What is role of vitamin A in treating cancer?

Joe Graymer

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.

[email protected]

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.

[email protected]

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.

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.

[email protected]

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

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.

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.

[email protected]

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

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