| References | Disclaimer | Abstracts | Print Version
Cancer Adjuvant Therapy
Carotenoids--have antioxidant activity, inhibit cellular proliferation,
and offer protection against numerous types of malignancies
Carotenoids, acting as immune enhancers and free-radical scavengers, are
important substances in oncology. When using carotenoids for antioxidant
and cancer protection, it appears wise to use mixed carotenoids, that
is, alpha-carotene, lycopene, zeaxanthin, canthaxanthin, beta-crytoxanthine,
and lutein rather than emphasizing only beta-carotene.
The following are illustrative of the worth of mixed carotenoids:
- Lycopene offers targeted protection against cancers arising in the
prostate (Kucuk et al. 2001), pancreas (Burney et al. 1989), digestive
tract (De Stefani 2000), and colon (Nair et al. 2001).
- The American Journal of Clinical Nutrition added that individuals
seeking broad-spectrum colon protection should also include lutein-rich
foods in their diet (spinach, broccoli, lettuce, tomatoes, oranges,
carrots, celery, and greens) (Slattery et al. 2000).
- Canthaxanthin, a less well-known carotenoid, was shown to induce
apoptosis and inhibit cell growth in both WiDR colon adenocarcinoma
and SK-MEL-2 melanoma cells (Palozza et al. 1998).
- Researchers showed that the risk of breast cancer approximately doubled
(2.21-fold) among subjects with blood levels of beta-carotene in the
lowest quartile, compared with those in the highest quartile. The risk
of breast cancer associated with low levels of other carotenoids was
similar, that is, a 2.08-fold increased risk if lutein is deficient
and a 1.68-fold greater risk if beta-cryptoxanthin is lacking (Toniolo
et al. 2001). A Swedish study found that menopausal status has an impact
on the protection delivered by carotenoids. Analysis showed that lycopene
was associated with decreased breast cancer risk in postmenopausal women,
but in premenopausal women, lutein offered greater protection (Hulten
et al. 2001).
- Leukoplakia (an often precancerous condition marked by white thickened
patches on the mucous membranes of the cheeks, gums, or tongue) is responsive
to spirulina, a source of proteins, carotenoids, and other micronutrients
(Sankaranarayanan et al. 1995). An inverse relationship between beta-carotene
and thyroid carcinoma was observed in both papillary and follicular
carcinomas (D'Avanzo et al. 1997). A high dietary intake of beta-carotene
appears a protective (though modest) factor for the development of ovarian
cancer (Huncharek et al. 2001).
- Lastly, Japanese researchers showed that all the carotenoids inhibited
hepatic (liver) invasion, probably through antioxidant properties (Kozuki
et al. 2000).
Men who consume 10 or more servings of tomato products per week reduce
their risk of prostate cancer by about 35%. The American Chemical Society
in August 2001 reported that 32 (largely African-American) patients diagnosed
with prostate cancer and awaiting radical prostatectomy were placed on
diets that included tomato sauce, providing 30 mg a day of lycopene. After
3 weeks, mean serum prostate specific antigen (PSA) concentrations fell
by 17.5%, oxidative burden by 21.3%, DNA damage by 40%, while programmed
cell death increased threefold in cancer cells (Holzman 2002). Part of
lycopene's protection involves the ability of carotenoids to counteract
the proliferation of cancer cells induced by insulin-like growth factors
(Agarwal et al. 2000a).
Beta-carotene exhibited a radio-protective effect among 709 children
exposed to radiation inflicted by the Chernobyl nuclear accident. For
example, the Chernobyl accident showed that irradiation increases the
susceptibility of lipids to oxidative damage and that natural beta-carotene
may act as an in vivo lipophilic antioxidant or radio-protective agent
(Ben-Amotz et al. 1998). Therefore, using beta-carotene following radiotherapy
may reduce the tissue damage caused during treatment.
Beta-carotene, perhaps the most controversial of the family of carotenoids,
has come under attack several times in the past few years. For example,
smokers who received synthetic beta-carotene (as a prophylactic) in the
CARET study had a higher rate of lung cancer and death than smokers not
supplemented. In fact, the study was terminated by the National Cancer
Institute (NCI) because of the widespread discrepancy between the two
groups. The CARET study is not new, but because it still concerns beta-carotene
users, we will attempt to explain the unexpected results of the study.
Dr. Packer described the subjects as "walking time bombs."
Many were victims of asbestos exposure or heavy smoking. The form of beta-carotene
selected for the study (synthetic versus natural) was also cited as another
possible explanation for the negative outcome.
Dr. Leo Galland, M.D. (practitioner and director of the Foundation of
Integrated Medicine, New York City), also explains that high-dose beta-carotene
(25,000 IU a day) administered to smokers results in a particular pattern
of metabolism (Galland 2000). The process is orchestrated as cytochrome
p450 enzymes (Phase I detoxification system) are summoned into action
by tars in cigarette smoke. As beta-carotene is acted on by cytochrome
p450, oxidized end products are formed, as well as toxic derivatives.
Simultaneously, vitamins C and A, as well as glutathione, are depleted,
severing antioxidant protection. This sequence can damage DNA and increase
the likelihood of lung cancer, particularly in an environment with initially
high oxidative stress, a profile common to smokers. Without full spectrum
antioxidant support, the single dose of beta-carotene produces an oxidative
environment rather than one of protection. (Comment: As one free radical
is neutralized by an antioxidant, another oxidant may be formed. It is
well established that vitamin C can serve as a pro-oxidant through the
formation of ascorbyl radicals. It is also known that this radical is
quenched by vitamin E to yield a tocopheryl radical, which in turn is
reduced by the conversion of glutathione to glutathione disulfide. Thus,
the full spectrum of antioxidants is preferable, rather than emphasizing
single antioxidants.)
Beta-carotene is largely considered nontoxic even at high doses; for
example, some nonconventional cancer therapies recommend large amounts
of carrot juice. One large glass of carrot juice can contain 100,000-200,000
IU of provitamin A or carotene. The problem with carrot juice is that
it is loaded with fructose (sugar). Cancer cells feed on sugar, and drinking
carrot juice may induce an insulin spike that could potentially fuel cancer
cell propagation.
Cancer patients should consider natural beta-carotene supplements in
lieu of carrot juice. Suggested phytonutrient dosages are from 9-20 mg
of sulphoraphane, 10-30 mg a day of lycopene, and 15-40 mg of lutein,
along with a mixed carotenoid blend that includes alpha- and beta-carotene.
A product called PhytoFood Powder provides potent amounts of sulphoraphane,
while carotenoid extracts are available in a variety of encapsulated preparations.
Note: What Should the Cancer Patient Eat, appearing later in this protocol,
contains a discussion regarding the value of sulphoraphanes in the diet.
Cimetidine (Tagamet)
Histamine (H2) receptor antagonists (such as cimetidine) became popular
in the late 1970s to treat gastrointestinal ulcers and other benign conditions
of the stomach, esophagus, and duodenum. In 1985, the Life Extension Foundation
announced that cimetidine had merit as a cancer adjunct. Since then, many
studies have been published encouraging the use of cimetidine as a means
of disabling tumors and expanding survival rates (Tonnesen et al.1988;
Yoshimatsuk et al. 2003).
Ways through which cimetidine impacts cancer involves a three-pronged
mechanism including (1) inhibition of cancer cell proliferation, (2) stimulation
of lymphocyte activity by inhibition of T-cell suppressor function, and
(3) inhibition of histamine's activity as a growth factor (Siegers et
al. 1999).
In a Japanese study, a total of 64 colorectal cancer patients (who had
earlier undergone surgery) were evaluated for the effects of cimetidine
on survival and disease recurrence. The cimetidine arm of the study received
800 mg a day of cimetidine along with 200 mg a day of the chemotherapy
drug 5-fluorouracil (5-FU); the control group received only 5-FU. The
treatment was initiated 2 weeks following surgery and terminated 1 year
later. Strikingly beneficial effects were noted: The 10-year survival
rate for patients treated with cimetidine/5-FU was 84.6%, whereas that
of the control group (5-FU alone) was only 49.8% (Matsumoto et al. 2002).
The effect of cimetidine on a particularly aggressive form of colon cancer
(Dukes grade C) was investigated. The cumulative 10-year survival rate
of the cimetidine-treated group was consistently 84.6%, whereas that of
the control group was only 23.1%. (Less virulent cancers (Dukes A or B)
responded less well to cimetidine treatment) (Matsumoto et al. 2002).
Cimetidine treatment is particularly effective in patients whose tumors
express higher levels of Lewis A and Lewis X antigens (i.e., breast and
pancreatic cancers, as well as about 70% of colon cancers). Lewis A and
Lewis X antigens are cell surface ligands that adhere to a molecule in
the blood vessels called E-selectin. (Ligand comes from the Latin word
ligare, meaning that which binds.)
The adhesion of the cancer cell to vascular endothelial cells expressing
E-selectin is a key step in invasion and metastasis. Cimetidine improved
patient outcome presumably by inhibiting the expression of E-selectin,
thus abolishing the binding site for continued cancer growth and metastasis.
The 10-year cumulative survival rate of the cimetidine group displaying
Lewis antigens was 95.5%, whereas the control group was only 35.1% (Matsumoto
et al. 2002). Comment: Patients are well-advised to undergo Lewis antigen
determinations for optimal therapy and a more favorable outcome. Contact
Impath Laboratories at 521 West 57 Street, New York, NY 10019, Telephone:
(800) 447-8881, for information regarding testing.
Researchers recently unearthed another mechanism through which cimetidine
offers cancer protection. Cimetidine enhanced cell-mediated immunity by
improving suppressed dendritic cell function (Kubota et al. 2002). Dendritic
cells capture foreign invaders and carry the antigen to lymph nodes and
spleen. The "hand-delivered" antigen shows the immune system
exactly what it has to fight. A more in-depth explanation regarding dendritic
cells appears in a separate protocol entitled Cancer
Vaccines.
The growth inhibitory effects of cimetidine were assessed on five cell
lines derived from human brain tumors of different tissue types and grades
of malignancy. Each cell line was treated with cimetidine 24 hours before
analysis. Cimetidine significantly inhibited cell proliferation in three
of five cell lines, which indicates the apparent dependence of these cells
on histamine stimulation (Finn et al. 1996).
Because we do not wish the reader to interpret positive material as a
universal ameliorant for all cancers, the following findings are noted:
- Fred Hutchinson Cancer Research Center researchers explored whether
cimetidine exerted a cancer-preventive effect on prostate and breast
cancers by tracking 48,512 individuals from 1977-1995. Unfortunately,
the study concluded that cimetidine did not influence the risk of female
breast cancers; in addition, the researchers concluded that there was
little evidence to support the previously hypothesized preventive effect
of cimetidine on the risk of prostate cancers (Rossing et al. 2000).
- In multiple myeloma patients, cimetidine reduced by about 30% the
bioavailability of melphalan (Alkeran), the standard treatment for the
disease (Sviland et al. 1987).
- A total of 132 male rats were evaluated for immune status after ingesting
cimetidine to forestall a diagnosis of gastric cancer. In the cimetidine-fed
group, 19 of 48 developed cancer, versus 12 of 43 in the control group.
The Norwegian researchers concluded that cimetidine had no significant
immune-modulating effects on the development of gastric cancer in rodents
(Hortemo et al. 1999).
While cimetidine is not efficacious in cancer prevention, it shows efficacy
in treating certain cancers. A suggested cimetidine dosage for cancer
patients is 800 mg (taken at night). Do not supplement with cimetidine
without physician awareness; the drug can interact with several medications
(such as digoxin, theophylline, phenytoin, warfarin, and lidocaine), increasing
or decreasing drug potency.
Clodronate--is a bisphosphonate that inhibits cell proliferation and the
threat of metastasis
Clodronate reduced the incidence and number of metastasis in bone and
viscera (organs enclosed in the abdominal, thoracic, or pelvic cavity)
in high-risk breast cancer patients by 50% (Diel et al. 1998; also see
Journal Club on the
Web).
Between 1990 and 1995, 302 patients (median age 51 years) with primary
breast cancer and tumor cells in the bone marrow (the presence of which
is a risk factor for the development of distant metastasis) were randomly
assigned to receive 1600 mg a day of oral clodronate for 2 years or standard
follow-up without clodronate supplementation (Diel et al. 1998).
At the conclusion of the trial, bone metastases were detected in 12 (8%)
of the clodronate group versus 25 (17%) of the control group. The mean
number of bony metastases per patient was 3.1 in the clodronate group
versus 6.3 in the nontreated group. Visceral metastasis was observed in
13 (8%) versus 27 (19%) of controls; 6 patients (4%) died in the clodronate
group, compared to 22 (15%) in the untreated group. Researchers concluded
that clodronate opposed metastasis by altering the binding capacities
of adhesion molecules on tumors and bone cells. Women with existing metastatic
breast cancer (who added bisphosphonates to their regimen) reported less
bone pain and fewer fractures with treatment.
The bisphosphonates (particularly zoledronic acid) appear to be effective
against the skeletal complications of multiple myeloma, reducing vertebral
fractures and pain. In the early phase of metastasis to bone, tumor cells
activate osteoclasts, cells that break down and resorb bony tissue. This
favors tumor growth, as growth factors are released when bone is degraded.
Bisphosphonates inhibit the development of monocytes into osteoclasts
(cells that digest and remove bone) and promote osteoclast death.
In addition, bisphosphonates restrain the production of bone-resorbing
cytokines such as interleukin-6, an inflammatory marker for myeloma prognosis.
Lastly, bisphosphonates directly affect myeloma by inducing apoptosis
of malignant plasma cells. The biochemical effects of zoledronic acid
continued for as long as 8 weeks after a single administration (Berenson
2001), but myeloma mortality was not decreased by bisphosphonates (Djulbegovic
et al. 2001; Fromique et al. 2000). Typically, a synergism (a cooperative
effort) exists between bisphosphonates and cytotoxic agents, increasing
chemotherapy's effectiveness.
The standard dose for treating cancer is 800 mg of clodronate taken twice
daily, although double this dosage has been used safely. Breast cancer
patients may consider a 3- to 5-year regimen of clodronate or other bisphosphonate
therapy. Blood tests to measure serum calcium levels and kidney function
are required 10 days after beginning clodronate and every 1-2 months thereafter.
Persons who are pregnant or who have severe renal insufficiency requiring
dialysis should avoid clodronate.
Note: Newer
bisphosphonate drugs such as Zometa, Actonel, Fosamax, and Aredia, more
potent than clodronate, are now FDA approved and readily available in
the United States and covered by most health insurance plans. Prophylactic
bisphosphonate therapy is highly recommended for cancers with a propensity
to metastasize to bone, such as prostate and breast cancers. Most cancer
patients should be on bisphosphonate therapy since any amount of bone
breakdown releases growth factors that fuel cancer cell growth. Refer
to Cancer Treatment: The Critical
Factors for more information about bisphosphonate drugs approved in
the United States.
Coenzyme Q10 and Statin Drugs
Statins, a class of cholesterol-lowering drugs, have been shown to inhibit
the activity of ras oncogenes. ras oncogenes are involved in the regulation
of cell growth, modulating the signals that govern the cancer cell cycle.
Mutations in genes encoding Ras proteins have been closely associated
with unregulated cell proliferation, a hallmark of cancer (refer to the
protocol Cancer Treatment: The Critical
Factors to read more about Ras oncogenes).
A number of studies have shown the value of statin drugs in a cancer
regimen, and the benefit escalates when a statin is combined with a nonsteroidal
anti-inflammatory drug (NSAID). People who regularly used NSAIDs lowered
their risk of colon cancer by as much as 50%; when lovastatin was added
to a cyclo-oxygenase 2 (COX-2) inhibitor, the rate of cell death of three
colon cancer cell lines increased up to five-fold (Agarwal et al. 1999).
The statin’s mode of operation, however, raises concern. Statin
drugs reduce cholesterol synthesis in the liver by inhibiting the activity
of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA
reductase is required for the conversion of HMG-CoA to mevalonic acid,
a step in cholesterol synthesis (Folkers et al. 1990). Inhibiting HMG-CoA
reductase results in lower amounts of cholesterol being produced. Disruption
of the cascade also interferes with the synthesis of coenzyme Q10 (CoQ10),
creating a potential tradeoff regarding advantages and disadvantages gathered
from statin usage (Folkers et al 1990; Hattersley 1994).
The impact upon CoQ10 levels when taking statin drugs can be significant.
For example, patients taking CoQ10, who later started lovastatin, lowered
their CoQ10 levels by 44-75%. The problems associated with drug-related
suppression of CoQ10 escalate when age-associated decline in serum CoQ10
levels are also present. A CoQ10 deficiency of 25% is linked with illness
in animals and a deficit of 75% with death (Hattersley 1996; Bliznakov
et al. 1988). Administering adequate amounts of CoQ10 with a statin drug
allows the cancer patient the value of the drug without the risks imposed
by depletion of the coenzyme.
|