Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Alternative Medicine Review
Volume 6, Number 2
2001 Page 167
Davis W. Lamson, MS, ND – Coordinator of Oncology, Bastyr University, Kenmore, WA. Private practice, Tahoma Clinic,Kent, WA. Product consultant, Thorne Research. Correspondence address: 9803 17th Ave NE, Seattle, WA 98115.E-mail: davisl@seanet.comMatthew S. Brignall, ND – Practicing with Seattle Cancer Treatment and Wellness Center; Evergreen Integrative Medicine,Kirkland, WA; Cascade Cancer Center, Kirkland, WA. Product consultant, Thorne Research.E-mail: mattandmolly@home.com
Introduction
This paper is the second of a series examining the use of nutritional supplements aschemopreventive agents. The first paper in the series examined the data from humanchemoprevention trials.
1
In the present paper the mechanisms of action of promising treatmentswill be discussed.
In vitro
and animal data are presented in support of the agents as appropriate.The subject of chemoprevention with nutritional agents has been the subject of voluminousresearch, and this review should not be considered exhaustive. In cases where review articlesalready exist regarding a particular agent (e.g., vitamin A, beta-carotene), these papers shouldbe consulted for a more complete summary.The data presented in this review will focus on three common tumor types: breast, pros-tate, and colon cancers. While data are available regarding prevention of other tumor types, it isnot as extensive as the data covered in this paper. It is the opinion of the authors that agents witha clear record of safety in human studies, evidence of chemoprevention in animal studies, andwell-understood mechanisms of action, should be considered for clinical use pending results of large human trials.
Natural Agents in the Prevention of Cancer,Part Two: Preclinical Data andChemoprevention for Common Cancers
Davis W. Lamson, MS, NDand Matthew S. Brignall, ND
AbstractThis paper is the second of a series examining the use of nutritional supplements aschemopreventive agents. The animal and
in vitro
data are reviewed in support of theiruse. Human safety data and mechanisms of action are described as well. Many over-the-counter dietary supplements have been shown to have significant chemopreventiveactivity in preclinical studies. Few side effects are associated with even long-term useof these agents. Along with dietary and lifestyle risk-reducing strategies, nutritionalsupplementation appears to be a viable intervention for those considered to be at highrisk of developing cancer.(
Altern Med Rev
2001;6(2):167-187)
Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Page 168
Alternative Medicine Review
Volume 6, Number 2
2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Vitamin A
Vitamin A is obtained from the diet inthe form of retinyl esters, which are subse-quently de-esterified to retinol. Retinol is thenirreversibly oxidized to become retinoic acid.Retinoic acid is the form of vitamin A thatbinds with nuclear receptor sites and is neces-sary for the normal growth and differentiationof epithelial tissue.
2
The effects of vitamin Aon cellular differentiation are mediated by twoseparate classes of nuclear receptors, whichin turn modify the effects of many compounds,including prostaglandins, vitamin D, and ste-roid and thyroid hormones.
3
Many studies haveexamined the effects of isomers of vitamin A,including all-trans retinoic acid, 9-cis retinoicacid, and 13-cis retinoic acid. These isomersare all considered to be interconverted in hu-mans, and may be less hepatotoxic than ret-inol.Animal research has demonstrated achemopreventive effect of retinoids in manytypes of cancer, including mammary cancerand colon cancer models.
4,5
In vitro
researchhas identified a number of promising mecha-nisms of action, including decreasing seruminsulin-like growth factor-1, inhibition of 5-alpha-reductase (the enzyme that catalyzesformation of dihydrotestosterone), and up-regulation of transforming growth factor-beta.
4
Epidemiological studies on the cancerpreventive activity of dietary vitamin A havebeen inconclusive, perhaps because of confounding factors. Vitamin A is only presentin animal foods, and thus dietary vitamin Aintake may be a marker for a high meat diet, arisk factor for many cancers. Prospective trialshave shown a very modest reduction in breastcancer risk in women with the highest intakesof dietary vitamin A.
6
One prospectiveepidemiological trial concluded that peopletaking supplemental vitamin A had a reducedrisk of developing breast cancer only if theywere in the lowest third of dietary vitamin Aintake.
7
Although the preclinical data havebeen promising, human studies using vitaminA or retinoids as chemopreventive agents havebeen largely disappointing.
1
It appears likelyfrom the epidemiological data that the protec-tive effect of retinoids is limited to those whoare deficient in dietary vitamin A. It is alsopossible that the effect is limited to particularclinical situations (e.g., bladder cancer, pre-menopausal breast cancer).
Carotenoids
Carotenoids are a family of conjugatedpolyene molecules found largely in fruits andvegetables. Carotenoids are antioxidant, andcertain carotenoids can serve as precursors toretinol in humans. Of the more than 600 caro-tenoids, beta carotene and lycopene have gen-erated the most attention in thechemoprevention field.As discussed in the first paper in thisseries,
1
beta carotene has been extensivelystudied in human trials as a chemopreventiveagent. In contrast to the human data, whichhave largely found beta carotene supplemen-tation to be associated with either no changeor an increase in cancer risk, epidemiologicalevidence has very strongly associated betacarotene intake with reduction in the risk of cancer of many different types.
8
Severalschools of thought exist regarding the discrep-ancy between epidemiology and human ex-perimental data.The first is that the human studies thatused synthetic beta carotene may not have usedthe right nutrient mixture forchemoprevention.
9
Animal
10
and preliminaryhuman research
11
have shown mixed caroteneshave a better chemopreventive action than syn-thetic beta carotene. Secondly, it has been theo-rized that beta carotene may have a pro-oxi-dant effect
in vivo
,
12
an effect that could po-tentially be carcinogenic. These two theoriesare not mutually exclusive, and it is possibleboth are true to some extent.
C a n c e r
Alternative Medicine Review
Volume 6, Number 2
2001 Page 169Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
In vitro
and animal studies have dem-onstrated a number of mechanisms by whichbeta carotene can inhibit carcinogenesis, in-cluding antioxidant activity, vitamin A precur-sor status, enhancement of gap junction com-munication, an immunological effect, and in-duction of hepatic detoxification of carcino-gens.
13
Epidemiological studies have corre-lated both high intake
14
and high serum con-centrations
15
of lycopene with reduced risk of prostate cancer. High adipose concentrationsof lycopene have been associated with a re-duced risk of breast cancer.
16
Lycopene hasbeen shown to inhibit cancer cell growth
invitro
, including prostate,
17
breast,
18
and lung
18
cancer cell lines. Animal studies have shownlycopene inhibited development of mammary
19
and colon
20
tumors.Lycopene’s mechanisms of action aresomewhat obscure. A human crossover trialfound that consumption of tomatoes contain-ing 16.5 mg of lycopene for 21 days led to a33-percent reduction in the amount of lympho-cyte DNA damage sustained after exposure tohydrogen peroxide
ex vivo
.
21
Lycopene hasbeen shown to reduce the growth-stimulatingeffect of insulin-like growth factor on humanbreast cancer cells.
22
Folic Acid
Expression of genes is controlled inpart by DNA methylation. Hypomethylationin the presence of folic acid deficiency hasbeen theorized to be one of the mechanismsby which cancer development can be encour-aged.
23
Both low folate status and DNAhypomethylation have been directly observedin squamous cell lung cancer tissue comparedto uninvolved bronchial mucosa from the samepatients.
24
Epidemiological studies have shownlow folate status to correlate with increasedrisk of cancers of the cervix, lung, esophagus,brain, pancreas, breast, and especially thecolon.
25
The benefits of folic acid may begreatest in those with significant deficiencies,such as in patients taking sulfasalazine (a drugthat depletes folate) for ulcerative colitis.
26
Data from the Nurses’ Health Study indicatefolic acid may at least partially offset theincreased breast cancer risk associated withconsumption of alcohol.
27
Humanchemoprevention trials using folic acid havebeen performed and were discussed in the firstpaper in this series.
1
Vitamin B6
Increased likelihood of recurrence of breast cancer after mastectomy has been cor-related in preliminary studies with both poormetabolism of a loading dose of L-tryptophan(indicating a functional deficiency of vitaminB6),
28
and low urinary concentration of 4-py-ridoxic acid, a major metabolite of vitaminB6.
29
Dietary intake of vitamin B6 was foundnot to correlate at all with the risk of breastcancer in a prospective study, however.
30
Elevated levels of prolactin have beenimplicated in the pathophysiology of bothbreast
31
and prostate
32
cancers. Although B6has been reported to suppress production of prolactin,
33
some studies have failed to find thiseffect.
34,35
Vitamin B12
Like folic acid, deficiency of vitaminB12 can lead to hypomethylation of DNA.
24
A role for vitamin B12 in the process of car-cinogenesis has been theorized since 1954,when abnormal cell types were found in thestomach lining of patients with pernicious ane-mia.
36
Women in the lowest quartile of serumvitamin B12 have been found to be at increasedrisk of developing breast cancer in a prospec-tive, epidemiological study.
30
High mean cor-puscular volume (MCV), which is often a signof either vitamin B12 or folate deficiency, hasbeen found to be predictive for a risk of colorectal polyps in men.
37
Vitamin B12 treat-ment, together with folic acid, has been shownto reverse a precancerous condition of the lung
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