Lung Cancer, Chemotherapy, & Antioxidants
BY JOHANNA ALTGELT & MICHAEL McCULLOCH
In the previous two issues of Avenues, we reported on the use of antioxidants
along with chemotherapy as it applies to prostate and breast cancer patients.
In this issue, we turn our focus to small cell lung cancer and non-small
cell lung cancer.
INTRODUCTION
Chemotherapy is a critical part of care for lung cancer patients. However,
there are some notable drawbacks to chemotherapy, such as lung cancer
cells becoming resistant to treatment or side effects becoming debilitating
and intolerable.
Although not commonly addressed in clinical consultation, scientific
evidence suggests that combining certain chemotherapy treatments with
specific antioxidants at defined dosages can help improve drug effectiveness,
or may reduce side effect severity.
This issue is important because it has long been the opinion of many
practicing oncologists that antioxidants should simply not be used concurrently
with chemotherapy in the belief that the combination might inhibit chemotherapy
effectiveness. This reluctance stems, in part, from the fact that some
chemotherapy drugs work by strongly promoting oxidation. This is especially
the case for the class of chemotherapy drugs called anthracyclines (Adriamycin
and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide,
thiotepa, and busulfan), and the platinum drugs (cisplatin and carboplatin).
Antioxidants, by definition, inhibit oxidation, so it was believed that
antioxidants would prevent these chemotherapy drugs from working properly.
The controversy around using antioxidants together with chemotherapy
is based, in part, on some studies of other cancer types and chemotherapy
drugs that show how depleting glutathione, which is a natural antioxidant
in the body, can enhance the treatment effect of chemotherapy. (Meijer,
Mulder et al. 1990; Mans, Schuurhuis et al. 1992; Doyle, Ross et al.
1995; Versantvoort, Broxterman et al. 1995; Zaman, Lankelma et al. 1995;
Kurokawa, Nishio et al. 1997; Lee, Park et al. 2004) Although this has
led many oncologists to believe that all antioxidants should not be combined
with chemotherapy, there are numerous laboratory and human studies showing
how combining chemotherapy with antioxidants can indeed be helpful.
In this systematic review in which we searched for every paper on the
combination of antioxidants and chemotherapy for lung cancer, we found
only two laboratory (and no human) studies demonstrating a harmful combined
effect.
Chemotherapy drugs that cause high levels of “oxidative stress” are
thought to rely in part on oxidative stress to kill cancer cells, but
other effects of that oxidative stress may also be getting in the way
of the effectiveness of the chemotherapy. This is because oxidative stress
slows cell replication and chemotherapy relies on fast cancer cell replication
to be effective because it is during replication that chemotherapy kills
cancer cells. (Conklin 2000) One approach to addressing this problem
is the addition of certain antioxidants at specific dosages to lessen
oxidative stress, thus making the chemotherapy treatment more effective.
(Perumal, Shanthi et al. 2005)
The interaction between chemotherapy and antioxidants is more complex,
however, than simply promoting and inhibiting oxidative stress. There
are several mechanisms by which chemotherapy drugs function and antioxidants
also have a number of different effects on the body. Each antioxidant
has a different interaction with chemotherapy and this effect can even
change based upon the dosage used.
In the end, the question is not whether antioxidants should be used
in combination with chemotherapy but rather which should be used and
at what dosages.
PURPOSE OF THIS PAPER
In this evidence-based review article, we discuss the results of current
research showing how antioxidants may enhance or, in some cases, inhibit
the therapeutic action of specific chemotherapy drugs used in the treatment
of lung cancer. Some of these antioxidants may also reduce chemotherapy
side effects or inhibit chemotherapy resistance in lung cancer cells.
Finally, some of these antioxidants have been found to be useful for
restoring the natural antioxidants in the body, which are often depleted
after the completion of chemotherapy.
HOW NUTRIENT DEPLETION FROM CHEMOTHERAPY CAN OCCUR
Chemotherapy can cause nutrient depletion from two major side effects.
One is nausea and vomiting, making it more difficult for the patient
to maintain adequate nutrient intake. Another is toxicity to cells
in the gastrointestinal tract, making it more difficult for the intestines
to adequately absorb nutrients. Antioxidants are not the only nutrients
to become depleted; vitamins, minerals, amino acids, and fatty acids
may also be compromised, especially in patients who have suffered these
side effects for a prolonged amount of time. For example, the following
chemotherapy drugs damage the cells in the gastrointestinal system and
can cause considerable nausea and vomiting: cisplatin, cyclophosphamide,
daunorubicin, doxorubicin, mitomycin, mitoxantrone, paclitaxel, and vinorelbine.
METHODS
We searched for clinical or laboratory data published in peer-reviewed
medical journals, conducted by cancer researchers in universities and
medical research facilities from around the world, most published in
prestigious, peer-reviewed journals. Some of these studies are still
in early stages and include only laboratory or animal data, while others
have advanced to include human volunteers.
We organized these data into the major categories of specific chemotherapy
drugs. Within each section for a specific drug are found the research
on combinations of that drug with various antioxidants, grouped by the
name of the antioxidant in alphabetical order. We also point out specifically
which studies were conducted in a laboratory (i.e. using cancer cell
cultures), which were conducted using animals, and which were conducted
with human volunteers. As each antioxidant appears in the paper for the
first time, we provide some introduction to the antioxidant including
what food sources naturally contain it, other common applications in
clinical use, and typical dosages. The dosages given are not necessarily
appropriate for all patients and should be individualized with practitioner
guidance.
RESULTS
Carboplatin (Paraplatin)
MELATONIN
Melatonin is a hormone that is released from the pineal gland in the
evening and promotes normal sleep; its secretion diminishes significantly
with age. It is known to help maintain cell health and many people
take it to improve sleep. It is also known to reduce metastasis in
cancer patients. In most published studies, melatonin shows a beneficial
effect, although it has been reported that in a small proportion of
people, melatonin can paradoxically cause sleep disturbance. In others,
there can be residual daytime drowsiness, which is usually resolved
by using a lower dose.
» Melatonin: Typical dosages range from 1 mg to 20 mg.
If aiming for a high dosage, one should start with 1 mg and increase
the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve
peak blood levels of melatonin at about 2am. To do so, one can take the
melatonin at bedtime, ideally between 9pm and 10pm.
Twenty previously untreated patients with inoperable small cell and
non-small cell lung cancer were randomized in a double blind study to
receive either chemotherapy alone or chemotherapy in combination with
melatonin (40 mg per day). Chemotherapy consisted of carboplatin and
etoposide. The trial investigated the potential of melatonin to protect
against chemotherapy-induced toxicity to the bone marrow, where blood
cells are produced. There was no significant difference between the groups
in blood counts. (Ghielmini, Pagani et al. 1999)
MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin
C, vitamin E, and beta-carotene with the chemotherapy drugs paclitaxel
and carboplatin.
Vitamin C (Ascorbic Acid)
Vitamin C, also called ascorbic acid, is a nutrient that humans cannot
synthesize and must obtain from the diet. Almost all fresh vegetables
and fruits are sources of vitamin C. Broccoli, cauliflower, citrus fruits,
and tomatoes are examples of food sources particularly high in vitamin
C.
» Vitamin C: Typical doses range from 60 mg to 1000 mg
a day or up to bowel tolerance.
Vitamin E, Alpha Tocopherol
Vitamin E includes several related compounds: Tocopherols and tocotrienols,
each of which have four subtypes of alpha, beta, gamma, and delta.
Previously, only alpha-tocopherol was considered important, however
each type has unique contributions to health. The best dietary sources
of vitamin E are considered to be unrefined, cold-pressed vegetable
oils such as wheat germ, sunflower seed, and olive oil as well as raw
or sprouted seeds, nuts, and grains.
» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol
or succinate. Seek out the mixed tocopherols, including tocopherols and
tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.
Beta-Carotene
Beta-carotene is the most well known carotenoid, producing the red, orange,
and yellow pigments in fruits and vegetables. It is a precursor of
vitamin A, but also has its own physiological functions. (See “What
about Lung Cancer and Beta-Carotene” sidebar
at the end of this article.)
» Beta-carotene: Typical supplemental doses range from
5000 to 25,000 IU (3 to 15 mg) daily.
In a human lung squamous cell carcinoma cell line, the antioxidant mixture
of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect
of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24
hours later led to an apoptosis (cancer cell killing) rate of 54%. In
contrast, the vitamins administered together with paclitaxel and 24 hours
later by carboplatin led to a 70% apoptosis rate. This effect was further
enhanced to an 89% apoptosis rate by pretreatment with the vitamins 24
hours before paclitaxel, then followed another 24 hours later by carboplatin.
(Pathak, Singh et al. 2002)
In a follow up human trial, the same combination of chemotherapy and
antioxidants was tested in 136 previously untreated patients with advanced
stage IIIB and IV non-small cell lung cancer. Patients were randomized
to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy
in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol
(vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response
(tumor size reduction) rate in the chemotherapy-only group was 33%, while
in the combination group was 37%. Overall survival (OS) was 32.9% at
one year in the chemotherapy-alone group and 39.1% in the combination
group. Median survival was 9 months in the chemotherapy-alone group and
11 months in the combination group. Toxicity was similar between the
two groups. Although the difference in effectiveness was not statistically
significant, it may nevertheless still be clinically significant, offering
a modest improvement in treatment response and survival. Furthermore,
the result of this study does not support the concern that these high-doses
of antioxidants compromise the efficacy of paclitaxel-carboplatin combination
chemotherapy. (Pathak, Bhutani et al. 2005)
Cisplatin (Platinol)
ASTRAGALUS
Astragalus is a tonic herb and the roots have been used for over 2000
years in Chinese medicine. It is used in the west for heart disease
and to support the immune system.
» Astragalus: Typical dosages of the dried root range
from 10 to 15 g daily by decoction, or as an extract 10 to 20 mL daily.
The Pine
Street Foundation’s 2006 published meta-analysis has shown
that adding Chinese herbal formulas based on the herb Astragalus membranaceus
(Huang Qi) to cisplatin-based chemotherapy reduced risk of death at
12 months by 33%, when compared to cisplatin-based chemotherapy alone.
The increase in tumor response ranged between 34% and 76% depending
on the herbal formula used. (McCulloch, See et al. 2006)
DOCOSAHEXAENOIC ACID (DHA)
Omega-3 fatty acids come from several different sources and in several
different forms. Sources include blue-green algae, fish oil, and eggs,
from which docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)
can be derived. It is used as a supplement in clinical practice for
many therapeutic uses, some of which include cancer, heart disease,
depression, diabetes, and multiple sclerosis.
» Omega
3 Polyunsaturated Fatty Acids (PUFA, from fish oil including DHA/EPA):
Typical dosage range is from 1,000 mg to 10,000 mg daily. When finding
a fish oil supplement, it is important to identify brands that can provide
assurance that they have tested for heavy metals, such as mercury.
In a laboratory study
of human small-cell lung cancer cells that were resistant to cisplatin,
supplementing with DHA led to an almost three-fold decrease in the ability
of tumor cells to be resistant to chemotherapy. In cancer cells that
were not resistant to cisplatin treatment, DHA did not increase the treatment
effectiveness of cisplatin. (Timmer-Bosscha, Hospers et al. 1989)
GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones
are antioxidants that counteract the damaging effects of free radicals
in body tissues. Isoflavones, such as genistein, also have anti-angiogenic
effects, blocking the formation of new blood vessels needed to support
the growth of tumors.
» Genistein: A good
product will use organic, non-GMO genistein. To achieve anti-tumor effects,
the target daily dose, based on animal studies and calculations for similar
human dosage, is between 100 mg and 1100 mg. (Boik 2001) One cup of soy
milk will contain, on average, about 45 mg of genistein and the other
related isoflavones.
Genistein was used in combination
with cisplatin, docetaxel, or doxorubicin in the treatment of non-small
cell lung cancer cells in a laboratory study. The treatment effect was
significantly greater when genistein was used together with cisplatin,
docetaxel, or doxorubicin than any of the chemotherapy agents alone.
A smaller dose of chemotherapy was applied in the combined treatment
and, despite the smaller dose, the treatment was more effective with
genistein. The mechanism was through inactivation of NF-kappaB by genistein.
(Li, Ahmed et al. 2005) Activation of NF-kappaB (a type of protein complex)
plays a role in drug resistance in cancer cells in some chemotherapy
agents, including cisplatin. (Yeh, Chuang et al. 2002)
GINSENOSIDE Rh2
Ginsenosides are an active ingredient derived from ginseng, one of the
most widely known herbal medicines in the world and commonly used for
its immune stimulating and anti-tumor properties. (Boik 2001)
» White American Ginseng Extract: Commonly used dosage
levels of ginseng extract range between 200 and 1000 mg.
In a study using human lung adenocarcinoma, Ginsenoside Rh2 reversed
resistance to cisplatin. In cisplatin resistant cells, the addition of
Ginsenoside Rh2 decreased by three-fold the amount of cisplatin needed
to achieve the same treatment effect of cisplatin alone. (Hu, Hu et al.
2005)
MELATONIN
Researchers from Italy published a study in 2007 about non-small cell
lung cancer patients receiving cisplatin and etoposide (58 patients)
or cisplatin and gemcitabine (16 patients) with or without melatonin
(20 mg per day). The response rate to treatment and disease control was
higher in patients treated with chemotherapy and melatonin than in patients
treated with chemotherapy alone. This difference was only significant
in the patients receiving cisplatin and etoposide but was not significant
in the group of patients receiving cisplatin and gemcitabine. (Lissoni
2007)
In a second
trial from Italy, 100 metastatic non-small cell lung cancer patients
were given cisplatin and etoposide with or without melatonin (20 mg per
day). The patients treated with chemotherapy and melatonin had significantly
less progressive disease, had better overall tumor regression, and better
5-year survival. Three patients in the melatonin group were alive at
five years after beginning treatment with chemotherapy whereas no patients
were alive after two years in the chemotherapy only group. Treatment
with melatonin also significantly decreased neurotoxicity, thrombocytopenia,
weight loss, and asthenia. No difference was observed in alopecia and
anemia. (Lissoni, Chilelli et al. 2003)
A third trial from Italy enrolled 104 metastatic non-small cell lung
cancer patients who received chemotherapy treatment that consisted of
cisplatin and etoposide or gemcitabine alone. Patients were randomized
to receive chemotherapy alone or chemotherapy and melatonin at 20 mg
per day. The response rate to chemotherapy was higher in patients treated
with melatonin, although this difference was only significant in patients
receiving cisplatin and etoposide but not gemcitabine. Nevertheless,
one year survival was significantly higher in the patients receiving
melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)
5-METHOXYTRYPTAMINE (5-MTT)
5-methoxytryptamine (5-MTT) is a pineal hormone.
» 5-methoxytryptamine
(5-MTT): Typical dosage used for cancer patients is 1 mg per day.
One hundred advanced non-small cell lung cancer patients were enrolled
in a trial from Italy published in 2007 who received either chemotherapy
(cisplatin and etoposide) alone or with melatonin (20 mg per day) or
5-MTT (1 mg per day). The overall response rate and disease control was
significantly higher in both the melatonin and 5-MTT groups. The chemotherapy-related
toxicity such as thrombocytopenia, neurotoxicity, and asthenia was significantly
reduced in patients receiving chemotherapy and melatonin or 5-MTT. 5-MTT
was better than melatonin at preventing anorexia. Therefore, the much
lower dose of 5-MTT was as effective as melatonin in the treatment of
non-small cell lung cancer. (Lissoni 2007)
In another study, 20 metastatic lung cancer
patients were treated with cisplatin and etoposide and were randomized
to either receive 5-MTT (1 mg per day) in addition to chemotherapy or
to receive chemotherapy treatment alone. The patients treated with chemotherapy
and 5-MTT had significantly reduced anemia and significantly less progressive
disease in comparison to the patients treated with chemotherapy alone.
(Lissoni, Malugani et al. 2003)
MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants alpha-lipoic
acid and N-acetyl cysteine with cisplatin, epirubicin, medroxyprogesterone
acetate (a hormonal drug that is a progestin derived from the naturally
occurring female hormone, progesterone), and recombinant IL-2.
Alpha-lipoic Acid
Alpha-lipoic acid is an important antioxidant that can regenerate other
essential antioxidants such as vitamins C and E, coenzyme Q10, and
glutathione. It is also a cofactor for some of the key enzymes (alpha-keto
acid dehydrogenases) involved in generating energy. Alpha-lipoic acid
comes in two forms: the “R” form
is biologically active and is naturally produced by the body while the “S” form
is manufactured and is less biologically active. Most alpha-lipoic supplements
have a mixture of the “R” and “S” forms.
Some manufacturers now make available a supplement containing pure R-dihydro-lipoic
acid.
» Alpha-lipoic
Acid: Typically used in a dosage range between 200 and 600 mg per day.
(Boik 2001) When using the Rdihydro-lipoic acid, half the dose may be
used.
N-acetyl Cysteine
N-acetyl cysteine is an efficiently absorbed and used form of the amino
acid, L-cysteine. L-cysteine, L-glutamic acid, and glycine are the
three amino acids that form glutathione, which is one of the most important
and powerful antioxidants in the body.
» N-acetyl Cysteine: Typical dosages range between 600 and 1,800
mg per day.
A phase II clinical trial using a combination regimen including cisplatin,
epirubicin, medroxyprogesterone acetate, recombinant IL-2, alpha-lipoic
acid (300 mg per day), and N-acetyl cysteine (1.8 g per day) enrolled
33 non-small cell lung cancer patients: 26 with stage IIIB disease and
7 with stage IV disease. Of thirty patients whose results could be measured,
the median overall survival was 15 months. The one year survival was
55.8%. The median progression free survival was 10 months. Neutropenia
was the most significant symptom of toxicity from treatment; other toxicity
was low. (Mantovani, Maccio et al. 2002)
QUERCETIN
Quercetin is the most abundant of the plant-derived flavonoid molecules
and is a very active antioxidant. Quercetin is a flavonoid found in
capers, apples, tea, onions, red grapes, citrus fruits, leafy green
vegetables, cherries, and raspberries. Quercetin has anti-inflammatory
activity, inhibiting allergic and inflammatory reactions. Dihydroquercetin
is a supplement very similar to quercetin that may be even safer than
quercetin and is most notable for its synergistic combination with vitamin
C. Dihydroquercetin inhibits the oxidation of vitamin C, helping to maintain
the concentration of vitamin C in the body over time. Together, vitamin
C and dihydroquercetin inhibit oxidative stress and inflammation, avert
complications of diabetes, protect against liver damage and hepatitis,
provide immune support, and sooth irritated skin.
» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.
» Dihydroquercetin: Typical dosage is 10 mg combined with
vitamin C (1000 mg).
Quercetin, when combined with cisplatin, was found to increase cell
death of human non-small cell lung cancer cells by 30.2% compared to
cisplatin alone in a laboratory study. (Kuhar, Sen et al. 2006) A second
laboratory study also confirmed that cisplatin had a much stronger treatment
effect in lung cancer cells when combined with quercetin. (Borska, Gebarowska
et al. 2004)
VITAMIN D
Vitamin D includes a series of compounds exhibiting the activity of calciferol.
The two most widely known types of vitamin D are ergocalciferol (vitamin
D2) and cholecalciferol (vitamin D3). Vitamin D3 has a greater potency
and longer duration of action than vitamin D2. (Armas, Hollis et al.
2004) It is a fat-soluble vitamin and a hormone and it can either be
absorbed through digestion or synthesized in the skin when exposed
to sunlight.
Twenty minutes of sun exposure to the face and arms is sufficient to
generate production of 600 to 1000 IU of vitamin D (during spring, summer,
and fall, in temperate regions such as the San Francisco Bay Area). In
an hour’s time, with sun exposure that produces mild
redness of the skin, 10,000 to 20,000 IU may be generated. During spring,
summer, and fall, 15 minutes of sun exposure, three times per week in
the morning or late afternoon on the arms, face, and hands provides sufficient
vitamin D stores to last through the end of winter (in latitudes between
35o and 50o; San Francisco is at about 37o). Sunscreen significantly
reduces the synthesis of vitamin D.
Although vitamin D comes primarily from sun exposure, food sources include
cod liver oil, butter, egg yolks, and vitamin D fortified milk and orange
juice.
» Vitamin D: Therapeutic dosages range between 200 IU to 2000
IU per day, and doses up to 10,000 IU have been tested in clinical trials.
Very high doses of vitamin D at 40,000 IU per day have been reported
to result in hypercalcemia. (Vieth 1999) Lymphoma and granulomatous disease
can cause vitamin D sensitivity and therefore people with these conditions
should be more cautious in taking vitamin D supplements. A simple blood
test for 25 hydroxy vitamin D can be used to monitor blood levels in
people using vitamin D supplements.
In human non-small cell lung carcinoma cells, vitamin D compounds decreased
the IC50 of cisplatin in a laboratory study (IC50 is the concentration
of drug needed to achieve 50% reduction in cancer cell growth). This
means that when vitamin D was added, less cisplatin was needed to achieve
the same anti-tumor effect as cisplatin alone. (Pelczynska, Wietrzyk
et al. 2005)
VITAMIN K
Vitamin K is a coenzyme involved in synthesis of proteins important for
blood clotting and bone metabolism. Vitamin K1 is non-toxic up to 500
times the recommended daily allowance, which is 1 microgram per kilogram
of body weight. It is a fat-soluble form that naturally occurs in plants
and fish. Vitamin K2 is another fat-soluble form that is synthesized
by the healthy bacteria in our intestines. Food sources of vitamin K2
are meat, fermented food products such as cheese, or the Japanese fermented
soy product natto.
» Vitamin K: Therapeutic dosages range from 45 to 500 micrograms
per day. Because vitamin K affects blood clotting, patients using anticoagulant
therapy should monitor vitamin K intake with their doctor.
Vitamin K2 was found to enhance small cell lung cancer cell death caused
by cisplatin in a laboratory study. (Yoshida, Miyazawa et al. 2003)
Cyclophosphamide(Cytoxan, Neosar)
BETA-1,3 D-CARBOXYMETHYLGLUCAN (BETA-1,3 D-GLUCAN)
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator.
Macrophages are an important part of the immune system.
» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg
per day.
In an animal study, Beta-1,3 D-glucan enhanced the treatment effect
of cyclophosphamide in Lewis lung carcinoma. The combination treatment
was more effective at inhibiting primary tumor node as well as reducing
metastasis. After cyclophosphamide treatment alone, metastasis occurred
in 40.9% of animals. With combined treatment, metastasis occurred in
7.5% of animals. (Falameeva, Poteryaeva et al. 2001)
GENISTEIN
In an animal study using mice with Lewis lung cancer, cyclophosphamide
alone reduced tumor blood supply by 38%, while the combination of cyclophosphamide
and genistein reduced tumor blood supply by 61%. (Wietrzyk, Boratynski
et al. 2001)
GINSENOSIDE Rg3
A low dose schedule of cyclophosphamide was enhanced by the angiogenic
inhibitor ginsenoside Rg3 in mice with Lewis lung carcinoma. Tumor
growth was delayed, side effects were mitigated, survival was increased,
and angiogenesis was enhanced in mice receiving combined treatment in
contrast to mice receiving cyclophosphamide alone. (Zhang, Kang et al.
2006) Angiogenic inhibitors decrease the blood vessels to the tumor so
that the supply of nutrients to the tumor is decreased and thus growth
is inhibited.
MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin
A, retinoic acid, vitamin E, vitamin D, melatonin, and beta-carotene
with somatostatin (a hormone that inhibits the release of various growth
hormones), cyclophosphamide, and bromocriptine (a dopamine agonist
that works by blocking the release of prolactin from the pituitary
gland and lowering growth hormone levels).
Vitamin A & Retinoic Acid
Retinoic acid is the acidified form of vitamin A (retinol), the animal
form of vitamin A. Retinoic acid is a prescription drug; the generic
name is tretinoin and one of the trade names is Vesanoid. Retinol is
a fat-soluble, antioxidant vitamin important for bone growth and vision.
Retinol is ingested in a precursor form from animal foods and is especially
plentiful in cod liver oil. Other good sources include butter and egg
yolks as well as whole milk, cream, and yogurt.
» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.
Twenty-three patients with stage IIIB or IV lung adenocarcinoma whose
disease had progressed after standard chemotherapy, and who also had
poor quality of life, received a combination of somatostatin, retinoids,
melatonin, vitamin D, bromocriptine, and cyclophosphamide. The median
overall survival was 95 days and the side effect consisted of grade
1-2 diarrhea, nausea/vomiting, and drowsiness. Fifty percent of patients
experienced improved respiratory as well as general symptoms. Most
of these were patients that survived longer than 95 days. (Norsa and
Martino 2006)
Daunorubicin, Daunomycin (Cerubidine)
GENISTEIN , BIOCHANIN A, APIGENIN, AND QUERCETIN
In Adriamycin resistant small cell lung cancer cells, genistein, biochanin
A, apigenin (an antioxidant flavonoid found in plants such as parsley,
artichoke, basil, and celery), and quercetin inhibited the flow of
daunorubicin out of the cancer cells. The antioxidants were not administered
together as a mixture but rather tested separately with daunorubicin.
(Versantvoort, Schuurhuis et al. 1993)
Docetaxel (Taxotere)
GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin
in the treatment of non-small cell lung cancer cells in a laboratory
study. The treatment effect was significantly greater when genistein
was used together with cisplatin, docetaxel, or doxorubicin than any
of the chemotherapy agents alone. A smaller dose of chemotherapy was
applied in the combined treatment and, despite the smaller dose, the
treatment was more effective with genistein. The mechanism was through
inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation
of NF-kappaB plays a role in drug resistance in cancer cells in some
chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)
Doxorubicin (Adriamycin)
CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice
plant turmeric. Curcumin is known for its anti-tumor, antioxidant,
anti-amyloid, and anti-inflammatory properties. It also promotes healthy
bile excretion and healthy platelet function.
» Curcumin: The best supplements contain curcumin at 75% or higher
concentration. Typical doses range from 500 mg to 4,000 mg daily. Take
with meals as it can cause stomach upset when taken on an empty stomach.
Bioavailability and potency are increased when combined with Bioperine,
from black pepper.
A laboratory study found that curcumin prevented doxorubicin from flowing
out of non-small cell lung cancer cells that were resistant to doxorubicin.
Therefore, curcumin may enhance the treatment effect of doxorubicin in
doxorubicin-resistant lung cancer cells in vitro. (Pesic, Markovic et
al. 2006)
DOCOSAHEXAENOIC ACID (DHA)
Slight to no enhancement of treatment effect (but no decreased effect)
was observed after combination treatment using doxorubicin and DHA
in a laboratory study using bronchial carcinoma cell lines. Interestingly,
that same combined treatment did enhance treatment effectiveness in brain
cancer cell lines, underscoring the importance of combining the right
antioxidant with the right drug and the appropriate cancer. (Rudra and
Krokan 2001) In a second laboratory study, DHA increased the concentration
of doxorubicin in small-cell lung cancer cells by 10 to 30%. Despite
the increase in concentration of doxorubicin, there was no increase in
treatment effect in doxorubicin sensitive cells, however there was a
partial reversal of resistance in the doxorubicin resistant cells. (Zijlstra,
de Vries et al. 1987)
FISH OIL
An animal study compared mice with lung cancer tumors treated with doxorubicin
and a diet rich in either corn oil or fish oil. In mice that received
fish oil and doxorubicin, there was significant tumor regression. In
mice that received corn oil and doxorubicin, the treatment only halted
the growth of the tumor. Thus fish oil was found to enhance the treatment
effect of doxorubicin. (Hardman, Moyer et al. 2000)
GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin
in the treatment of non-small cell lung cancer cells in a laboratory
study. The treatment effect was significantly greater when genistein
was used together with cisplatin, docetaxel, or doxorubicin than any
of the chemotherapy agents alone. A smaller dose of chemotherapy was
applied in the combined treatment and, despite the smaller dose, the
treatment was more effective with genistein. The mechanism was through
inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation
of NF-kappaB plays a role in drug resistance in cancer cells in some
chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)
MELATONIN
In a laboratory study, melatonin intensified doxorubicin effectiveness
in non-small cell lung cancer cells. (Fic, Podhorska-Okolow et al.
2007)
SELENIUM
Selenium is an essential trace mineral in the body and is found in variable
amounts in food depending on the soil content of selenium. Brazil nuts
are the single best food source of selenium. One of its roles in the
body is as an antioxidant and it is most widely known as a cancer preventive.
» Selenium (mineral): The US Adult Tolerable Upper Intake
Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects
Level (LOAEL) for adults is about 900 micrograms daily. There are several
different forms of selenium; Se-Methylselenocysteine is a highly bioavailable
form because it is not incorporated within a protein such as the form
selenomethionine. We recommend getting selenium either in the organically
bound forms, such as of Se-Methylselenocysteine, or a combination of
selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione,
and Se-methylselenocysteine.
Selenium in combination with doxorubicin or paclitaxel enhanced the
chemotherapeutic effect of doxorubicin and paclitaxel in human squamous
lung cancer cells in a laboratory study. (Vadgama, Wu et al. 2000)
In human small cell lung carcinoma cells that had developed resistance
to doxorubicin, treatment with selenium caused significant apoptosis.
In contrast, the cells that were sensitive to doxorubicin did not respond
to treatment with selenium as strongly. It is important to note that
this study does not comment on the combination of doxorubicin and selenium
as a combined treatment, but rather only selenium treatment of cancer
cells that are resistant or sensitive to doxorubicin. (Jonsson-Videsater,
Bjorkhem-Bergman et al. 2004)
SILIBININ
Silibinin (also called silybin) is an important active compound found
in silymarin, extracted from blessed milk thistle (Silybum marianum)
which is a member of the sunflower family (Compositae).
» Silymarin: Typical dosages range from 100 mg to 900
mg daily. An example of a good product is one containing 900 mg, standardized
to 80% silymarin (720 mg), 30% Silibinin (270 mg), and 4.5% Isosilybin
B complex (40.5mg). Silibinin is the most biologically active constituent
found in silymarin and Isosilybin B complex is the most efficient constituent
of silymarin in maintaining healthy cell division.
An animal study observed the effects of combined treatment with Silibinin
and doxorubicin in mice with non-small cell lung cancer. Silibinin enhanced
the treatment effect of doxorubicin. The tumor weight was decreased 76%
in mice with combined treatment, and only 61% in mice treated with doxorubicin
alone. The combined treatment prevented weight loss that otherwise occurred
in mice treated with doxorubicin alone. Microvessel density was inhibited
by doxorubicin by 58% whereas in combination treatment, microvessel density
inhibition was enhanced significantly to 70%. Microvessel density inhibition
means that there is less blood supply to the tumor and this leads to
better treatment outcomes. The inhibition of the NF-kappaB pathway was
found to play a role in the synergistic combination. (Singh, Mallikarjuna
et al. 2004)
VITAMIN D
In human non-small cell lung carcinoma cells, vitamin D compounds decreased
the IC50 of doxorubicin in a laboratory study (IC50 is the concentration
of drug needed to achieve 50% reduction in cancer cell growth). This
means that when vitamin D was added, less doxorubicin was needed to
achieve the same anti-tumor effect as doxorubicin alone. (Pelczynska,
Wietrzyk et al. 2005)
Epirubicin (Ellence)
MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin,
epirubicin, medroxyprogesterone acetate (a hormonal drug that is a
progestin derived from the naturally occurring female hormone, progesterone),
recombinant IL-2, alpha-lipoic acid (300mg per day), and N-acetyl cysteine
(1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with
stage IIIB disease and 7 with stage IV disease. Of thirty patients whose
results could be measured, the median overall survival was 15 months.
The one year survival was 55.8%. The median progression free survival
was 10 months. Neutropenia was the most significant symptom of toxicity
from treatment, but other toxicities were minimal. (Mantovani, Maccio
et al. 2002)
Etoposide (Toposar , Etopophos, VePesid)
MELATONIN
Twenty previously untreated patients with inoperable small cell and non-small
cell lung cancer were randomized in a double blind study to receive
either chemotherapy alone or chemotherapy in combination with melatonin
(40 mg per day). Chemotherapy consisted of carboplatin and etoposide.
The trial investigated the potential of melatonin to protect against
chemotherapy-induced toxicity to the bone marrow, where blood cells
are produced. There was no significant difference between the groups
in blood counts. (Ghielmini, Pagani et al. 1999)
Researchers from Italy published a study last year about nonsmall cell
lung cancer patients receiving cisplatin and etoposide (58 patients)
or cisplatin and gemcitabine (16 patients) with or without melatonin
(20 mg per day). The response rate to treatment and disease control was
higher in patients treated with chemotherapy and melatonin than in patients
treated with chemotherapy alone. This difference was only significant
in the patients receiving cisplatin and etoposide but was not significant
in the group of patients receiving cisplatin and gemcitabine. (Lissoni
2007)
In a second trial from Italy, 100 metastatic non-small cell lung cancer
patients were given cisplatin and etoposide with or without melatonin
(20 mg per day). The patients treated with chemotherapy and melatonin
had significantly less progressive disease, had better overall tumor
regression, and higher 5-year survival. Three patients in the melatonin
group were alive at five years after beginning treatment with chemotherapy
whereas no patients were alive after two years in the chemotherapy only
group. Treatment with melatonin also significantly decreased neurotoxicity,
thrombocytopenia, weight loss, and asthenia. No difference was observed
in alopecia and anemia. (Lissoni, Chilelli et al. 2003)
A third trial from Italy enrolled 104 metastatic non-small cell lung
cancer patients who received chemotherapy treatment that consisted of
cisplatin and etoposide or gemcitabine alone. Patients were randomized
to receive chemotherapy alone or chemotherapy and melatonin at 20 mg
per day. The response rate to chemotherapy was higher in patients treated
with melatonin, although this difference was only significant in patients
receiving cisplatin and etoposide but not gemcitabine. Nevertheless,
one year survival was significantly higher in the patients receiving
melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)
5-METHOXYTRYPTAMINE (5-MTT)
One hundred advanced non-small cell lung cancer patients were enrolled
in a trial from Italy published last year who received either chemotherapy
(cisplatin and etoposide) alone or with melatonin (20 mg per day) or
5-MTT (1 mg per day). The overall response rate and disease control
was significantly higher in both the melatonin and 5-MTT groups. The
chemotherapy-related toxicity such as thrombocytopenia, neurotoxicity,
and asthenia was significantly reduced in patients receiving chemotherapy
and melatonin or 5-MTT. 5-MTT was better than melatonin at preventing
anorexia. Therefore, the much lower dose of 5-MTT was as effective as
melatonin in the treatment of non-small cell lung cancer. (Lissoni 2007)
In another study, 20 metastatic lung cancer patients were treated with
cisplatin and etoposide and were randomized to either receive 5-MTT (1
mg per day) in addition to chemotherapy or to receive chemotherapy treatment
alone. The patients treated with chemotherapy and 5-MTT had significantly
reduced anemia and significantly less progressive disease in comparison
to the patients treated with chemotherapy alone. (Lissoni, Malugani et
al. 2003)
Gemcitabine (Gemzar)
MELATONIN
Researchers from Italy published a study last year about non-small cell
lung cancer patients receiving cisplatin and etoposide (58 patients)
or cisplatin and gemcitabine (16 patients) with or without melatonin
(20 mg per day). The response rate to treatment and disease control was
higher in patients treated with chemotherapy and melatonin than in patients
treated with chemotherapy alone. This difference was only significant
in the patients receiving cisplatin and etoposide but was not significant
in the group of patients receiving cisplatin and gemcitabine. (Lissoni
2007)
A second trial from Italy enrolled 104 metastatic nonsmall cell lung
cancer patients who received chemotherapy treatment that consisted of
cisplatin and etoposide or gemcitabine alone. Patients were randomized
to receive chemotherapy alone or chemotherapy and melatonin at 20 mg
per day. The response rate to chemotherapy was higher in patients treated
with melatonin, although this difference was only significant in patients
receiving cisplatin and etoposide but not gemcitabine. Nevertheless,
one year survival was significantly higher in the patients receiving
melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)
Interleukin-2, Aldesleukin (Proleukin)
MELATONIN
Twenty-five lung cancer patients received either melatonin alone, melatonin
and interleukin-2, or interleukin-2 alone. Patients treated with melatonin
and interleukin-2 did not experience thrombocytopenia and their platelet
number was significantly higher than patients receiving interleukin-2
alone, several of whom developed thrombocytopenia. (Bregani, Lissoni
et al. 1995)
MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin,
epirubicin, medroxyprogesterone acetate (a hormonal drug that is a
progestin derived from the naturally occurring female hormone, progesterone),
recombinant IL-2, alpha-lipoic acid (300 mg per day), and N-acetyl cysteine
(1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with
stage IIIB disease, and 7 with stage IV. Of thirty patients whose results
could be measured, the median overall survival was 15 months. The one
year survival was 55.8%. The median progression free survival was 10
months. Neutropenia was the most significant symptom of toxicity from
treatment, other toxicity was low. (Mantovani, Maccio et al. 2002)
Mitomycin C & 5-Fluorouracil
VITAMIN C (ASCORBIC ACID)
In Lewis lung cancer-bearing mice, administering ascorbic acid at 1000
mg per kg twice a week together with mitomycin C and 5-fluorouracilonce
once per week was more effective than treatment with mitomycin C and
5-fluorouracil alone. (Nakano, Fujimoto et al. 1988)
COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE, MELATONIN, OR RUTIN
Rutin is a flavonoid obtained from many sources, such as from buckwheat
and the buds of the Chinese herb Saphora japonica. It is also found in
propolis.
In a laboratory study, mitomycin C-induced small cell lung cancer cell
death was inhibited by N-acetylcysteine, melatonin, and rutin. (Lee,
Park et al. 2004)
Paclitaxel (Taxol, Onxol, Abraxane)
HYALURONIC ACID
Hyaluronic acid is produced naturally in the body. It is important for
healthy joints and skin.
» Hyaluronic Acid: A typical dose is 100 mg and it is
often combined with other supplements for joint or skin health, so it
is important to read all the ingredients on the label.
Hyaluronic acid in combination with paclitaxel provides an antimetastatic
effect in mice with Lewis lung cancer. Paclitaxel alone did not result
in inhibition of metastasis as a negative 0.9% inhibition was achieved
with paclitaxel alone. However, when hyaluronic acid was added to paclitaxel,
a positive 36.3% inhibition of metastasis was achieved. (Yin, Ge et al.
2006)
MULTI-COMPOUND REGIMEN
In a human lung squamous cell carcinoma cell line, the antioxidant mixture
of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect
of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24
hours later led to an apoptosis (cancer cell killing) rate of 54%.
In contrast, the vitamins administered together with paclitaxel and
24 hours later by carboplatin led to a 70% apoptosis rate. This effect
was further enhanced to an 89% apoptosis rate by pretreatment with
the vitamins 24 hours before paclitaxel, then followed another 24 hours
later by carboplatin. (Pathak, Singh et al. 2002)
In a follow up human trial, the same combination of chemotherapy and
antioxidants was tested in 136 previously untreated patients with advanced
stage IIIB and IV non-small cell lung cancer. Patients were randomized
to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy
in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol
(vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response
(tumor size reduction) rate in the chemotherapy-only group was 33%, while
in the combination group it was 37%. The overall survival in the chemotherapy
group was 9 months and for the combination group was 11 months. Toxicity
was similar between the two groups. Although the difference in effectiveness
was not statistically significant, it may nevertheless still be clinically
significant, offering a modest improvement in treatment response and
survival. Furthermore, the result of this study does not support the
concern that these antioxidants compromise the efficacy of paclitaxel-carboplatin
combination chemotherapy. (Pathak, Bhutani et al. 2005)
RESERVATROL
Resveratrol is an antioxidant that can be derived from the red pigment
of grape skins.
» Resveratrol: Typical doses range from 25 to 250 mg per day.
A laboratory study used three different lung cancer cell lines including
lung epithelial carcinoma, non-small cell lung cancer, and giant cell
carcinoma of the lung. Pretreatment of cells with resveratrol resulted
in significant increase in the treatment effect of paclitaxel. However,
simultaneous treatment of resveratrol and paclitaxel did not result in
significant change in treatment effect. (Kubota, Uemura et al. 2003)
SELENIUM
Selenium in combination with doxorubicin or paclitaxel enhanced the chemotherapeutic
effect of doxorubicin and paclitaxel in human squamous lung cancer
cells in a laboratory study. (Vadgama, Wu et al. 2000)
COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE AND GLUTATHIONE
Glutathione is an natural antioxidant produced in the body. Nacetylcysteine
and glutathione were found to increase paclitaxel IC50 by four fold in
a laboratory study using lung cancer cells. This means that when N-acetylcysteine
and glutathione were added, the concentration of paclitaxel had to be
four times greater to achieve the same effect as paclitaxel alone. The
animal study included in the same paper found that supplementing with
N-acetylcysteine in mice with induced lung cancer negated the anticancer
treatment effect of paclitaxel. (Alexandre, Batteux et al. 2006)
Vincristine (Oncovin, Vincasar)
VITAMIN C (ASCORBIC ACID)
Two studies found that treatment with L-ascorbic acid of nonsmall cell
lung cancer cells that had developed resistance to vincristine increased
drug uptake, and partially reversed vincristine resistance. In a study
from 1995, the multi-drug resistance inhibitor drug called verapamil
had no added effect. (Song, Yang et al. 1995) (Chiang, Song et al. 1994)
Vinorelbine (Navelbine)
CURCUMIN
In a laboratory study, vinorelbine alone caused 37.9% cell death in non-small
cell lung cancer cells. However, when pretreated with curcumin 24 hours
prior to vinorelbine, the cell death rose to 61.3%, dramatically increasing
the treatment effect of vinorelbine. (Sen, Sharma et al. 2005)
PHOSPHATIDYLSERINE
Phosphatidylserine is a phospholipid found in fish, green leafy vegetables,
soybeans, and rice and is essential for neural cell membranes. It is
best known for use to increase memory.
» Phosphatidylserine: Typical dosages range from 50 to 300 mg
per day.
In a laboratory study, combined treatment with vinorelbine and phosphatidylserine
significantly delayed growth of non-small cell lung cancer compared to
vinorelbine given alone. In an animal study reported in the same paper,
adding phosphatidylserine increased growth reduction of tumors by 59%
compared to 47% with vinorelbine treatment alone. This effect was dramatically
increased to 73% tumor reduction when a unique formulation was created
with vinorelbine encapsulated by phosphatidylserine. (Webb, Johnstone
et al. 2007)
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WHAT ABOUT LUNG CANCER AND BETA-CAROTENE?
A few studies are specifically worth mentioning here, even though they
are not about combining chemotherapy and antioxidants in lung cancer
patients: Two large clinical trials testing the ability of synthetic
betacarotene to prevent lung cancer and a large cohort study at the Mayo
Clinic of vitamin and mineral use in lung cancer patients.
In the two beta-carotene studies, researchers found that supplementing
with synthetic beta-carotene resulted in increased risk for developing
lung cancer. (Omenn, Goodman et al. 1994) There are two mechanisms
that may explain this alarming finding: First, the high-dose synthetic
beta-carotene used in these studies may have functioned more as a pro-oxidant
and in both studies a high proportion of patients were smokers that
had been exposed to asbestos. Second, beta-carotene at high dosages
may cause a decrease in other protective carotenes, which may already
be low in smokers and people exposed to asbestos. Therefore, high dose
betacarotene supplementation is not advised in smokers or those who
have been exposed to asbestos. Additionally, when considering the use
of beta-carotene, a natural form is preferable to the synthetic form.
In the large cohort study from the Mayo Clinic, researchers analyzed
self-selected vitamin and mineral use in 1,129 non-small cell lung cancer
patients receiving appropriate medical treatment. They found that median
survival was 4.3 years in vitamin and mineral users, verses 2 years for
non-users. After adjustment for confounding factors, a significant survival
advantage remained. In addition, vitamin and mineral users had better
quality of life as measured by the Lung Cancer Symptom Scale (LCSS).
(Jatoi, Williams et al. 2005) A second, smaller cohort study from the
the Mayo Clinic with 178 small cell lung cancer patients, treated as
appropriate, found that there was a smaller but still statistically significant
survival advantage in vitamin and mineral users, but no improvement in
quality of life. (Jatoi, Williams et al. 2005)
Jatoi, A., B. Williams, et al. (2005). “Is voluntary vitamin and
mineral supplementation
associated with better outcome in non-small cell lung cancer patients?
Results from
the Mayo Clinic lung cancer cohort.” Lung Cancer 49(1):
77-84.
Jatoi, A., B. A. Williams, et al. (2005). “Exploring vitamin and
mineral supplementation
and purported clinical effects in patients with small cell lung cancer:
results from the
Mayo Clinic lung cancer cohort.” Nutr Cancer 51(1): 7-12.
Omenn, G. S., G. Goodman, et al. (1994). “The beta-carotene and
retinol efficacy trial
(CARET ) for chemoprevention of lung cancer in high risk populations:
smokers and
asbestos-exposed workers.” Cancer Res 54(7 Suppl): 2038s-2043s.
....................................................................................................................
REFERENCES
(1994). "The effect of vitamin E and beta carotene on the incidence of lung
cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene
Cancer Prevention Study Group." N Engl J Med 330(15): 1029-35.
Alexandre,
J., F. Batteux, et al. (2006). "Accumulation of hydrogen peroxide is an early
and crucial step for paclitaxel-induced cancer cell death both in vitro and
in vivo." Int J Cancer 119(1): 41-8.
Armas, L. A., B. W. Hollis, et al. (2004). "Vitamin
D2 is much less effective than vitamin D3 in humans." J Clin Endocrinol Metab
89(11): 5387-91.
Boik, J. (2001). Natural Compounds in Cancer Therapy. Princeton,
Oregon Medical Press.
Borska, S., E. Gebarowska, et al. (2004). "The effects
of quercetin vs cisplatin on proliferation and the apoptotic process in A549
and SW1271 cell lines in in vitro conditions." Folia Morphol (Warsz) 63(1):
103-5.
Bregani, E. R., P. Lissoni, et al. (1995). "Prevention of interleukin-2-induced
thrombocytopenia during the immunotherapy of cancer by a concomitant administration
of the pineal hormone melatonin." Recenti Prog Med 86(6): 231-3.
Chiang,
C. D., E. J. Song, et al. (1994). "Ascorbic acid increases drug accumulation
and reverses vincristine resistance of human non-small-cell lung-cancer cells." Biochem
J 301 (Pt 3): 759-64.
Conklin, K. A. (2000). "Dietary antioxidants during
cancer chemotherapy: impact on chemotherapeutic effectiveness and development
of side effects." Nutr Cancer 37(1): 1-18.
Doyle, L. A., D. D. Ross, et al.
(1995). "An etoposide-resistant lung cancer subline overexpresses the multidrug
resistance-associated protein." Br J Cancer 72(3): 535-42.
Falameeva, O.
V., O. N. Poteryaeva, et al. (2001). "Macrophage Stimulator beta-(1-->3)-D-carboxymethylglucan
improves the efficiency of chemotherapy of Lewis lung carcinoma." Bull Exp
Biol Med 132(2): 787-90.
Fic, M., M. Podhorska-Okolow, et al. (2007). "Effect
of melatonin on cytotoxicity of doxorubicin toward selected cell lines (human
keratinocytes, lung cancer cell line A-549, laryngeal cancer cell line Hep-2)." In
Vivo 21(3): 513-8.
Ghielmini, M., O. Pagani, et al. (1999). "Double-blind
randomized study on the myeloprotective effect of melatonin in combination
with carboplatin and etoposide in advanced lung cancer." Br J Cancer 80(7):
1058-61.
Hardman, W. E., M. P. Moyer, et al. (2000). "Dietary fish oil sensitizes
A549 lung xenografts to doxorubicin chemotherapy." Cancer Lett 151(2): 145-51.
Hu, S., C. P. Hu, et al. (2005). "[Examination of resistance of lung adenocarcinoma
cells to cisplatin by technetium-99m methoxyisobutyl isonitrile]." Zhonghua
Yi Xue Za Zhi 85(21): 1493-8.
Jatoi, A., B. Williams, et al. (2005). "Is
voluntary vitamin and mineral supplementation associated with better outcome
in non-small cell lung cancer patients? Results from the Mayo Clinic lung
cancer cohort." Lung Cancer 49(1): 77-84.
Jatoi, A., B. A. Williams, et al.
(2005). "Exploring vitamin and mineral supplementation and purported clinical
effects in patients with small cell lung cancer: results from the Mayo Clinic
lung cancer cohort." Nutr Cancer 51(1): 7-12.
Jonsson-Videsater, K., L. Bjorkhem-Bergman,
et al. (2004). "Selenite-induced apoptosis in doxorubicin-resistant cells
and effects on the thioredoxin system." Biochem Pharmacol 67(3): 513-22.
Kubota, T., Y. Uemura, et al. (2003). "Combined effects of resveratrol and
paclitaxel on lung cancer cells." Anticancer Res 23(5A): 4039-46.
Kuhar,
M., S. Sen, et al. (2006). "Role of mitochondria in quercetin-enhanced chemotherapeutic
response in human non-small cell lung carcinoma H-520 cells." Anticancer
Res 26(2A): 1297-303.
Kurokawa, H., K. Nishio, et al. (1997). "Effect of
glutathione depletion on cisplatin resistance in cancer cells transfected
with the gamma-glutamylcysteine synthetase gene." Jpn J Cancer Res 88(2):
108-10.
Lee, C. S., S. Y. Park, et al. (2004). "Effect of change in cellular
GSH levels on mitochondrial damage and cell viability loss due to mitomycin
c in small cell lung cancer cells." Biochem Pharmacol 68(9): 1857-67.
Li,
Y., F. Ahmed, et al. (2005). "Inactivation of nuclear factor kappaB by soy
isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic
agents in human cancer cells." Cancer Res 65(15): 6934-42.
Lissoni, P. (2007). "Biochemotherapy
with immunomodulating pineal hormones other than melatonin: 5-methoxytryptamine
as a new oncostatic pineal agent." Pathol Biol (Paris) 55(3-4): 198-200.
Lissoni, P. (2007). "Biochemotherapy with standard chemotherapies plus the
pineal hormone melatonin in the treatment of advanced solid neoplasms." Pathol
Biol (Paris) 55(3-4): 201-4.
Lissoni, P., S. Barni, et al. (1999). "Decreased
toxicity and increased efficacy of cancer chemotherapy using the pineal hormone
melatonin in metastatic solid tumour patients with poor clinical status." Eur
J Cancer 35(12): 1688-92.
Lissoni, P., M. Chilelli, et al. (2003). "Five
years survival in metastatic non-small cell lung cancer patients treated
with chemotherapy alone or chemotherapy and melatonin: a randomized trial." J
Pineal Res 35(1): 12-5.
Lissoni, P., F. Malugani, et al. (2003). "Reduction
of cisplatin-induced anemia by the pineal indole 5-methoxytryptamine in metastatic
lung cancer patients." Neuro Endocrinol Lett 24(1-2): 83-5.
Mans, D. R.,
G. J. Schuurhuis, et al. (1992). "Modulation by D,L-buthionine-S,R-sulphoximine
of etoposide cytotoxicity on human non-small cell lung, ovarian and breast
carcinoma cell lines." Eur J Cancer 28A(8-9): 1447-52.
Mantovani, G., A.
Maccio, et al. (2002). "Dose-intense phase II study of weekly cisplatin and
epidoxorubicin plus medroxyprogesterone acetate and recombinant interleukin
2 in stage IIIB-IV non-small cell lung cancer." Oncol Rep 9(3): 661-70.
McCulloch,
M., C. See, et al. (2006). "Astragalus-based Chinese herbs and platinum-based
chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized
trials." J Clin Oncol 24(3): 419-30.
Meijer, C., N. H. Mulder, et al. (1990). "The
role of glutathione in resistance to cisplatin in a human small cell lung
cancer cell line." Br J Cancer 62(1): 72-7.
Nakano, K., S. Fujimoto, et al.
(1988). "Antitumor activity of ascorbic acid in combination with antitumor
agents against Lewis lung carcinoma." In Vivo 2(3-4): 247-52.
Norsa, A. and
V. Martino (2006). "Somatostatin, retinoids, melatonin, vitamin D, bromocriptine,
and cyclophosphamide in advanced non-small-cell lung cancer patients with
low performance status." Cancer Biother Radiopharm 21(1): 68-73.
Omenn, G.
S., G. Goodman, et al. (1994). "The beta-carotene and retinol efficacy trial
(CARET) for chemoprevention of lung cancer in high risk populations: smokers
and asbestos-exposed workers." Cancer Res 54(7 Suppl): 2038s-2043s.
Pathak,
A. K., M. Bhutani, et al. (2005). "Chemotherapy alone vs. chemotherapy plus
high dose multiple antioxidants in patients with advanced non small cell
lung cancer." J Am Coll Nutr 24(1): 16-21.
Pathak, A. K., N. Singh, et al.
(2002). "Potentiation of the effect of paclitaxel and carboplatin by antioxidant
mixture on human lung cancer h520 cells." J Am Coll Nutr 21(5): 416-21.
Pelczynska,
M., J. Wietrzyk, et al. (2005). "Correlation between VDR expression and antiproliferative
activity of vitamin D3 compounds in combination with cytostatics." Anticancer
Res 25(3B): 2235-40.
Perumal, S. S., P. Shanthi, et al. (2005). "Augmented
efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with
riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants
in mitochondria." Chem Biol Interact 152(1): 49-58.
Pesic, M., J. Z. Markovic,
et al. (2006). "Induced resistance in the human non small cell lung carcinoma
(NCI-H460) cell line in vitro by anticancer drugs." J Chemother 18(1): 66-73.
Rudra, P. K. and H. E. Krokan (2001). "Cell-specific enhancement of doxorubicin
toxicity in human tumour cells by docosahexaenoic acid." Anticancer Res 21(1A):
29-38.
Sen, S., H. Sharma, et al. (2005). "Curcumin enhances Vinorelbine
mediated apoptosis in NSCLC cells by the mitochondrial pathway." Biochem
Biophys Res Commun 331(4): 1245-52.
Singh, R. P., G. U. Mallikarjuna, et
al. (2004). "Oral silibinin inhibits lung tumor growth in athymic nude mice
and forms a novel chemocombination with doxorubicin targeting nuclear factor
kappaB-mediated inducible chemoresistance." Clin Cancer Res 10(24): 8641-7.
Song, E. J., V. C. Yang, et al. (1995). "Potentiation of growth inhibition
due to vincristine by ascorbic acid in a resistant human non-small cell lung
cancer cell line." Eur J Pharmacol 292(2): 119-25.
Timmer-Bosscha, H., G.
A. Hospers, et al. (1989). "Influence of docosahexaenoic acid on cisplatin
resistance in a human small cell lung carcinoma cell line." J Natl Cancer
Inst 81(14): 1069-75.
Vadgama, J. V., Y. Wu, et al. (2000). "Effect of selenium
in combination with Adriamycin or Taxol on several different cancer cells." Anticancer
Res 20(3A): 1391-414.
Versantvoort, C. H., H. J. Broxterman, et al. (1995). "Regulation
by glutathione of drug transport in multidrug-resistant human lung tumour
cell lines overexpressing multidrug resistance-associated protein." Br J
Cancer 72(1): 82-9.
Versantvoort, C. H., G. J. Schuurhuis, et al. (1993). "Genistein
modulates the decreased drug accumulation in non-P-glycoprotein mediated
multidrug resistant tumour cells." Br J Cancer 68(5): 939-46.
Vieth, R. (1999). "Vitamin
D supplementation, 25-hydroxyvitamin D concentrations, and safety." Am J
Clin Nutr 69(5): 842-56.
Webb, M. S., S. Johnstone, et al. (2007). "In vitro
and in vivo characterization of a combination chemotherapy formulation consisting
of vinorelbine and phosphatidylserine." Eur J Pharm Biopharm 65(3): 289-99.
Wietrzyk, J., J. Boratynski, et al. (2001). "Antiangiogenic and antitumour
effects in vivo of genistein applied alone or combined with cyclophosphamide." Anticancer
Res 21(6A): 3893-6.
Yeh, P. Y., S. E. Chuang, et al. (2002). "Increase of
the resistance of human cervical carcinoma cells to cisplatin by inhibition
of the MEK to ERK signaling pathway partly via enhancement of anticancer
drug-induced NF kappa B activation." Biochem Pharmacol 63(8): 1423-30.
Yin,
D. S., Z. Q. Ge, et al. (2006). "Inhibition of tumor metastasis in vivo by
combination of paclitaxel and hyaluronic acid." Cancer Lett 243(1): 71-9.
Yoshida, T., K. Miyazawa, et al. (2003). "Apoptosis induction of vitamin
K2 in lung carcinoma cell lines: the possibility of vitamin K2 therapy for
lung cancer." Int J Oncol 23(3): 627-32.
Zaman, G. J., J. Lankelma, et al.
(1995). "Role of glutathione in the export of compounds from cells by the
multidrug-resistance-associated protein." Proc Natl Acad Sci U S A 92(17):
7690-4.
Zhang, Q., X. Kang, et al. (2006). "Antiangiogenic effect of low-dose
cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma." Biochem
Biophys Res Commun 342(3): 824-8.
Zijlstra, J. G., E. G. de Vries, et al.
(1987). "Influence of docosahexaenoic acid in vitro on intracellular adriamycin
concentration in lymphocytes and human adriamycin-sensitive and -resistant
small-cell lung cancer cell lines, and on cytotoxicity in the tumor cell
lines." Int J Cancer 40(6): 850-6.
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