A Pilot Beta‐carotene Intervention Trial With Inuits Using Smokeless Tobacco

Stich, H. F.; Hornby, A.P.; Dunn, Bruce P.

doi:10.1002/ijc.1985.36.3.321

Cited by 84 publications

(16 citation statements)

References 31 publications

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“…The approximately 30% reduction in micronuclei after P-carotene treatment is in accordance with the effect of Pcarotene reported in buccal mucosa of betel nut chewers (Stich et al, 1984a) and tobacco chewers (Stich et al, 1985(Stich et al, , 1988. Our findings extend these observations to cigarette smoke-induced tracheobronchial micronuclei, which may reflect lung cancer risk (Stich & Rosin, 1984b;Lippman et al, 1990a,b).…”

Section: Discussionsupporting

confidence: 91%

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Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum

Poppel

Kok²,

Hermus³

1992

Br J Cancer

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Summary P-carotene has been hypothesised to reduce lung cancer risk. We studied the effect of 14 weeks of P-carotene supplementation (20 mg d-1) on the frequency of micronuclei in sputum in 114 heavy smokers in a double-blind trial. Micronuclei reflect DNA damage in exfoliated cells and may thus provide a marker of early-stage carcinogenesis.Pre-treatment blood levels of cotinine, P-carotene, retinol and vitamins C and E were similar in the placebo group (n = 61) and the treatment group (n = 53). Plasma 1-carotene levels increased 13-fold in the treatment group during intervention. Initial micronuclei counts (per 3,000 cells) were higher in the treatment group than in the placebo group (5.0 vs 4.0, P<0.05). During intervention, the treatment group showed a 47% decrease, whereas the placebo group showed a non-significant decrease (16%). After adjustment for the initial levels, the treatment group had 27% lower micronuclei counts than the placebo group at the end of the trial (95% CI: 9-41%).These results indicate that P-carotene may reduce lung cancer risk in man by preventing DNA damage in early-stage carcinogenesis.The scientific interest in the role of carotenoids and retinoids in the prevention of human cancer has culminated in recent years (Editorial, 1991;Meyskens, 1990 al., 1987;Fontham, 1990). Since these studies cannot prove causal associations, two large randomised trials are currently conducted to evaluate the beneficial effect of P-carotene on human cancer development (Hennekens & Eberlein, 1985;Albanes et al., 1986). These intervention studies, however, provide little information on biological mechanisms.Damage to DNA is considered a crucial mechanism in cancer development (Weinstein, 1988). Micronuclei, DNA fragments in exfoliated cells, may thus provide a marker of early-stage carcinogenesis in target tissues (Lippman et al., 1990a,b;Stich et al., 1984a). In cigarette smokers, elevated micronuclei counts in expectorated sputum (Fontham et al., 1986) or bronchial brushings (Lippman et al., 1990a) are thought to reflect increased lung cancer risk.So far, no studies have investigated the effect of P-carotene supplementation on sputum micronuclei, as a reflection of lung cancer risk. P-Carotene has been shown to reduce micronucleated buccal mucosal cells in tobacco chewers (Stich et al., 1984a(Stich et al., , 1985(Stich et al., , 1988 and may thus reduce risk for oral cancer. These trials, however, did not measure plasma levels of P-carotene and retinol. Moreover, other antioxidant vitamins may modify the effects of P-carotene (Meyskens, 1990 Blood and sputum samples were collected before and after the 14-week treatment. The participants were instructed to take capsules daily with the evening meal, two capsules per day during the first 2 weeks, followed by one capsule per day over the next 12 weeks. Every 4 weeks, the participants were sent their next strip of 28 capsules, and were asked to return the used strips with the capsules not taken to monitor compliance. In addition, P-carotene was determined...

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Section: Discussionsupporting

confidence: 91%

“…P-Carotene has been shown to reduce micronucleated buccal mucosal cells in tobacco chewers (Stich et al, 1984a(Stich et al, , 1985(Stich et al, , 1988 and may thus reduce risk for oral cancer. These trials, however, did not measure plasma levels of P-carotene and retinol.…”

mentioning

confidence: 99%

Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum

Poppel

Kok²,

Hermus³

1992

Br J Cancer

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“…19 Previous studies on retinoids as primary chemopreventives (to reverse oral leukoplakias) showed that the protective effect persisted while the drug was being taken but that leukoplakias recurred when it was stopped. [11][12][13][14][15] How long the effect lasted after drug withdrawal was not assessed. We found that the protective effect of 4-HPR against recurrences and new leukoplakias lasted for 7 months after drug withdrawal, though CIs were dependent on the size of the sample, both because of the original sample size and the fact that it reduced with follow-up.…”

Section: Discussionmentioning

confidence: 99%

“…Some have found that these substances may have such an action by promoting the disappearance of oral leukoplakias. [11][12][13][14][15] In other studies, retinoids had an adjuvant chemopreventive effect by reducing the incidence of new head-and-neck carcinomas. [16][17][18][19] However, no studies have been conducted on the use of retinoids for adjuvant chemoprevention of new head-and-neck carcinomas after removal of oral leukoplakia.…”

mentioning

confidence: 95%

Randomized trial of fenretinide (4‐HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: Long‐term results

Chiesa

Tradati

Grigolato

et al. 2005

Intl Journal of Cancer

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We assessed the efficacy of fenretinide at preventing relapses, new lesions and carcinomas after surgical excision of oral leukoplakia. In a controlled multicenter study, 170 patients operated on for oral leukoplakias with benign postoperative histology were randomized to 200 mg fenretinide daily for 1 year vs. no intervention. Preliminary analysis indicated that fenretinide had good tolerability and was effective at preventing relapses and new lesions during treatment. Analysis after 5-year follow-up suggested that fenretinide protected against relapses and new lesions up to 19 months after randomization, with both limits of the 95% hazard ratio CI for fenretinide vs. control below 1 for 7 months after randomization. There was also a protective effect against all first events, including cancer, for 25 months, with both limits of the 95% CI below 1 up to 11 months after randomization. Subsequently, risk ratio estimates were unstable. Fenretinide was well tolerated and effective at preventing relapses and new leukoplakias during treatment and after. The trial had to be stopped prematurely for very low recruitment and had insufficient power to reveal any protective effect against oral carcinoma; nevertheless, continuing studies on this promising chemopreventive are justified. ' 2005 Wiley-Liss, Inc.

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“…One of the markers used to define chromosomal aberrations is the staining for micronuclei in exfoliated buccal mucosal cells (Stich et al, 1985). Micronuclei have also been used to evaluate the reversal of leukoplakia and the effectiveness of retinoids, carotenoids, and vitamin E (Stich et al, 1988;Brenner et al, 1993 for oral cancer development will be noted in this review only as they have been covered in detail in other recent articles (Andrewetal., 1994;Field etal., 1995;Jin etal., 1995).…”

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confidence: 99%

Biomarkers and Molecular Epidemiology and Chemoprevention of Oral Carcinogenesis

Schwartz

2000

Critical Reviews in Oral Biology & Medicine

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Chemopreventives are chemicals that prevent the formation of cancers such as oral cancer. They can take the form of nutrients or synthetic molecules, and their fundamental characteristic is that they do not produce disease processes that would result in debilitating symptoms. Current evidence indicates that they function by modifying the oxidative state of transforming cells. Biomarkers can take the form of genetic and molecular indicators, which characterize the function of chemopreventives and cancer processes such as oral carcinogenesis. Biomarkers cannot provide all the required information for risk assessment or possible activity of the chemopreventives. Other methods, such as epidemiological analyses and techniques, must be used to enhance our understanding of the risk for oral cancer in human populations. One common epidemiologic method, the questionnaire, helps to determine the use and carcinogenic potential of tobacco and alcohol during oral carcinogenesis. Genetic and molecular changes in human patient populations may result in a reduction in the number and function of tumor suppressor genes. If these changes are to be assessed, the tissues (e.g., buccal mucosa) must be accessible and harvested in a reliable and consistent manner for the acquisition of DNA, mRNA, and protein. Oral tissues provide sufficient quantities of these molecules and, under stringent conditions, the quality required for the isolation of these molecular constituents. In conjunction with epidemiologic techniques, various genotypic polymorphisms, such as glutathione-S-transferase (GSTM 1) or cytochrome P450 (CYP450Al), have indicated a loss in carcinogen detoxification or the processing of internal growth control signals. Biomarkers are composed of a large diverse group of genetic and molecular structures. Some of these biomarkers are indicators for programmed cell death (PCD), while others describe malignant tumor growth. Many of these classes of molecules are oxidative-responsive (e.g., tumor suppressor p53, Bcl-2, growth factors, immune-derived proteins, and death-inducing molecules) and induce PCD by triggering a cascade of cysteine proteases and regulators (e.g., caspases, death receptors). This pathway results in cell-cycle alterations and DNA fragmentation. It is hoped that a detailed knowledge of the processes involved in malignant transformation will better define the biomarker-screening tools for oral cancer. These tools will enhance our ability to predict the incidence of cancer, detect early malignant change, and quantitate chemoprevention during oral carcinogenesis. Chemopreventives such as the retinoids have already demonstrated their ability to suppress potential malignant changes in pre-malignant oral leukoplakias and decrease the incidence of second head-and-neck cancer primaries. It is our hope that this review will increase investigators' interest in developing new screening and detection systems for oral cancer.

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A Pilot Beta‐carotene Intervention Trial With Inuits Using Smokeless Tobacco

Cited by 84 publications

References 31 publications

Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum

Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum

Randomized trial of fenretinide (4‐HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: Long‐term results

Biomarkers and Molecular Epidemiology and Chemoprevention of Oral Carcinogenesis

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