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March 11, 1988, Vol 259, No. 10 >
ARTICLE | March 11, 1988

Improvement in Bronchial Squamous Metaplasia in Smokers Treated With Folate and Vitamin B12: Title and subTitle BreakReport of a Preliminary Randomized, Double-blind Intervention Trial FREE

Douglas C. Heimburger, MD; C. Bruce Alexander, MD; Robert Birch, PhD; C. E. Butterworth, Jr, MD; William C. Bailey, MD; Carlos L. Krumdieck, PhD, MD
[+] Author Affiliations

Reprint requests to the Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 (Dr Krumdieck).


JAMA. 1988;259(10):1525-1530. doi:10.1001/jama.1988.03720100043036
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References

To test whether changes in folate and vitamin B12 nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 μg of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12 used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers.

(JAMA 1988;259:1525-1530)

REFERENCES

1 +
Butterworth CE Jr, Hatch KD, Gore H, et al:  Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;;35:73-82.
2 +
Krumdieck CL:  Role of folate deficiency in carcinogenesis , in Butterworth CE Jr, Hutchinson ML (eds): Nutritional Factors in the Induction and Maintenance of Malignancy . New York, Academic Press Inc, 1983;, pp 225-245.
3 +
Eto I, Krumdieck CL:  Role of vitamin B12 and folate deficiencies in carcinogenesis , in Poirier LA, Newberne PM, Pariza MW (eds): Essential Nutrients in Carcinogenesis , vol 206, in Advances in Experimental Medicine and Biology. New York, Plenum Press, 1986;, pp 313-330.
4 +
Yunis JJ, Soreng AL:  Constitutive fragile sites and cancer. Science 1984;;226:1199-1204.
5 +
Heimburger DC, Krumdieck CL, Alexander CB, et al:  Localized folic acid deficiency and bronchial metaplasia in smokers: Hypothesis and preliminary report. Nutr Int 1987;;3:54-60.
6 +
Francis KT, Thompson RW, Krumdieck CL:  Reaction of tetrahydrofolic acid with cyanate from urea solutions: Formation of an inactive folate derivative. Am J Clin Nutr 1977;;30:2028-2032.
7 +
Khaled MA, Krumdieck CL:  Association of folate molecules as determined by proton NMR: Implications on enzyme binding. Biochem Biophys Res Commun 1985;;130:1273-1280.
8 +
Khaled MA, Watkins CL, Krumdieck CL:  Inactivation of B12 and folate coenzymes by butyl nitrite as observed by NMR: Implications on one-carbon transfer mechanism. Biochem Biophys Res Commun 1986;;135:201-207.
9 +
Witter FR, Blake DA, Baumgardner R, et al:  Folate, carotene, and smoking. Am J Obstet Gynecol 1982;;144:857.
10 +
Nakazawa Y, Chiba K, Imatoh N, et al:  Serum folic acid levels and antipyrine clearance rates in smokers and non-smokers. Drug Alcohol Depend 1983;;11:201-207.
11 +
Linnell JC, Smith ADM, Smith CL, et al:  Effects of smoking on metabolism and excretion of vitamin B12. Br Med J 1968;;2:215-216.
12 +
Dastur DK, Quadros EV, Wadia NH, et al:  Effect of vegetarianism and smoking on vitamin B12, thiocyanate, and folate levels in the blood of normal subjects. Br Med J 1972;;3:260-263.
13 +
Shane B, Stokstad ELR:  Vitamin B12—folate interrelationships. Annu Rev Nutr 1985;;5:115-141.
14 +
Robbins SL, Kumar V: Basic Pathology , ed 4. Philadelphia, WB Saunders Co, 1987;, p 185.
15 +
Riotton G, Christopherson WM, Lunt R: Cytology of Non-gynaecological Sites (International Histological Classification of Tumours, No. 17). Geneva, World Health Organization, 1977;.
16 +
Scott JM, Ghanta V, Herbert V:  Trouble-free microbiologic serum and red cell folate assays. Am J Med Technol 1974;;40:125-133.
17 +
Lau K-S, Gottlieb C, Wasserman LR, et al:  Measurement of serum vitamin B12 level using radioisotope dilution and coated charcoal. Blood 1965;;26:202-214.
18 +
Zannoni V, Lynch M, Goldstein S, et al:  A rapid micromethod for the determination of ascorbic acid in plasma and tissues. Biochem Med 1974;;11:41-48.
19 +
Garry PJ, Pollack JD, Owen GM:  Plasma vitamin A assay by fluorometry and use of a silicic acid column technique. Clin Chem 1970;;167:766-772.
20 +
Baker H, Frank O: Clinical Vitaminology . New York, John Wiley & Sons Inc, 1968;, pp 161-168.
21 +
Fabianek J, DeFilippi J, Rickards T, et al:  Micromethod for tocopherol determination in blood serum. Clin Chem 1968;;14:456-462.
22 +
Zelen M:  The analysis of several 2×2 contingency tables. Biometrika 1971;;38:129-137.
23 +
Colditz GA, Stampfer MJ, Willett WC:  Diet and lung cancer: A review of the epidemiologic evidence in humans. Arch Intern Med 1987;;147:157-160.
24 +
Misset JL, Mathe G, Santelli G, et al:  Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment. Cancer Detect Prev 1986;;9:167-170.
25 +
Herbert V, Colman N, Jacob E:  Folic acid and vitamin B12 , in Goodhart RS, Shils ME (eds): Modern Nutrition in Health and Disease , ed 6. Philadelphia, Lea & Febiger, 1980;, pp 229-259.
26 +
Cottrell JE, Casthely P, Brodie JD, et al:  Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 1978;;298:809-811.
27 +
Graham JDP:  Hydroxocobalamin as an antidote to acrylonitrile. Toxicol Appl Pharmacol 1965;;7:367-372.

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1 +
Butterworth CE Jr, Hatch KD, Gore H, et al:  Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;;35:73-82.
2 +
Krumdieck CL:  Role of folate deficiency in carcinogenesis , in Butterworth CE Jr, Hutchinson ML (eds): Nutritional Factors in the Induction and Maintenance of Malignancy . New York, Academic Press Inc, 1983;, pp 225-245.
3 +
Eto I, Krumdieck CL:  Role of vitamin B12 and folate deficiencies in carcinogenesis , in Poirier LA, Newberne PM, Pariza MW (eds): Essential Nutrients in Carcinogenesis , vol 206, in Advances in Experimental Medicine and Biology. New York, Plenum Press, 1986;, pp 313-330.
4 +
Yunis JJ, Soreng AL:  Constitutive fragile sites and cancer. Science 1984;;226:1199-1204.
5 +
Heimburger DC, Krumdieck CL, Alexander CB, et al:  Localized folic acid deficiency and bronchial metaplasia in smokers: Hypothesis and preliminary report. Nutr Int 1987;;3:54-60.
6 +
Francis KT, Thompson RW, Krumdieck CL:  Reaction of tetrahydrofolic acid with cyanate from urea solutions: Formation of an inactive folate derivative. Am J Clin Nutr 1977;;30:2028-2032.
7 +
Khaled MA, Krumdieck CL:  Association of folate molecules as determined by proton NMR: Implications on enzyme binding. Biochem Biophys Res Commun 1985;;130:1273-1280.
8 +
Khaled MA, Watkins CL, Krumdieck CL:  Inactivation of B12 and folate coenzymes by butyl nitrite as observed by NMR: Implications on one-carbon transfer mechanism. Biochem Biophys Res Commun 1986;;135:201-207.
9 +
Witter FR, Blake DA, Baumgardner R, et al:  Folate, carotene, and smoking. Am J Obstet Gynecol 1982;;144:857.
10 +
Nakazawa Y, Chiba K, Imatoh N, et al:  Serum folic acid levels and antipyrine clearance rates in smokers and non-smokers. Drug Alcohol Depend 1983;;11:201-207.
11 +
Linnell JC, Smith ADM, Smith CL, et al:  Effects of smoking on metabolism and excretion of vitamin B12. Br Med J 1968;;2:215-216.
12 +
Dastur DK, Quadros EV, Wadia NH, et al:  Effect of vegetarianism and smoking on vitamin B12, thiocyanate, and folate levels in the blood of normal subjects. Br Med J 1972;;3:260-263.
13 +
Shane B, Stokstad ELR:  Vitamin B12—folate interrelationships. Annu Rev Nutr 1985;;5:115-141.
14 +
Robbins SL, Kumar V: Basic Pathology , ed 4. Philadelphia, WB Saunders Co, 1987;, p 185.
15 +
Riotton G, Christopherson WM, Lunt R: Cytology of Non-gynaecological Sites (International Histological Classification of Tumours, No. 17). Geneva, World Health Organization, 1977;.
16 +
Scott JM, Ghanta V, Herbert V:  Trouble-free microbiologic serum and red cell folate assays. Am J Med Technol 1974;;40:125-133.
17 +
Lau K-S, Gottlieb C, Wasserman LR, et al:  Measurement of serum vitamin B12 level using radioisotope dilution and coated charcoal. Blood 1965;;26:202-214.
18 +
Zannoni V, Lynch M, Goldstein S, et al:  A rapid micromethod for the determination of ascorbic acid in plasma and tissues. Biochem Med 1974;;11:41-48.
19 +
Garry PJ, Pollack JD, Owen GM:  Plasma vitamin A assay by fluorometry and use of a silicic acid column technique. Clin Chem 1970;;167:766-772.
20 +
Baker H, Frank O: Clinical Vitaminology . New York, John Wiley & Sons Inc, 1968;, pp 161-168.
21 +
Fabianek J, DeFilippi J, Rickards T, et al:  Micromethod for tocopherol determination in blood serum. Clin Chem 1968;;14:456-462.
22 +
Zelen M:  The analysis of several 2×2 contingency tables. Biometrika 1971;;38:129-137.
23 +
Colditz GA, Stampfer MJ, Willett WC:  Diet and lung cancer: A review of the epidemiologic evidence in humans. Arch Intern Med 1987;;147:157-160.
24 +
Misset JL, Mathe G, Santelli G, et al:  Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment. Cancer Detect Prev 1986;;9:167-170.
25 +
Herbert V, Colman N, Jacob E:  Folic acid and vitamin B12 , in Goodhart RS, Shils ME (eds): Modern Nutrition in Health and Disease , ed 6. Philadelphia, Lea & Febiger, 1980;, pp 229-259.
26 +
Cottrell JE, Casthely P, Brodie JD, et al:  Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 1978;;298:809-811.
27 +
Graham JDP:  Hydroxocobalamin as an antidote to acrylonitrile. Toxicol Appl Pharmacol 1965;;7:367-372.

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