study. Likewise, folate levels were not associated with
reduced breast cancer risk in a recent meta-analysis. Several studies have shown
that a high proportion of women at-risk for breast cancer or affected by the
disease have deficient vitamin D levels, i.e., 250 H-D
Tretinoin / Retinoic Acid (RA) is a differentiation-inducing agent. Tretinoin for APL drives leukemic promyelocytes to differentiate into mature granulocytes. Some of the leukemia-initiating cells (LICs) remain, albeit in lower numbers. Combining RA with arsenic trioxide (AS) leads to better survival of APL patients because AS induces APL cell apoptosis and RA+AS synergize to eradicate LICs via PML-RARα degradation (PML-RARα fusion is blocking retinoic signalling and thus cell differentiation by the way).
Huynh TT, Sultan M, Vidovic D, Dean CA, Cruickshank BM, Lee K, Loung CY, Holloway RW, Hoskin DW, Waisman DM, Weaver IC. Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells. Scientific reports. 2019 Jul 1;9(1):1-3.
Orfali N, O'Donovan TR, Cahill MR, Benjamin D, Nanus DM, McKenna SL, Gudas LJ, Mongan NP. All‐trans retinoic acid (ATRA) induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL). European Journal of Haematology. 2019 Dec 6.
Vit A has the possibility of toxicity from too high dosing, also, the trial on Vit A for prevention of Lung cancer resulted in having a noxious effect. Action of carotenes may differ, sometimes. Salut +
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