Ovarian Cancer, Chemotherapy, & Antioxidants
BY JOHANNA ALTGELT, HELEN LY, and MICHAEL McCULLOCH
INTRODUCTION
Oxidative stress is a condition in animal cells where increased
free radicals are produced, or when the cell doesn't have enough antioxidants.
Oxidative stress happens in inflammation and infection, and can lead
to cellular degeneration. Oxidative stress also helps cause many types
of cancer, including ovarian cancer. One of the most important cancer
journals, the Journal of National Cancer Institute, said that ovarian
cancer is caused by inflammation. (Ness and Cottreau 1999) It is also
now known that ovarian cancer patients have increased levels of oxidative
stress and decreased levels of antioxidants, such as vitamins C and E,
in comparison to healthy controls. (Senthil, Aranganathan et al. 2004)
Chemotherapy drugs used in the treatment of ovarian cancer work, in
part, by inducing even higher levels of oxidative stress to attack cancer
cells. This increased oxidative stress also causes chemotherapy related
side effects. Oncologists have been concerned that antioxidants, which
can decrease oxidative stress, can therefore also decrease chemotherapy
treatment effectiveness or increase resistance to chemotherapy.
Using
antioxidants during chemotherapy is an important and controversial question
among health care providers, patients, and their support teams and we
have previously researched this subject thoroughly for prostate, breast,
lung, and colon cancers. In this article, we turn our focus to ovarian
cancer and have searched for published research that would support or
discourage the use of antioxidants in combination with chemotherapy.
The overwhelming majority of studies find a favorable interaction between
antioxidants and chemotherapy because antioxidants can decrease chemotherapy
side effects, increase treatment effectiveness, and decrease resistance
to chemotherapy.
No substantial clinical research has emerged to support
the assertion that antioxidants are contraindicated during chemotherapy.
The research that supports the concern about the use of antioxidants
during chemotherapy treatment does not directly combine antioxidants
and chemotherapy in human, animal, or cell culture studies. Rather, the
studies that support this view simply show that ovarian cancer cells
that are resistant to chemotherapy often have naturally higher levels
of glutathione, which is one of the body's most important and natural
antioxidants. (Zeller, Fruhauf et al. 1991; Kudoh, Kita et al. 1994;
Chen, Hutter et al. 1995; Parekh and Simpkins 1996; Akcay, Dincer et
al. 2005; Das, Bacsi et al. 2006) Glutathione can facilitate the detoxification
and excretion of many chemotherapy agents. (Akcay, Dincer et al. 2005;
Das, Bacsi et al. 2006) Buthionine sulfoximine is a chemical that lowers
glutathione levels and numerous studies also find that adding buthionine
sulfoximine sensitizes ovarian cancer cells to chemotherapy drugs. (Zeller,
Fruhauf et al. 1991; Kudoh, Kita et al. 1994; Parekh and Simpkins 1996;
Sharp, Smith et al. 1998; Lewandowicz, Britt et al. 2002) Beyond the
references provided here, many other studies have also explored this
topic with similar findings.
For this paper, we searched for clinical
or laboratory data published in peer-reviewed medical journals, conducted
by cancer researchers in universities and medical research facilities
around the world. 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.
used cancer cell cultures), used animals, or involved 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.
5-Fluorouracil
LENTINAN
Lentinan is a polysaccharide derived from the edible Japanese shiitake
mushroom (Lentinula edodes). It possesses immunostimulating antitumor
properties.
» Shiitake mushroom extracts: Typical doses range from 100 to 400 mg
per day.
A patient with recurrent ovarian cancer in the pelvis had a
partial response to cisplatin and 5-fluorouracil. She then received an
operation but the tumor could not be completely removed. Following the
operation, cisplatin no longer produced any effect against the remaining
tumor. She was then treated with lentinan (2 mg per week) and 5-fluorouracil.
Four months after the start of this therapy, the tumor, which had become
resistant to cisplatin, disappeared completely. At the time this case
report was written in 1989, the patient had resumed normal activities
and had been free of disease for six months, confirmed by physical exam,
cytologic examination, CT, scintigraphy, and B scope. (Shimizu, Hasumi
et al. 1989)
Cisplatin
ACETYL-L-CARNITINE
Acetyl-L-carnitine is an antioxidant
that comes from dietary sources, such as dairy and meat. As a supplement,
it is used for Alzheimer's, age related memory loss, cognitive deficits,
and neuropathies.
» Acetyl-L-carnitine: Typical doses range from 500 to 4000 mg. If using high
doses, taking half the dose twice daily is beneficial.
In an animal study
with rats, cisplatin or paclitaxel was combined with Acetyl-L-carnitine.
Acetyl-L-carnitine significantly reduced toxicity to the nerves of both
cisplatin and paclitaxel. In two different ovarian cancer cell lines,
Acetyl-L-carnitine did not change the anti-tumor activity of cisplatin
or paclitaxel. (Pisano, Pratesi et al. 2003)
CAFFEINE
Caffeine is one
of the most consumed drugs in the world and sources include coffee, black
tea, green tea, oolong tea, guarana, mate, and kola nut. Caffeine in
combination with pain medication can be used in treating headaches.
» Caffeine: Typical doses range from 150 mg to 600 mg. Six ounces of drip coffee
typically contains between 80 mg and 130 mg of caffeine. A double shot
of espresso typically contains between 60 mg and 100 mg of caffeine.
Caffeine
was found to significantly enhance cisplatin cytotoxicity in human ovarian
cancer cells in two different laboratory studies. (Boike, Petru et al.
1990; Schiano, Sevin et al. 1991)
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 2,000
mg daily. Take with meals, as curcumin can cause stomach upset when taken
on an empty stomach. Bioavailability and potency are increased when
combined with Bioperine, an extract from black pepper.
In two different ovarian cancer cell types, curcumin increased cisplatin
effectiveness. Curcumin was effective when added at the same time as
cisplatin, or 24 hours prior to cisplatin treatment. One of the ovarian
cancer cell lines had a high level of IL-6 (a cytokine linked to cancer,
poor prognosis, and cisplatin resistance). Curcumin inhibited the production
of IL-6 in these cells. (Chan, Fong et al. 2003)
ETHYLENEDIAMINETETRAACETIC ACID (EDTA)
EDTA is a chelating agent that binds to metals and assists in their removal
from the body.
» EDTA: The dose when used for lead poisoning is typically
administered intravenously at 50 mg per kilogram of body weight to a
maximum dose of 3 g diluted with 5% dextrose or 9% sodium chloride. Intravenously,
EDTA commonly causes abdominal cramps, anorexia, nausea, vomiting, diarrhea,
headache hypotension, exfoliative dermatitis, and a burning sensation
and pain at the site of infusion. EDTA must be administered by a qualified
health care practitioner.
When EDTA was combined with one of the chelatable elements, such as
bismuth, calcium, cadmium, copper, iron, magnesium, selenium, vanadium,
or zinc in cisplatin sensitive and resistant human ovarian cancer cells,
together with the chemotherapy drug cisplatin, the treatment effect of
cisplatin was enhanced as compared to cisplatin treatment alone. (Maier,
Purser et al. 1997)
EGCG
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in
green tea.
» EGCG: One cup of green tea contains between 10 mg and
400 mg of polyphenols depending on the source, amount of leaves used,
and steeping time. EGCG may be conveniently obtained from extracts. A
good product contains 725 mg, standardized to 98% polyphenols, 45% of
which is EGCG.
In ovarian cancer cells, EGCG increased cisplatin treatment effect.
In three different types of ovarian cancer cells (SKOV3, CAOV3, and C200),
EGCG increased the potency of cisplatin by three to six fold. (Chan,
Soprano et al. 2006)
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 1,500 mg. The recommended
dose for further research is between 100 mg and 1,100 mg. (Boik 2001)
One cup of soy milk will contain on average about 45 mg of genistein
and the other related isoflavones.
When genistein and daidzein were used in combination with cisplatin
and topotecan in five different ovarian cancer cell lines, the treatment
effect was enhanced. In combination with paclitaxel, genistein and daidzein
did not interfere with the treatment, but also did not increase the effect
of the treatment. (Gercel-Taylor, Feitelson et al. 2004)
GINSENOSIDE RH2 FROM PANAX GINSENG
Ginsenosides are active ingredients 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 mg and 1,000 mg.
In three animal studies, ginsenoside administered together with cisplatin
significantly inhibited ovarian tumor growth and prolonged survival beyond
that of cisplatin treatment given alone. Ginsenoside did not cause any
side effects. (Kikuchi, Sasa et al. 1991; Tode, Kikuchi et al. 1992;
Nakata, Kikuchi et al. 1998) One of these studies found that oral (but
not intraperitoneal) treatment with Rh2 resulted in apoptosis in tumor
cells and an increase in natural killer activity in spleen cells. (Nakata,
Kikuchi et al. 1998)
GINGER
Ginger, also known as sheng jiang or gan jiang in Chinese, is a spice
and dietary ingredient that can also be obtained as a supplement. It
is often used for motion sickness and nausea.
» Ginger: Typical dosage levels of ginger range between 2 g to
4 g daily.
In a randomized controlled crossover study, researchers at the Gynecologic
Oncology Unit of Bangkok Medical College investigated whether a daily
dose of 1,000 mg of ginger could reduce vomiting in women with ovarian
cancer receiving cisplatin chemotherapy. At the first cycle of chemotherapy,
women were randomized to either ginger or placebo, in addition to standard
anti-nausea medication. For the second cycle, women then crossed over
to the other group, so the group which first received ginger then received
placebo, and the group first on placebo switched to ginger. There was
no reduction in either nausea or vomiting with ginger treatment, however
there was less restlessness. (Manusirivithaya, Sripramote et al. 2004)
GLUTATHIONE
Glutathione is one of the most powerful and important natural antioxidants
produced in the body.
» Glutathione: Typical dosage ranges between 50 mg and
600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and
is more efficiently absorbed. When taking glutathione or N-acetyl cysteine,
combine with three times as much vitamin C to prevent these amino acids
from being oxidized in the body and to ensure their ability to act
as antioxidants.
In a double-blind, randomized trial from England, 151 patients with
ovarian cancer (stages I to IV) were given either cisplatin alone (100
mg per m2) or cisplatin combined with intravenous glutathione (3 g per
m2). The researchers' goal was to see whether
the addition of glutathione could help patients complete the planned
six cycles of cisplatin chemotherapy. They found that 58% of patients
receiving additional glutathione completed six cycles of treatment, while
only 39% of patients receiving cisplatin alone were able to complete
all six cycles. Patients in the glutathione plus cisplatin group also
had significantly less depression, vomiting, neuropathy, hair loss, shortness
of breath, difficulty concentrating, and kidney side effects. They were
also better able to continue their ordinary daytime activities. (Smyth,
Bowman et al. 1997)
In a randomized controlled trial from Italy, 31 patients with recurrent
ovarian cancer who had been in remission for at least one year were given
either cisplatin alone (50 mg per m2) or cisplatin and glutathione (2.5
g). Researchers found that 56% of patients in the glutathione group were
able to complete the full dose of chemotherapy, compared to only 27%
in the cisplatin only group. The glutathione plus cisplatin group also
experienced lower levels of neuropathy, without decreasing the anti-tumor
activity. (Colombo, Bini et al. 1995)
In a prospective, randomized study,
33 women with recurrent ovarian cancer were given cisplatin alone or
cisplatin combined with glutathione. The patients experienced minimal
neurotoxicity with no reduction in treatment effectiveness by the addition
of glutathione to cisplatin therapy. (Bogliun, Marzorati et al. 1992)
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 2 am. To do so, one can take
the melatonin at bedtime, ideally between 9 pm and 10 pm.
In cisplatin-sensitive and resistant ovarian cancer cells, melatonin
enhanced cisplatin treatment effectiveness. (Futagami, Sato et al. 2001)
PROTEIN-BOUND POLYSACCHARIDE-K (PSK)
Polysaccharide-K (PSK) is extracted from a mushroom called turkey tail.
Other names include Trametes versicolor and Coriolus versicolor (Latin),
yun zhi (Chinese), and kawaratake (Japanese). It is commonly used to
boost immune health and often used with cancer patients.
» PSK: Typical doses for cancer patients range between
2 g and 6 g.
In human ovarian cancer cells, PSK was found to enhance the treatment
effect of cisplatin in a laboratory study. (Kobayashi, Kariya et al.
1994)
QUERCETIN
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, inhibits allergic and inflammatory reactions,
and has strong antioxidant activity.
» Quercetin: Typical dosages range from 200 mg to 1,200
mg daily.
Quercetin increased the treatment effect of cisplatin in ovarian cancer
cells. (Scambia, Ranelletti et al. 1990) In another laboratory study,
when quercetin and genistein were combined, their anticancer effect was
greater than either antioxidant used alone. (Shen and Weber 1997)
RESVERATROL
Resveratrol is an antioxidant derived from the red pigment of grape skins.
» Resveratrol: Typical doses range from 25 mg to 250 mg per day.
Resveratrol in combination with either cisplatin or doxorubicin increased
the treatment effect in ovarian and uterine cancer cells. In addition,
resveratrol protected rats from doxorubicininduced heart toxicity. (Rezk,
Balulad et al. 2006)
RUTIN AND HESPERIDIN
The flavonoid rutin can be obtained from sources such as buckwheat, the
buds of the Chinese herb Sophora japonica, and propolis. Hesperidin
is a flavonoid found in citrus fruits, such as lemons and oranges.
» Rutin: Typical doses range from 500 mg to 1,000 mg daily.
» Hesperidin: Typical doses range from 10 mg to 100 mg.
Rutin and hesperidin had no effect on ovarian cancer cells, either alone
or in combination with cisplatin. (Scambia, Ranelletti et al. 1990)
SELENIUM
Selenium is an essential trace mineral 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.
Mice with ovarian tumors did not develop drug resistance to cisplatin
treatment when they were also treated with selenite or selenomethionine.
In contrast, when mice did not receive supplements, and only received
cisplatin treatment, they quickly developed drug resistance. Selenite
was found to enhance cisplatin treatment in ovarian tumors. Treatment
with sulfite or methionine did not affect resistance to cisplatin.
(Caffrey and Frenkel 2000; Frenkel and Caffrey 2001)
SILYBIN
Silybin (also called silibinin) is an important active compound found
in silymarin, extracted from blessed milk thistle (Silybum marianum).
» Silymarin: 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. 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 (40.5 mg).
When silybin was used together with cisplatin in human ovarian cancer
cells, there was a statistically significant increase in treatment effectiveness.
In mice with ovarian cancer, tumor weight inhibition increased from 80%
in mice treated with cisplatin alone to 90% in mice treated with a combination
of silybin and cisplatin. Mice receiving a combination of silybin and
cisplatin also recovered earlier in regards to weight loss compared to
mice treated with cisplatin alone. Antiangiogenic (reduction in blood
supply to the tumor) effect of silybin was also demonstrated. (Giacomelli,
Gallo et al. 2002) In a second study, silybin was found to increase the
effect of cisplatin in ovarian cancer cells resistant to cisplatin. (Scambia,
De Vincenzo et al. 1996)
VITAMIN B3
Niacin (nicotinic acid) and niacinamide (nicotinamide) are two forms
of vitamin B3. Dietary sources include poultry, fish, eggs, peanuts,
brewers yeast, rice bran, wheat bran, legumes, mushrooms, and nuts.
» Vitamin B3: Typical doses can range between 100 mg
and 1200 mg per day. Slow dose escalation is essential to acclimate the
body to the “niacin flush.” Some people find that the niacinamide
version does not cause flush.
In a laboratory study using cisplatin-resistant rat ovarian tumor cells,
vitamin B3 significantly enhanced the treatment effect of cisplatin.
However, this same treatment had no substantial effect on the cisplatin-sensitive
rat ovarian tumor cells. In the live animal part of the same study, cisplatin
given alone had no antitumor activity in the resistant tumor. When vitamin
B3 was added, the survival time increased almost 50% in the group receiving
both cisplatin and vitamin B3. (Chen and Zeller 1993)
VITAMIN E
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 oils) and 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.
Researchers from Italy's National Cancer Institute conducted a
study in which they randomized 47 patients to receive either vitamin
E (alpha-tocopherol, 300 mg per day) during cisplatin chemotherapy or
cisplatin alone. Vitamin E was given orally before cisplatin chemotherapy
and continued for three months after completion of treatment. Twenty-seven
patients completed six cycles of cisplatin chemotherapy. The vitamin
E plus cisplatin group had significantly less neurotoxicity compared
to the chemotherapy alone group. Severity of neurotoxicity was also significantly
lower. Addition of vitamin E also did not reduce anti-tumor effectiveness
of cisplatin or longevity. (Pace, Savarese et al. 2003)
Carboplatin and Cisplatin
GLUTATHIONE
Researchers at the National Institute for the Study and Cure of Cancer
in Milan, Italy published a study in which they tested whether glutathione
can reduce side effects and increase effectiveness of high-dose carboplatin
and cisplatin chemotherapy. In this study, fifty consecutive eligible
patients with previously untreated stage III or IV ovarian cancer received
two cycles of cisplatin and carboplatin chemotherapy, followed by surgery,
and again two cycles of chemotherapy. Patients received glutathione (2,500
mg) before each cisplatin or carboplatin treatment. The toxicity was
moderate with lack of significant kidney toxicity. In this group of patients,
median survival was 48 months, better than would have been expected if
treating with chemotherapy alone. (Bohm, Oriana et al. 1999)
Cisplatin and Paclitaxel
VITAMIN E
Peripheral neuropathy, or damage to the nerves in the hands and feet,
can be a painful and sometimes long-lasting side effect of chemotherapy
treatment, making walking and handling objects with the hands more
difficult. Paclitaxel and the family of platinum chemotherapy drugs
are the most likely to cause this often debilitating problem. In a
randomized controlled trial, researchers at the University of Patras
Medical Center in Greece tested the ability of vitamin E at a daily dose
of 600 mg (900 IU) to prevent neuropathy caused by six courses of cisplatin
and/or paclitaxel. The sixteen patients in the treatment group received
vitamin E during chemotherapy and continuing for three months after that
treatment ended, while the fifteen patients in the control group received
no vitamin E. The risk of developing peripheral neuropathy was reduced
by 66% in the group receiving vitamin E. It is important to add that
the research team also did a pre-clinical animal study, which showed
that in mice, vitamin E did not interfere with the ability of cisplatin
to suppress tumor growth or increase life span. (Argyriou, Chroni et
al. 2005)
Cyclophosphamide
GINSENOSIDE RG 3
In an animal study using mice with ovarian cancer, ginsenoside Rg3 was
used in combination with cyclophosphamide. Mice treated with this combination
lived longer and tumor inhibition was higher than mice receiving chemotherapy
alone. The combination of ginsenoside Rg3 and cyclophosphamide decreased
blood supply to the tumor more than cyclophosphamide alone. Mice receiving
ginsenoside Rg3 alone had even greater decrease in blood supply to
the tumor than mice receiving chemotherapy alone or a combination of
chemotherapy and ginsenoside Rg3. (Xu, Xin et al. 2007)
Cisplatin and Cyclophosphamide
SELENIUM, VITAMIN E, VITAMIN C, BETA-CAROTENE,
RIBOFLAVIN, AND NIACIN
In a pilot clinical study, the dietary supplement Protecton Zellactiv
(Smith Kline Beecham, Germany), which contains selenium (200 mcg daily),
vitamin E, beta-carotene, riboflavin, niacin, and vitamin C was used
together with chemotherapy. Researchers from Pomeranian Academy of Medicine
in Poland investigated whether the Protecton Zellactiv could influence
oxidative stress, glutathione levels, or reduce side effects in women
with ovarian cancer receiving cisplatin and cyclophosphamide chemotherapy.
Women using this dietary supplement experienced significantly less nausea,
vomiting, diarrhea, mouth sores, hair loss, flatulence, abdominal pain,
weakness, malaise, or loss of appetite. Researchers also found an increase
in glutathione peroxidase, which may have helped protect those women
against chemotherapy toxicity. (Sieja and Talerczyk 2004)
GLUTATHIONE
In a phase II study from Italy, researchers gave 20 women with stage
III or IV ovarian cancer a combination of cisplatin (45 mg per m2),
cyclophosphamide (900 mg per m2), and intravenous glutathione (2,500
mg). Of these women, 55% achieved a complete response. Median survival
was 26.5 months. At 35 month followup, five patients were still alive.
There was little toxicity in general, and no kidney toxicity. (Locatelli,
D'Antona
et al. 1993)
In a clinical study from Italy, 79 women with stage III or IV ovarian
cancer were treated with up to five courses of high-dose cisplatin (40
mg per m2 daily in normal saline, for four days) plus glutathione (2,500
mg as a short-term infusion before cisplatin), together with cyclophosphamide
(600 mg per m2 as an i.v. bolus on day four). Of these women, 57% achieved
a complete response and 25% achieved a partial response. These benefits
were seen with only minimal toxicity, with severe neuropathy side effects
occurring in only 4% of these women. (Di Re, Bohm et al. 1993)
In study of high-dose cisplatin (160 mg per m2) and cyclophosphamide
(600 mg per m2) plus glutathione, 32 women with ovarian cancer were examined
for neurotoxicity. After five courses of chemotherapy, no cases of
disabling neuropathy were observed. (Pirovano, Balzarini et al. 1992)
In a pilot study, twelve patients with localized or stage III ovarian
cancer were treated with cisplatin (90 mg per m2, i.v. in 250 ml of normal
saline over 30 minutes), cyclophosphamide (600 mg per m2 i.v.) every
3 weeks, and glutathione (5 g in 200 ml of normal saline) prior to cisplatin.
No cases of kidney toxicity or neurotoxicity were seen. Nine of 11 evaluable
patients with stage III ovarian cancer achieved complete remission. (Bohm,
Battista Spatti et al. 1991)
Forty consecutive patients with stage III and IV ovarian carcinoma were
treated with cisplatin (40 mg per m2 daily for four consecutive days),
cyclophosphamide (600 mg per m2 on day four) and glutathione (1,500 mg
per m2, which is roughly equivalent to 37.5 mg per kg, based on a conversion
using median height of 175 cm and median weight of 80 kg). Glutathione
was administered over 15 minutes before each cisplatin treatment. This
treatment was given every three to four weeks for five courses providing
no severe toxicity or progression occurred. Surgery was performed on
18 patients prior to chemotherapy. After two to three courses of chemotherapy,
16 other patients received surgery. Surgery could not be carried out
in six patients. Three patients were not evaluable for response because
they discontinued treatment. Twenty-three patients (62%) achieved complete
clinical remission. The overall (complete plus partial) response rate
was 86%. Two patients achieved disease free status after a second surgery.
Patients experienced some nausea and vomiting. Myelosuppression (a condition
in which bone marrow activity is decreased, resulting in fewer red blood
cells, white blood cells, and platelets) was acceptable. There was no
renal impairment (likely because of the protective effect from glutathione).
Neurotoxicity was the most significant cumulative toxicity, however it
was not associated with motor dysfunction. It occurred in 24 out of 32
patients who received four to five courses. (Di Re, Bohm et al. 1990)
In a non-randomized study, 15 consecutive patients with ovarian cancer
were treated with cisplatin and cyclophosphamide or the same regimen
in combination with reduced glutathione (1,500 mg per m2, which is roughly
equivalent to 37.5 mg per kg, based on a conversion using median height
of 175 cm and median weight of 80 kg). Glutathione was administered prior
to each chemotherapy treatment to seven patients. The efficacy of chemotherapy
treatment was equal in both groups and therefore it was not reduced by
glutathione pretreatment. Severity of myelosupression was reduced with
glutathione. Two patients who received chemotherapy alone developed transient
nephrotoxicity (toxicity to the nerves) while no patients receiving glutathione
developed nephrotoxicity. (Oriana, Bohm et al. 1987)
Cisplatin and Hexamethylmelamine
VITAMIN B6 (PYRIDOXINE)
Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna,
spinach, banana, lentils, and potatoes.
» Vitamin B6: Typical doses range between 10 mg and 200
mg per day. Individuals using more than 100 mg per day for more than
two months should be supervised by a health care professional as chronic
overdose may lead to sensory neuropathy.
A randomized clinical trial included 248 patients with stage III to
IV ovarian epithelial cancer. Of these, 114 patients had prior chemotherapy
and 134 did not. They were randomized to one of four cisplatin and hexamethylmelamine
regimens. Hexamethylmelamine was given at 200 mg per m2 orally on days
8 to 21 of each 21 day cycle. Cisplatin was given at two doses of 37.5
mg per m2 or 75 mg per m2. Half of the patients were randomized to also
receive vitamin B6 at a dose of 300 mg per m2 (which is roughly equivalent
to 7.5 mg per kg, based on a conversion using median height of 175 cm
and median weight of 80 kg) orally on days 1 to 21. The overall response
rate was 54% and 25% achieved a complete response. Patients receiving
the higher dose of cisplatin had a greater response rate of 61%, while
patients receiving lower doses had a response rate of 47%. The median
response duration was 8.3 months. Response duration was shortened in
the vitamin B6 group of patients and thus had an unfavorable effect on
treatment effectiveness. Patients treated with higher dose cisplatin
had more nausea and vomiting as well as increased neurotoxicity. Vitamin
B6 significantly reduced neurotoxicity.
Doxorubicin
7-MONOHYDROXYETHLRUTOSIDE (MONOHER)
Flavonoids are beneficial antioxidants found in fruits and vegetables,
especially red grape juice, green tea, soy, and many other legumes.
One potential useful example of a beneficial flavonoid is monoHER, one
of the most powerfully active antioxidants in flavonoid products, such
as Venoruton, which is used to treat varicose veins. (van Acker and
Boven, 1997) MonoHER is a derivative of the flavonoid rutin, obtained
from many sources, such as buckwheat and the buds of the Chinese herb Saphora
japonica. It is also found in propolis.
» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.
The flavonoid monohydroxyethylrutoside (monoHER) prevented heart cell
damage from doxorubicin by 15 fold. However, monoHER may also protect
ovarian cancer cells from being effectively treated by doxorubicin. Specifically,
monoHER reduced doxorubicin effectiveness in one type of ovarian cancer
cell culture (A2780) and did not interfere with doxorubicin treatment
in another ovarian cancer cell line (OVCAR-3). In practical terms, this
means that monoHER used at high concentrations as demonstrated in this
study has the potential to decrease the effectiveness of doxorubicin
treatment. The authors of this study note that lower concentrations of
monoHER, which are more realistic in clinical use, do not influenced
the antitumor activity of doxorubicin. (Bruynzeel, Abou El Hassan et
al. 2007)
In a combined laboratory and animal study, monoHER protected mice against
doxorubicin-induced cardiotoxicity. Furthermore, monoHER did not interfere
with the treatment effect of doxorubicin in human ovarian cancer cells
or in mice with ovarian cancer. (van Acker, Boven et al. 1997)
TOPICAL 99% DIMETHYL SULFOXIDE (DMSO)
Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp.
» Dimethyl sulfoxide (DMSO): This product is used topically
in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin
prior to use is essential. Drying of the skin can occur. This should
be a practitioner-guided approach.
Two patients with recurrent ovarian cancer receiving pegylated liposomal
doxorubicin chemotherapy at the University of Arizona developed the painfully
debilitating side effect called hand-foot syndrome, at the severe intensity
level of grade 3. Their symptoms resolved over a period of one to three
weeks while receiving topical 99% DMSO four times daily for 14 days.
(Lopez, Wallace et al. 1999)
SPIRULINA
Spirulina is blue green algae that grows in tropical and subtropical
alkaline waters with high-salt content. It is a rich source of dietary
protein, B-vitamins, and iron.
» Spirulina: Typical doses range from 250 mg to 5 grams per day.
Spirulina did not interfere with the treatment effect of cisplatin in
ovarian cancer cells. Additionally, spirulina protected rats from cisplatin-induced
toxicity to the kidneys. The spirulina was given four days prior to chemotherapy
treatment, on the day of chemotherapy, and four days after. (Mohan, Khan
et al. 2006)
When mice were treated with spirulina (orally) along with doxorubicin,
they were significantly protected from doxorubicininduced damage to the
heart. They also had lower mortality: only 26% compared to 53% in mice
treated with doxorubicin alone. In the laboratory portion of the study,
spirulina did not reduce the anti-tumor activity of doxorubicin in ovarian
cancer cells. (Khan, Shobha et al. 2005)
THEANINE
Theanine is an amino acid that is used for its anti-anxiety calming effects.
Dietary sources include green tea as well as the edible Bay Bolete
mushroom (Boletus badius).
» Theanine: Typical doses range from 50 mg to 200 mg per day.
In an animal study, mice with ovarian cancer were treated with either
adriamycin alone or with adriamycin in combination with theanine. Adriamycin
alone did not inhibit tumor growth. In contrast, when the same dose of
adriamycin was used with theanine, tumor weight was reduced to 62% of
the control level. When combined with theanine, the concentration of
adriamycin in the tumor increased by 2.7 fold, however adriamycin concentrations
in normal tissue decreased. (Sugiyama and Sadzuka 1998)
In a second animal study with mice with ovarian sarcoma, theanine was
used in combination with doxorubicin. The combination enhanced reduction
of metastasis to the liver. In the laboratory portion of the study, theanine
increased the concentration of doxorubicin in ovarian cancer cells. (Sugiyama
and Sadzuka 1999)
VITAMIN E
In 2004, a group of clinicians at New York's Memorial Sloan-Kettering
Cancer Center reported on the case of a women with ovarian cancer receiving
the new chemotherapy drug pegylated liposomal doxorubicin in combination
with vitamin E. This patient was experiencing significant vaginal irritation
and burning, which began several days after her first round of chemotherapy.
She was advised to avoid intercourse for three to five days after chemotherapy
and to use both intravaginal vitamin E suppositories three times per
week and vaginal estrogen tablets (initial course of 14 days followed
by twice weekly usage), use of lubricants (Astroglide) during intercourse,
and counseling. This combination approach allowed her to resume intercourse
throughout the rest of her chemotherapy treatment. (Krychman, Carter
et al. 2004)
Docetaxel
CURCUMIN
In mice with ovarian cancer, the combination of curcumin and docetaxel
was more effective than docetaxel alone. Tumor mass was reduced by
66% compared to docetaxel therapy alone . In mice with ovarian cancer
(which had developed resistance to docetaxel), treatment with docetaxel
did not reduce tumor growth. Treatment with a combination of docetaxel
and curcumin resulted in 58% tumor reduction. Docetaxel alone did not
reduce angiogenesis, but when combined with curcumin, angiogenesis
was reduced. Interestingly, curcumin alone had the strongest effect
in reducing angiogenesis. This study found that one of the mechanisms
by which curcumin controls cancer cell growth is by inhibition of NF-kappaB.
(Lin, Kunnumakkara et al. 2007) Activation of NF-kappaB, a protein
complex, is not favorable in cancer treatment as it leads to cellular
events that promote inflammation, cell proliferation, angiogenesis,
metastasis, and discourages cell death. NF-kappaB is associated with
cancer risk, poor prognosis, and contributes to chemotherapy resistance.
(Lee, Jeon et al. 2007; Sethi, Sung et al. 2008)
Irinotecan and Topotecan
GENISTEIN
In a cell culture study, genistein was used in combination with either
irinotecan or topotecan. Genistein enhanced the treatment effect of
these two chemotherapy drugs in ovarian as well as cervical cancer
cells. (Papazisis, Kalemi et al. 2006)
Melphalan
SELENITE
In an animal study using mice with ovarian tumors, intraperitoneal injection
of selenite (another form of selenium) prevented the development of
resistance to melphalan as well as cisplatin. Selenite injection prevented
increase in cellular glutathione. The method of selenite administration
was important. When administered in drinking water or injected subcutaneously,
selenite had little effect on the development of resistance. (Caffrey,
Zhu et al. 1998) In a laboratory study by the same authors, Selenite
was found to completely prevent ovarian cancer cell resistance to melphalan.
(Caffrey, Zhu et al. 1998)
Forty patients with ovarian cancer had significantly lower selenium
levels than matched control subjects. Higher stage of disease was associated
with lower selenium levels. Patients with progressive disease had lower
selenium levels than patients in remission. (Sundstrom, Yrjanheikki et
al. 1984)
COMBINATIONS TO AVOID :
GLUTAMINE, LEUCINE, METHIONINE, AND TYROSINE
In human ovarian cancer cells, the amino acids glutamine, tyrosine, methionine,
and leucine significantly reduced uptake of melphalan thereby decreasing
effectiveness of treatment. (Vistica, Von Hoff et al. 1981; Dufour, Panasci
et al. 1985)
Paclitaxel
COMBINATIONS TO AVOID: N-ACETYLCYSTEINE
In ovarian cancer cells, the antioxidant N-acetylcysteine decreased paclitaxel-induced
cell death. (Goto, Takano et al. 2008)
Paclitaxel and Carboplatin
VITAMIN C, VITAMIN E, AND COENZYME Q10
Vitamin C, also called ascorbic acid, is a nutrient that humans cannot
synthesize and must obtain from food. 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.
Coenzyme Q10 (CoQ10) is naturally synthesized in the body and is also
available from food sources such as meat, poultry, fish, nuts, vegetables,
fruits, and dairy. The amount of CoQ10 obtained from food is quite small
compared to taking a supplement. The average intake of CoQ10 from food
is less than 10 mg per day.
» Coenzyme Q10: Oil softgels have higher absorption. Typical daily
doses of CoQ10 range from 30 mg to 300 mg and is best taken with food.
About three weeks of daily dosing are necessary to reach maximal serum
concentrations of CoQ10. Bioavailability is increased when combined with
piperine. The most advanced version of CoQ10 is the more highly absorbable
version called Ubiquinol.
Researchers in the Department of Obstetrics and Gynecology at University
of Kansas Medical Center published a remarkable case report of two women
with stage III-C ovarian cancer being treated with carboplatin and paclitaxel.
The first woman began high-dose antioxidant therapy during her first
round of chemotherapy, consisting of vitamin C, vitamin E, beta-carotene,
CoQ10, a multivitamin/mineral complex, and intravenous vitamin C at a
total dose of 60 g given twice weekly at the end of her carboplatin chemotherapy
and prior to paclitaxel. Her CA-125 levels normalized after her first
cycle of chemotherapy and remained normal at the time of publication,
three and a half years after diagnosis. She also had no evidence of disease
on CT scans of her abdomen and pelvis.
The second woman added antioxidants just prior to beginning chemotherapy,
including vitamin C, beta-carotene, vitamin E, coenzyme Q10, and a multivitamin/mineral
complex. At the completion of her six cycles of paclitaxel/carboplatinum
chemotherapy, even though scans showed she still had remaining tumors,
she refused further chemotherapy. She switched to intravenous ascorbic
acid at 60 g twice weekly. Three years after diagnosis, she has normal
CA-125 and no evidence of recurrent disease on physical exam. (Drisko,
Chapman et al. 2003) Based on the successful treatment with these two
patients, this team at the University of Kansas has initiated a non-randomized
trial in which vitamin C is being combined with chemotherapy. For information,
contact Jeanne Drisko, MD, at (913) 588-6104.
VITAMIN E AND VITAMIN A
Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for
bone growth and vision. Vitamin A 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.
The natural levels of antioxidants in the body in 28 ovarian and breast
cancer patients were measured in a study to determine if decreased antioxidants
correlate with toxicity from paclitaxel and carboplatin chemotherapy.
The antioxidants that were measured were vitamin E (alpha-tocopherol)
and vitamin A (retinol). Note that these antioxidants were not given
as supplements, rather the natural level of these antioxidants was
measured before and after chemotherapy and the amount varied among
patients. There was a significant increase in vitamin E and vitamin
A during chemotherapy treatment. Patients who experienced significant
side effects from chemotherapy had low levels of vitamins A and E.
Patients who had significantly higher levels of these vitamins during
chemotherapy did not experience serious toxicity. (Melichar, Kalabova
et al. 2007)
Antioxidants Used Alone
QUECETIN
In a phase I clinical trial of the flavonoid quercetin, researchers from
Birmingham, UK gave quercetin by intravenous infusion at escalating
doses at three week intervals, starting at 60 mg per m2 and increasing
to 1,700 mg per m2 (which is roughly equivalent to 1.5 and 42 mg per
kg respectively, based on a conversion using median height of 175 cm
and median weight of 80 kg). At the highest dose, dose-limiting kidney
toxicity occurred but there was no suppression of blood-cell production
in the bone marrow. Overall, two of ten patients had kidney toxicity
at the highest dose. The dose with the optimum ratio of effectiveness
and safety was 945 mg per m2 (23.6 mg per kg) (eight at three week intervals
and six at weekly intervals). From among these patients, one was a woman
with ovarian cancer resistant to cisplatin. Following two courses of
quercetin (420 mg per m2 or 10.5 mg per kg), the CA 125 had fallen from
295 to 55 units per ml. The researchers concluded that quercetin can
be safely administered by intravenous bolus. They also saw inhibition
of lymphocyte tyrosine kinase activity and evidence of antitumor activity.
(Ferry, Smith et al. 1996)
Top of Page
....................................................................................................................
REFERENCES
Akcay, T., Y. Dincer, et al. (2005). "Significance of the O6-methylguanine-DNA
methyltransferase and glutathione S-transferase activity in the sera of patients
with malignant and benign ovarian tumors." Eur J Obstet Gynecol Reprod
Biol 119(1): 108-13.
Argyriou, A. A., E. Chroni, et al. (2005). "Vitamin E for prophylaxis
against chemotherapy-induced neuropathy: a randomized controlled trial." Neurology
64(1): 26-31.
Bogliun, G., L. Marzorati, et al. (1992). "Evaluation by
somatosensory evoked potentials of the neurotoxicity of cisplatin alone or
in combination with glutathione." Ital J Neurol Sci 13(8): 643-7.
Bohm,
S., G. Battista Spatti, et al. (1991). "A feasibility study of
cisplatin administration with low-volume hydration and glutathione protection
in the treatment of ovarian carcinoma." Anticancer Res 11(4): 1613-6.
Bohm,
S., S. Oriana, et al. (1999). "Dose intensification of platinum
compounds with glutathione protection as induction chemotherapy for advanced
ovarian carcinoma." Oncology 57(2): 115-20.
Boike, G. M., E. Petru, et
al. (1990). "Chemical enhancement of cisplatin
cytotoxicity in a human ovarian and cervical cancer cell line." Gynecol
Oncol 38(3): 315-22.
Caffrey, P. B. and G. D. Frenkel (2000). "Selenium
compounds prevent the induction of drug resistance by cisplatin in human
ovarian tumor xenografts in vivo." Cancer Chemother Pharmacol 46(1):
74-8.
Caffrey, P. B., M. Zhu, et al. (1998). "Prevention of the development
of melphalan resistance in vitro by selenite." Biol Trace Elem Res 65(3):
187-95.
Chan, M. M., D. Fong, et al. (2003). "Inhibition of growth and
sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic
chemopreventive agents." J Cell Physiol 194(1): 63-70.
Chen, G., K. J.
Hutter, et al. (1995). "Positive correlation between
cellular glutathione and acquired cisplatin resistance in human ovarian cancer
cells." Cell Biol Toxicol 11(5): 273-81.
Chen, G. and W. J. Zeller (1993). "Reversal
of acquired cisplatin resistance by nicotinamide in vitro and in vivo." Cancer
Chemother Pharmacol 33(2): 157-62.
Colombo, N., S. Bini, et al. (1995). "Weekly
cisplatin +/- glutathione in relapsed ovarian carcinoma." Int J Gynecol
Cancer 5(2): 81-86.
Das, G. C., A. Bacsi, et al. (2006). "Enhanced gamma-glutamylcysteine
synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity." Mol
Carcinog 45(9): 635-47.
Di Re, F., S. Bohm, et al. (1993). "High-dose
cisplatin and cyclophosphamide with glutathione in the treatment of advanced
ovarian cancer." Ann Oncol
4(1): 55-61.
Di Re, F., S. Bohm, et al. (1990). "Efficacy and safety
of high-dose cisplatin and cyclophosphamide with glutathione protection in
the treatment of bulky advanced epithelial ovarian cancer." Cancer Chemother
Pharmacol 25(5): 355-60.
Drisko, J. A., J. Chapman, et al. (2003). "The
use of antioxidants with first-line chemotherapy in two cases of ovarian
cancer." J Am Coll Nutr
22(2): 118-23.
Dufour, M., L. C. Panasci, et al. (1985). "Effects of
amino acids on the transport and cytotoxicity of melphalan by human bone
marrow cells and human tumor cells." Cancer Chemother Pharmacol 15(2):
125-31.
Ferry, D. R., A. Smith, et al. (1996). "Phase I clinical trial
of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine
kinase inhibition." Clin Cancer Res 2(4): 659-68.
Frenkel, G. D. and
P. B. Caffrey (2001). "A prevention strategy for
circumventing drug resistance in cancer chemotherapy." Curr Pharm Des
7(16): 1595-614.
Futagami, M., S. Sato, et al. (2001). "Effects of melatonin
on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity
of cultured human ovarian cancer cells." Gynecol Oncol 82(3): 544-9.
Gercel-Taylor,
C., A. K. Feitelson, et al. (2004). "Inhibitory effect
of genistein and daidzein on ovarian cancer cell growth." Anticancer
Res 24(2B): 795-800.
Giacomelli, S., D. Gallo, et al. (2002). "Silybin
and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro
and in vivo the activity of cisplatin." Life Sci 70(12): 1447-59.
Goto,
T., M. Takano, et al. (2008). "The involvement of FOXO1 in cytotoxic
stress and drug-resistance induced by paclitaxel in ovarian cancers." Br
J Cancer 98(6): 1068-75.
Khan, M., J. C. Shobha, et al. (2005). "Protective
effect of Spirulina against doxorubicin-induced cardiotoxicity." Phytother
Res 19(12): 1030-7.
Kikuchi, Y., H. Sasa, et al. (1991). "Inhibition
of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and
adjuvant effects to cisplatin in vivo." Anticancer Drugs 2(1): 63-7.
Kobayashi,
Y., K. Kariya, et al. (1994). "Enhancement of anti-cancer
activity of cisdiaminedichloroplatinum by the protein-bound polysaccharide
of Coriolus versicolor QUEL (PS-K) in vitro." Cancer Biother 9(4): 351-8.
Krychman,
M. L., J. Carter, et al. (2004). "Chemotherapy-induced dyspareunia:
a case study of vaginal mucositis and pegylated liposomal doxorubicin injection
in advanced stage ovarian carcinoma." Gynecol Oncol 93(2): 561-3.
Kudoh,
K., T. Kita, et al. (1994). "[Potentiation of cisplatin sensitivity
of cisplatin-resistant human ovarian cancer cell lines by L-buthionine-S,R-sulfoximine]." Nippon
Sanka Fujinka Gakkai Zasshi 46(6): 525-32.
Lewandowicz, G. M., P. Britt, et
al. (2002). "Cellular glutathione content,
in vitro chemoresponse, and the effect of BSO modulation in samples derived
from patients with advanced ovarian cancer." Gynecol Oncol 85(2): 298-304.
Locatelli,
M. C., A. D'Antona, et al. (1993). "A phase II study of combination
chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide
plus reduced glutathione as potential protective agent against cisplatin
toxicity." Tumori 79(1): 37-9.
Lopez, A. M., L. Wallace, et al. (1999). "Topical
DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar
erythrodysesthesia." Cancer
Chemother Pharmacol 44(4): 303-6.
Maier, R. H., S. M. Purser, et al. (1997). "The
cytotoxic interaction of inorganic trace elements with EDTA and cisplatin
in sensitive and resistant human ovarian cancer cells." In Vitro Cell
Dev Biol Anim 33(3): 218-21.
Manusirivithaya, S., M. Sripramote, et al. (2004). "Antiemetic
effect of ginger in gynecologic oncology patients receiving cisplatin." Int
J Gynecol Cancer 14(6): 1063-9.
Melichar, B., H. Kalabova, et al. (2007). "Serum
alpha-tocopherol, retinol and neopterin during paclitaxel/carboplatin chemotherapy." Anticancer
Res 27(6C): 4397-401.
Nakata, H., Y. Kikuchi, et al. (1998). "Inhibitory
effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian
cancer cells." Jpn
J Cancer Res 89(7): 733-40.
Ness, R. B. and C. Cottreau (1999). "Possible
role of ovarian epithelial inflammation in ovarian cancer." J Natl Cancer
Inst 91(17): 1459-67.
Oriana, S., S. Bohm, et al. (1987). "A preliminary
clinical experience with reduced glutathione as protector against cisplatin-toxicity." Tumori
73(4): 337-40.
Pace, A., A. Savarese, et al. (2003). "Neuroprotective
effect of vitamin E supplementation in patients treated with cisplatin chemotherapy." J
Clin Oncol 21(5): 927-31.
Parekh, H. and H. Simpkins (1996). "Cross-resistance
and collateral sensitivity to natural product drugs in cisplatin-sensitive
and -resistant rat lymphoma and human ovarian carcinoma cells." Cancer
Chemother Pharmacol 37(5): 457-62.
Pirovano, C., A. Balzarini, et al. (1992). "Peripheral
neurotoxicity following high-dose cisplatin with glutathione: clinical and
neurophysiological assessment." Tumori 78(4): 253-7.
Pisano, C., G. Pratesi,
et al. (2003). "Paclitaxel and Cisplatin-induced
neurotoxicity: a protective role of acetyl-L-carnitine." Clin Cancer
Res 9(15): 5756-67.
Scambia, G., R. De Vincenzo, et al. (1996). "Antiproliferative
effect of silybin on gynaecological malignancies: synergism with cisplatin
and doxorubicin." Eur
J Cancer 32A(5): 877-82.
Scambia, G., F. O. Ranelletti, et al. (1990). "Synergistic
antiproliferative activity of quercetin and cisplatin on ovarian cancer cell
growth." Anticancer
Drugs 1(1): 45-8.
Schiano, M. A., B. U. Sevin, et al. (1991). "In vitro
enhancement of cis-platinum antitumor activity by caffeine and pentoxifylline
in a human ovarian cell line." Gynecol Oncol 43(1): 37-45.
Senthil, K.,
S. Aranganathan, et al. (2004). "Evidence of oxidative
stress in the circulation of ovarian cancer patients." Clin Chim Acta
339(1-2): 27-32.
Sharp, S. Y., V. Smith, et al. (1998). "Lack of a role
for MRP1 in platinum drug resistance in human ovarian cancer cell lines." Br
J Cancer 78(2): 175-80.
Shen, F. and G. Weber (1997). "Synergistic action
of quercetin and genistein in human ovarian carcinoma cells." Oncol
Res 9(11-12): 597-602.
Shimizu, Y., K. Hasumi, et al. (1989). "[Successful
treatment of a patient with recurrent ovarian cancer by lentinan combined
with intraarterial 5FU]." Nippon
Gan Chiryo Gakkai Shi 24(3): 647-51.
Sieja, K. and M. Talerczyk (2004). "Selenium
as an element in the treatment of ovarian cancer in women receiving chemotherapy." Gynecol
Oncol 93(2): 320-7.
Smyth, J. F., A. Bowman, et al. (1997). "Glutathione
reduces the toxicity and improves quality of life of women diagnosed with
ovarian cancer treated with cisplatin: results of a double-blind, randomised
trial." Ann Oncol
8(6): 569-73.
Sugiyama, T. and Y. Sadzuka (1998). "Enhancing effects
of green tea components on the antitumor activity of adriamycin against M5076
ovarian sarcoma." Cancer Lett 133(1): 19-26.
Sugiyama, T. and Y. Sadzuka
(1999). "Combination of theanine with doxorubicin
inhibits hepatic metastasis of M5076 ovarian sarcoma." Clin Cancer Res
5(2): 413-6.
Sundstrom, H., E. Yrjanheikki, et al. (1984). "Serum selenium
in patients with ovarian cancer during and after therapy." Carcinogenesis
5(6): 731-4.
Tode, T., Y. Kikuchi, et al. (1992). "[In vitro and in vivo
effects of ginsenoside Rh2 on the proliferation of serous cystadenocarcinoma
of the human ovary]." Nippon Sanka Fujinka Gakkai Zasshi 44(5): 589-94.
van
Acker, S. A., E. Boven, et al. (1997). "Monohydroxyethylrutoside,
a dose-dependent cardioprotective agent, does not affect the antitumor activity
of doxorubicin." Clin Cancer Res 3(10): 1747-54.
Vistica, D. T., D. D.
Von Hoff, et al. (1981). "Uptake of melphalan
by human ovarian carcinoma cells and its relationship to the amino acid content
of ascitic fluid." Cancer Treat Rep 65(1-2): 157-61.
Xu, T. M., Y. Xin,
et al. (2007). "Inhibitory effect of ginsenoside
Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian
cancer." Chin Med J (Engl) 120(7): 584-8.
Zeller, W. J., S. Fruhauf,
et al. (1991). "Chemoresistance in rat ovarian
tumours." Eur J Cancer 27(1): 62-7.
Top of Page
....................................................................................................................
Donate
Now |
Home |
Programs | Avenues Newsletter | Becoming
Your Own Advocate | Events | Search |
Site Map
Pine Street Foundation · 124 Pine Street · San Anselmo · California · 94960-2674
P: (415) 455-5878 · F: (415) 485-1065 · Email Us
Copyright © 1989-2008 Pine Street Foundation, a 501(c)(3) non-profit
public charity.
All rights reserved. Legal.
| 
