Vitamin A/Beta-Carotene:
Role in Cancer Prevention and Treatment
Introduction
Vitamin A and related carotenoid compounds have a sterling role in cancer
prevention and are of crucial importance to health, in their capacities
as potent antioxidants and immune modulators. Despite this, there hasn't
been the massive public awareness, publicity and sex appeal that has
surrounded other nutrients such as Vitamin C. Advice abounds about eating
your carrots (to see better in the dark) or your greens (for antioxidant
and cancer protection). The cartoon character Popeye grew muscles from
quaffing his spinach, that green veggie singularly detested by children
and prized by gourmands for florentine dishes.
While Vitamin A deficiencies are widespread throughout many parts of
the developing world, and some 50,000 people go blind each year through
lack of Vitamin A, much of the publicity in the UK and the US from medical
circles is of the scare-mongering varity:
* Eating gross numbers of carrots will turn your skin
yellow (this reverses when you reduce carotene intake);
* Don't eat liver if you are pregnant;
* Don't overdose on cod liver oil;
In fact, while Vitamin A in excessive levels is toxic,
most of us should be more concerned about obtaining as much of Vitamin
A and carotene anti-oxidant activity in our diet. The medical research
community and the pharmaceutical industry have done extensive clinical
research with Vitamin A and carotene-derived substances, as evidenced
by the publication record in numerous scholarly journals, resulting
in numerous diverse health care products, ranging from acne medication
(Retin A) to anti-cancer compounds.
What is Vitamin A/Beta-carotene?1
Fat-soluble Vitamin A compounds include retinol, retinal and retinoic
acid. This vitamin group is vital to eye and retina function (whence
its name retinol is derived), protects the mucous membranes of the mouth,
nose, throat and lungs from damage, and reduces risk of infection (immune
enhancer) and cancer. Low Vitamin A levels are correlated with increased
incidence of several cancers, most notably those of the lung, larynx,
oesophagus, mouth, stomach, colon, prostate and cervix. Vitamin A is
found in animal and fish liver, eggs, milk and butter; levels above
20,000 IU per day may be toxic.
Carotenoids such as beta carotene, sometimes called pro-vitamin A, are
water-soluble precursors which are made into Vitamin A by the body.
While you can overdose on fat-soluble Vitamin A, large doses of water-soluble
beta carotene, found in carrots, broccoli, spinach, cabbage, orange
and yellow fruits, are non-toxic and constitute an extremely potent
source of antioxidant activity.
Role in Cancer Prevention and Treatment
A considerable wealth of research data has been accumulated regarding
the efficacy of various Vitamin A/Carotene compounds in prevention,
treatment and adjuvant treatment of cancers (combined with chemotherapy
and/or radiotherapy). This research is part of a larger body of published
information regarding Nutrition and Cancer which has been compiled and
assembled into a computerised database at the Bristol Cancer Help Centre.2
This information is available for an administrative cost fee to physicians,
researchers, cancer patients and the public, telephone (0272) 743216.
A selection of published data regarding Vitamin A/Beta-carotene in cancer
prevention and treatment is extracted below.
Prevention of Cancer
* Knekt and colleagues, from the Social Insurance Institution,
Helsinki, Finland studied the relation between intake of retinoids,
carotenoids, vitamins E and C, and selenium and the subsequent risk
of lung cancer in 4,500 men, with a follow-up period of 20 years. This
study showed an inverse correlation between intake of carotenoids, vitamins
E and C and the incidence of lung cancer among nonsmokers, demonstrating
the protective effects of these nutrients against lung cancer;3
* Stahelin and colleagues from University of Basel, Switzerland researched
the role of the antioxidant vitamins A, C and E and carotene in some
3000 men followed for about 15 years. Results indicated that overall
cancer mortality was related to low plasma levels of carotene and Vitamin
C. In particular, cancers of the bronchus and stomach were associated
with low carotene levels, with stomach cancers also associated with
low Vitamin A levels. Low plasma carotene was associated with a significantly
increased risk for bronchus cancer, low plasma levels of carotene and
Vitamin A with increased risk for all cancers, and low plasma Vitamin
A in older people with increased risk of lung cancer;4
* de Vries and Snow from Free University Hospital, Amsterdam studied
the relationship of Vitamins A, E and beta-carotene to the role of the
development of head and neck cancers in patients with and without second
primary tumours. Both groups of patients had decreased levels of beta-carotene,
and patients with second tumours had statistically lower levels of Vitamins
A and E than people with single tumours, suggesting a role for these
vitamins in the development of second head and neck tumours;5
* Chen and colleagues from the Chinese Academy of Preventive Medicine,
Beijing studied antioxidant status and cancer mortality in a study of
65 mainly rural counties. Results indicated that low plasma levels of
antioxidants were associated with increased cancer mortality rates.
Beta-carotene was found to have a protective effect independent of retinol,
particularly for stomach cancer;6
* Bos and colleagues from University of Nijmegen, The Netherlands studied
the protective effects of beta-carotene in smokers. In a double-blind,
placebo-controlled intervention trial, they showed that, compared with
the placebo group, the beta-carotene group had a 15% lower level of
thioether excretion, a possibly carcinogenic intermediate product of
smoking;7
Treatment of Cancer
* Schwartz and Shklar at Harvard School of Dental Medicine
studied the selective cytotoxic effects of various carotenoids, including
beta-carotene and alpha-tocopherol (Vitamin E) upon breast, oral, lung
and melanoma human tumor cell lines. Consistent changes in cell shape
and appearance were observed 1-5 hours following treatment with carotenoid
or vitamin E, as were reductions in cell enzyme activity, increased
expression of one particular protein and a decrease in tumour cell proliferation;8
* ElAttar and Lin from University of Missouri-Kansas City School of
Dentistry studied the effects of retinoid and carotenoid compounds upon
prostaglandin formation in oral cancer cells. Tumour promotion and immune
suppression is associated with excessive prostaglandins (PGs) production,
and inhibition of PGs enhances immune response and suppresses tumour
growth in animal studies. This study demonstrated that several retinol
compounds (retinol; all-trans-retinoic acid; N-4-Hydroxyphenyl) retinamide
(N-4-HPR); and carotenoid canthaxanthin all inhibited the bioconversion
of arachidonic acid to PGE2 by tongue cancer cells, the most potent
inhibitor being N-4-HPR. These inhibitory effects, together with antioxidant
properties might contribute to retinoids' antiinflammatory and anticancer
activity;9
* The Santamarias, Golgi Institute, University of Pavia, Italy have
reported levels of cancer (skin, breast, gastric, colon) prevention
from 60-100% in animals supplemented with carotenoids (beta-carotene,
canthaxanthin and retinol-BC) one months prior to tumour induction (via
carcinogenic agents or transplantation). In addition, 15 cancer patients
who had surgery to remove primary tumours (lung, breast, colon, bladder,
head and neck) and who took supplements of beta-carotene and retinol
experienced a longer than expected disease-free interval preliminarily;10
* Bhide and colleagues from Tata Memorial Centre, Bombay, India studied
the anticarcinogenic effects of betel leaf (tropical Asian palm, betel-nut
=areca nut) against tobacco nitrosamine mutagens. In addition to suppressing
the mutagenic effects of these nitrosamines, betel-leaf extract reduced
the tumor-causing effects by 25%, and inhibited the decrease in Vitamin
A levels in liver and plasma caused by nitrosamines, thus demonstrating
protective effects against these carcinogens and mutagens;11
* Nagasawa et al, Maiji University, Japan who previously reported the
inhibition of breast cancer in mice by the beta-carotene-rich algae
Dunaliella bardawil, now confirm that D. bardawil inhibits the progression
of spontaneous breast tumours by increasing the host animals' homeostatic
potential and by the antioxidant function of beta-carotene;12
* Stich and colleagues from Vancouver, Canada report that in tobacco-chewers
from Kerala, India, Vitamin A (60 mg/wk) administered for 6 months resulted
in complete remission of oral precancerous lesions (leukoplakias) in
57% and a reduction in micronucleated cells in 96% and that beta-carotene
(2.2 mmol/wk) resulted in leukoplakia remission in 14.8% and reduction
of micronucleated cells in 98% of the individuals. Vitamin A completely
suppressed and beta-carotene suppressed by 50% the formation of new
leukoplakia within the 6 month trial period. Lower doses of Vitamin
A or beta-carotene could maintain the protective effect of the original
treatment for at least 8 additional months;13
* Gensler and Holladay, University of Arizona have studied how Vitamin
A and carotenoid compounds prevent photo-induced cancer and UV-irradiation
induced immune suppression in mice. Dietary supplementation with retinyl
palmitate (a form of Vitamin A) and canthaxanthin (a carotenoid) together
but not alone, prior to UV irradiation, prevented the enhanced growth
of tumour implants;14
Combination and Adjuvant
Cancer Treatment
Conventional medical cancer treatments, particularly radiotherapy and
chemotherapy, are toxic by virtue of their purposeful design to kill
cancer cells, and place an increased burden upon the body's detoxification
systems. Because of Vitamin A and carotene's antioxidant and immune
stimulatory properties, researchers have been studying the fate of Vitamin
A levels in the body of cancer patients undergoing these treatments,
and in certain instances, have developed synergistic cancer treatment
applications for Vitamin A, in combination with chemotherapy.
* Lacroix and colleagues from University of Montreal, Quebec conducted
a pilot study to determine whether it is possible to increase Vitamin
A plasma levels of cancer patients receiving chemotherapy (Vitamin A
levels decrease during chemotherapy). Cancer patients received either
25,000 or 50,000 IU oral Vitamin A daily; controls were non-cancer individuals.
Initial Vitamin A levels were lower in cancer patients than the control
group. Women cancer patients receiving both levels of Vitamin A had
a significant increase in Vitamin A levels, although only the 50,000
IU group demonstrated a sustained increase during the 3 months of supplementation.
Men showed a similar but non-significant trend;15
* Mehta and colleagues from University of Illinois, Chicago researched
the relationship of retinol-binding protein (RBP) levels to the recurrence
of breast tumours in premenopausal women with node-positive breast cancer
receiving chemotherapy. Significantly lower RBP levels were associated
with early tumour recurrence. Patients who maintained a disease-free
status for 2 years or longer had significantly higher RBP levels than
those with distant tumour metastasis. Also, breast cancer patients with
a prior history of benign breast disease had significantly lower RBP
levels than did healthy premenopausal women. The reduced RBP levels
in these patients was not due to inadequate dietary Vitamin A/beta-carotene
intake nor protein malnutrition;16
* Komiyama and colleagues from Japan reported that Vitamin A potentiated
the RNA inhibitory action of the chemotherapy drug 5-fluorouracil (5-FU).
Furthermore, they applied the triple combination of 5-FU, Vitamin A
and cobalt-60 radiation (FAR therapy) to hundreds of patients with various
head and neck tumours, with highly effective synergistic effects;17
* Nakagawa and colleagues from Japan reported on the combination of
retinol palmitate (RP) with six different anticancer agents on ascites
sarcoma or leukemia in mice. With ascites sarcoma, RP considerably enhanced
the antitumour activity of 5-fluorouracil (5-FU) methotrexate (MTX)
and 1-(4-amino-2-mthyl-5-pyrimidinyl)methyl-3- (2-chlorethyl) -3-nitrosourea
(ACNU), but not the action of adriamycin (ADM) or 6-mercaptopurine (6-MP).
Against leukemia, RP enhanced antitumour activity of 6-MP. MTX, ADM,
ACNU and cis-dichlorodiammine- platinum (CDDP), but not of 5-FU.18
Conclusions
The above studies demonstrate that Vitamin A and carotenoids are of
considerable importance to the prevention and treatment of many diverse
cancers in a variety of ways: attack and destroy cancer cells; prevent
the appearance or proliferation of tumours, and actually reverse precancerous
lesions. The mechanisms of this anti-cancer activity, still being researched,
are attributed to the anti-inflammatory and antioxidant properties of
Vitamin A and carotenoids. In addition to the above anti-cancer properties
of Vitamin A and carotene lies their potential in potentiating and mitigating
against some of the more toxic effects of radiotherapy and chemotherapy.
As evidenced by this selection of research articles on the role of Vitamin
A and carotene in cancer prevention and treatment, there is a huge research
effort worldwide into all aspects of the role of Nutrition in cancer.
To reiterate a somewhat familiar theme in this series of articles, is
the question: Why don't we hear more about all this research? The article
in the next issue will review research on the role of Vitamin E in cancer.
Hopefully, reviewing the incredibly extensive research literature will
feed your appetite to see more research reported in all the various
media.
References
1. Davies S and Stewart A. Nutrititional Medicine. 1987.
Pan Books.
2. The Bristol Cancer Help Centre Nutrition and Cancer Database, a compilation
of some 3000 published research papers relating to the role of Nutrition
in the Prevention and Treatment of Cancer. Telephone (0117) 974 3216
for information service and access to the database.
3. Knekt P et al. Dietary antioxidants and the risk of lung cancer.
Am J Epidemiol. Sep 1 145(5): 471-9. 1991.
4. Stahelin HB et al. Plasma antioxidant vitamins and subsequent cancer
mortality in the 12-year follow-up of the prospective Basel Study. Am
J Epidemiol. 133(8): 766-75. April 15 1991.
5. de Vries N and Snow GB. Relationships of vitamins A and E and beta-carotene
serum levels to head and neck cancer patients with and without second
primary tumors. Eur Arch Otorhinolaryngol. 247(6): 368-70. 1990.
6. Chen J et al. Antioxidant stats and cancer mortality in China. Int
J Epidemiol. 21(4): 625-35. Aug 1992.
7. Bos RP et al. Decreased excretion of thioethers in urine of smokers
after the use of beta-carotene. Int Arch Occup Environ Health. 64(3):
189-93. 1992.
8. Schwartz J and Shklar G. The selective cytotoxic effect of carotenoids
and alpha-tocopherol on human cancer cell lines in vitro. J Oral Maxillofac
Surg. 50(4):367-73). Apr 1992;
9. ElAttar TM and Lin HS. Effect of retinoids and carotenoids on prostaglandin
formation by oral squamous carcinoma cells. Prostaglandins Leukot Essent
Fatty Acids. 43(3): 175-8. July 1991.
10. Santamaria LA and Santamaria AB. Cancer chemoprevention by supplemental
carotenoids and synergism with retinol in mastodynia treatment. Med
Oncol Tumor Pharmacother; 7(2-3): 153-67. 1990
11. Bhide SV et al. Antimutagenic and anticarcinogenic effects of betal
leaf extract against the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)
-1-butanone (NNK). IARC Sci Publ. 105: 520-4. 1991
12. Nagasawa H et al. Suppression by beta-carotene-rich algae Dunaliella
bardawil of the progression, but not the development of spontaneous
mammary tumours in SHN virgin mice. Anticancer Res. 11(2): 713-7. Mar-Apr
1991.
13. Stich HF et al. Remission of precancerous lesions in the oral cavity
of tobacco chewers and maintenance of the protective effect of beta-carotene
or vitamin A. Am J Clin Nutr. 53(1 Suppl): 298S-304S. Jan 1991.
14. Gensler HL and Holladay K. Enhanced resistance to an antigenic tumor
in immunosuppressed mice by dietary retinyl palmitate plus canthaxanthin.
Cancer Lett. 49(3): 231-6. Mar 1990.
15. Lacroix A et al. Plasma levels of retinol in cancer patients supplemented
with retinol. Oncology 44(2): 108-14. 1987.
16. Mehta RR et al. Significance of plasma retinol binding protein levels
in recurrence of breast tumors in women. Oncology 44(6): 350-5. 1987.
17. Komiyama S et al. Synergistic combination therapy of 5-fluorouracil,
vitamin A, and cobalt-60 radiation for head and neck tumors - antitumor
combination therapy with vitamin A. Auris Nasus Larynx. 12(Suppl 2):
S239-43. 1985.
18. Nakagawa M et al. Potentiation by vitamin A of the action of anticancer
agents against murine tumors. Jpn J Cancer Res 76(9): 887-94.. Sep 1985.
Vitamin A--offers protection against radiation induced
tissue damage, down-regulates telomerase activity, and is involved at
almost every juncture of cancer control
Retinoids induce cell differentiation, control cancer growth and angiogenesis,
repair precancerous lesions, prevent secondary carcinogenesis and metastasis,
and act as an immunostimulant. After FAR therapy (5-fluorouracil-retinol
palmitate with radiation and surgery), the disease-specific, 5-year
survival was nearly 50% in various head and neck cancers (Yamamoto 2001).
Retinoids, at pharmacological levels, assist in preventing the appearance
of secondary tumors following curative therapy for epithelial malignancies.
It is well-established that a vitamin A deficiency (in
laboratory animals) correlates with a higher incidence of cancer and
an increased susceptibility to chemical carcinogens. This is in agreement
with epidemiological studies, which indicate that individuals with a
lower dietary vitamin A intake are at a higher risk of developing cancer
(Sun et al. 2002). The chemotherapeutic possibilities surrounding vitamin
A areplentiful.
Two vitamin A analogs currently in large chemoprevention,
intervention trials, or epidemiological studies are all-trans-retinoic
acid (ATRA) and 13-cis-retinoic acid (13-cis-RA).
Note: Retinoic acid is biologically active in two forms:
all- trans- retinoic acid and 9-cis-retinoic acid. Vitamin A and 13-cis-RA
are converted to these biologically active forms.
Thirty-two women with previously untreated cervical carcinoma
(ages 14-60) were treated for at least 2 months using oral 13-cis-RA
(1 mg per kg body weight a day) and alpha-interferon subcutaneously
(6 million units daily): 16 of the women (50%) had major reactions,
including four complete clinical responses. Remission occurred in 15
of the patients within 2 months and in one patient within 1 month; toxicity
to treatment was described as manageable (Espinoza et al. 1994). The
positive results were replicated in other studies using a similar model
(Hansgen et al. 1998, 1999).
The role of 13-cis-RA on a human prostate cancer cell
line (LNCaP) was studied. It was found that 13-cis-RA significantly
inhibited PSA secretion and the ability to form new tumors. It was also
noted that tumors that appeared (having escaped 13-cis-RA inhibition)
were smaller compared to tumors in nontreated animals (Dahiya et al.
1994). During the course of 13-cis-RA therapy, prostate cancer cells
became more differentiated, that is, they resembled (microscopically)
normal prostate cells.
A combination of phenylbutyrate and 13-cis-RA as a differentiation
and anti-angiogenesis strategy against prostate cancer was evaluated.
Phenylbutyrate, considered nontoxic, is used to arrest tumor growth
and induce differentiation of premalignant and malignant cells. Tissue
examination of tumors showed decreased cell proliferation and increased
apoptosis, as well as reduced microvessel density in animals treated
with 13-cis-RA and phenylbutyrate; tumor growth was inhibited by 82-92%.
In contrast, researchers reported 13-cis-RA and phenylbutyrate, when
used singularly, were suboptimal in terms of clinical benefit (Pili
et al. 2001).
A pilot study conducted at M.D. Anderson Cancer Center
found ATRA alone ineffective as a long-term treatment for chronic myelogenous
leukemia (CML). Only four of 13 subjects showed a transient, nonsustaining
indication of an anti-leukemic effect (Cortes et al. 1997). However,
combinations of therapeutic agents that included ATRA were promising
in the treatment of CML. The combination included alpha-interferon plus
ATRA, which reduced proliferation 50-60% (Marley et al. 2002).
Cisplatin (a popular chemotherapeutic agent) shares a
similar chemotherapeutic profile with ATRA (the ability to induce cytotoxicity
through apoptosis). A combination of ATRA and cisplatin induced apoptosis
in significantly more cancer cells, particularly in ovarian and head
and neck carcinomas, than either drug alone (Aebi et al. 1997). A combination
of ATRA and IL-2 showed therapeutic value in treating resistant metastatic
osteosarcoma, a malignant tumor of the bone (Todesco et al. 2000).
For decades, researchers have searched for ways to minimize
the damage to the heart during Adriamycin therapy. Adriamycin, though
relatively effective, damages the heart muscle. Several animal studies
indicated that supplemental vitamin A reduced Adriamycin-induced inflammation
and preserved heart tissue. Vitamin A appears not only to counter Adriamycin
damage, but also to increase survival in animals (Tesoriere et al. 1994).
Vitamin A extends similar protection to patients using cisplatin, a
drug often used for bladder and ovarian cancer, as well as small cell
carcinoma.
Radiation-induced lung injury frequently limits the total
dose of thoracic radiotherapy that can be delivered to a patient undergoing
treatment, restricting its effectiveness. Animal studies suggest that
supplemental vitamin A may reduce lung inflammation after thoracic radiation
and modify radiotherapy damage to the lungs (Redlich et al. 1998).
Vitamin A (in dosages of 25,000 IU a day) offers significant
protection against radiation-induced tissue damage. Various cancer patients
use more than 100,000 IU of a water-soluble vitamin A liquid a day,
a dosage that must be supervised by a physician. Do not supplement with
vitamin A if the cancer involves the thyroid gland or if the liver is
damaged. Both professionals and patients should consult Appendix A to
read about avoiding vitamin A toxicity. Good food sources of vitamin
A include liver and fish liver oils, green and yellow fruits and vegetables
such as apricots, asparagus, broccoli, cantaloupe, carrots, collards,
papayas, peaches, pumpkins, spinach, and sweet potatoes. High-potency
water-soluble vitamin A is available as a dietary supplement.
Vit A 100t SN0828 $NZ10.69
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