Chemotherapy drugs act by blocking DNA
precursor synthesis; damaging DNA integrity; or interfering with DNA
replication, separation of the two helices after replication, or the
function of the mitotic spindle. For chemotherapy to be effective,
tumor cells must be rapidly proliferating.
Rates of DNA
synthesis and cellular division are inversely related to the degree
of lipid peroxidation; cancer cells normally limit lipid
peroxidation by having levels of vitamin E higher, and of cytochrome
P450 components lower, than those of normal cells. However, under
conditions of excessive oxidative stress, lipid peroxidation occurs,
cell proliferation slows, and cells spend more time in the
nonproliferative G0 state, during which they are little affected by
anticancer drugs. After chemotherapy is completed, they can reenter
the cell cycle and resume proliferation, leading to recurrence of
the cancer. Oxidative stress also prolongs the G1 phase (preparation
for DNA synthesis and cell division), and these cells may also be
resistant to anticancer drugs. Even the alkylating agents and
platinum coordination complexes, which do not require that DNA
synthesis be ongoing, may be less effective when cells are in the G0
phase, because the DNA can be repaired before the cells reenter the
cycle.
Cancer itself creates oxidative stress and impairs
antioxidant status in the organism as a whole; cancer cells can
adapt and maintain their rapid proliferation, and in fact the higher
levels of reactive oxygen species in the host promote the
development of cancer. However, during administration of
chemotherapy the cancer cells’ antioxidant defenses cannot
compensate for the additional oxidative stress, so the cells’
proliferation is slowed or stopped and the drugs’ antineoplastic
activity is decreased. The author of this review suggests,
therefore, that patients with compromised antioxidant status have a
reduced response to chemotherapy, and that supplementation with
antioxidants might enable cancer cells to overcome the oxidative
stress and remain responsive to chemotherapeutic agents. He also
says it is unlikely that supplementation with antioxidants would
decrease the effectiveness of anticancer drugs because (except for
bleomycin) their mechanism of action is not related to their
production of reactive oxygen species.
The creation by
chemotherapy drugs of reactive oxygen species contributes to many
side effects: cardiotoxicity (doxorubicin), pulmonary fibrosis
(bleomycin), nephrotoxicity, neurotoxicity, and ototoxicity
(cisplatin). Other side effects, like those on the gastrointestinal
tract as well as hair loss and myelosuppression, are mainly or
entirely due to the fact that the cells involved are rapidly
proliferating (because normal tissues are affected by
chemotherapeutic agents too). Antioxidant supplementation would not
prevent these latter side effects, although topical vitamin E was
shown in at least one study to promote healing of
chemotherapy-induced oral lesions. In fact, the degree to which
these effects persist may serve as an indicator of the efficacy of a
treatment even during antioxidant supplementation. (Because vitamin
E is the antioxidant most important to limiting lipid peroxidation,
and therefore may boost the effectiveness of anticancer therapy, it
may be particularly important to monitor hematological profiles
carefully while patients are taking antioxidant supplements.)
Vitamin E has been shown to increase the efficacy of
5-fluorouracil, doxorubicin, vincristine, dacarbazine, cisplatin,
and tamoxifen in vitro. Although in vitro studies have suggested
that it might decrease doxorubicin-induced cardiotoxicity, in vivo
studies did not demonstrate that it has such an effect.
Vitamin C
inhibits formation of the reactive oxygen species in the aqueous
phase that initiate lipid peroxidation. It has been seen to increase
the efficacy of doxorubicin, cisplatin, paclitaxel, dacarbazine,
5-FU, and bleomycin in vitro and that of cyclophosphamide,
vinblastine, 5-FU, procarbazine,
N,N'-bis(20chloriesthyl)-N-nitrosurea, and doxorubicin in animals
(although in some studies it did not affect doxorubicin activity).
In other studies, it decreased lipid peroxidation and acute
cardiotoxicity in animals given doxorubicin, and both in vitro and
in vivo it has been seen to decrease chemotherapy-induced
mutagenesis.
Doxorubicin, which generates free radicals,
produces mitochondrial peroxidation in the mitochondria of the cells
of the heart and lowers CoQ10 levels; these actions are thought to
be the cause of its cardiotoxic effects. Coenzyme Q10 may, as a
lipid-soluble antioxidant, reduce lipid peroxidative damage to
mitochondrial membranes. In animals, CoQ10 administration can
prevent acute doxorubicin-induced cardiotoxicity. Similar results
have been seen in humans; adults who were taking doxorubicin,
vincristine, and cyclophosphamide had a greater risk of developing
prolonged STI values and congestive heart failure than did those who
took 50 mg CoQ10 a day. Children receiving 100 mg CoQ10 twice a day
(by mouth) along with the chemotherapy drugs daunorubicin and
adryblastin had only a small reduction of left ventricular
fractional shortening. It is important to note that CoQ10 seems to
be the only antioxidant that can prevent chronic doxorubicin-induced
cardiotoxicity; other antioxidants are protective only against the
acute form.
In mice, beta-carotene has been seen to enhance the
effects of a variety of chemotherapeutic drugs (including
cyclophosphamide, melphalan, BCNU, doxorubicin, and etopside) and to
reduce the genotoxicity of cyclophosphamide.
Administration of
GSH esters leads to higher cellular levels of GSH than does
administration of GSH. Only normal cells have the enzyme that
hydrolyzes GSH and enables it to be transported into the cell, so
they take up far more GSH than do cancer cells. This is probably the
reason that GSH protects normal cells and not cancer cells from
cytotoxic effects of antineoplastic drugs. Although GSH has received
positive attention for its ability to decrease the nephrotoxicity
and peripheral neuropathy induced by cisplatin, its thiol group can
bind with cisplatin or carboplatin; if this binding takes place
before the drug is taken up by cells, it inhibits the drug’s
antineoplastic activity. Another class of drugs with which GSH can
interact is alkylating agents; GSH may inhibit the effects of these
drugs by competing with DNA for alkylation. The author of this
review therefore notes that GSH or other thiol compounds (e.g.,
N-acetylcysteine) must be used with caution by patients who are
being treated with platinum coordination complexes (cisplatin or
carboplatin) or with alkylating agents.
With that caveat, he
cites studies indicating that, because both GSH and cisplatin are
rapidly cleared from the circulation, taking them separately seems
to eliminate the problem of inactivation of cisplatin by GSH.
Studies with mice indicate that GSH reduces the myocardiotoxicity of
doxorubicin, the hepatic venoocclusive disease normally seen with
administration of high doses of BCNU or cyclophosphamide, and the
bladder damage often seen with cyclophosphamide, in each case
without decreasing the drugs’ antitumor activity.
In humans, GSH
has been seen to reduce neurotoxicity, nephrotoxicity, and
myelosuppression in studies in which patients given GSH along with
their chemotherapeutic regimen had higher rates of remission [in the
review it is not stated whether these differences were statistically
significant].
Although N-acetylcysteine (NAC) has
free-radical-scavenging activity, it is as a source of cysteine (a
substrate for synthesis of GSH) that it seems to exert its greatest
effects. As noted above, it should be used with caution by patients
who are being given cisplatin or electrophilic alkylating
agents.
NAC has been shown in animal studies to prevent the
hemorrhagic cystitis that often follows cyclophosphamide or
ifosfamide administration. Unfortunately, the results of one human
study suggests that the dosages necessary to completely prevent
ifosfamide-induced cystitis (>9 g/day) lead to a high incidence
of nausea and vomiting; in another study, a dosage of 4 g/day
reduced the severity of cystitis due to ifosfamide without affecting
myelosuppression or the drug’s antitumor activity.
In mice NAC
has been shown to be protective against the acute cardiotoxicity
caused by doxorubicin, although it failed to protect dogs from
chronic doxorubicin-induced cardiotoxicity. Other studies [animal
and human] have similarly shown that NAC can inhibit acute but not
chronic cardiotoxicity from doxorubicin administration.
Glutamine
is a primary fuel source for enterocytes and a source of glutamate
for GSH synthesis. In animal and human studies, oral administration
has been shown to reduce mucosal injury when administered during
treatment with several different chemotherapy drugs; some studies
have also shown that there are similar effects from intravenous
administration of glutamine, but others have not.
Although at
least one animal study has indicated that selenium supplementation
sufficient to protect against nephrotoxicity does not inhibit the
anticancer effects of cisplatin, selenium has been shown to reduce
the myelosuppression that may serve as a marker for the
effectiveness of an antineoplastic regimen. In addition, selenium
has chemical properties similar to those of sulfur, suggesting that
selenium supplementation should be done only with caution by
patients taking cisplatin or carboplatin.
Parenteral and oral
supplementation with selenium have, in separate animal studies,
shown that this mineral can protect against acute, but not chronic,
doxorubicin-induced cardiotoxicity. Oral supplementation with 4,000
µg Se/day in four divided doses for 8 days, beginning 4 days before
cisplatin chemotherapy, decreased nephrotoxicity but also reduced
myelosuppression. The author of the review reiterates the concern
that this effect on myelosuppression may indicate that the
chemotherapy was therefore less effective.
Genistein, a soy
isoflavone, inhibits topoisomerase I and II, as does doxorubicin or
etoposide; genistein also inhibits the binding of ATP to
topoisomerase II, an activity neither of these agents has, and
therefore might enhance their anticancer activity. Concentrations of
genistein that have been shown in vitro to have some cytotoxic
effects are higher than those that can be achieved by oral
administration, although the author points out that genistein may
have a complementary effect on the actions of antineoplastic drugs
at concentrations lower than those that are necessary to achieve an
effect when genistein is present alone. Genistein may also increase
the accumulation of cisplatin and doxorubicin in resistant cancer
cells. The antioxidant isoflavones and glutamate in soy protein may
help reduce damage to the GI mucosa induced by methotrexate.
In
in vitro studies, quercitin inhibits the growth of a number of cell
lines. It also enhances the effects of a number of antineoplastic
agents and has been seen to increase the ability of doxorubicin to
inhibit growth in multidrug-resistant cancer cells. In
drug-sensitive cells, it increases the antiproliferative effects of
cisplatin, nitrogen mustard, busulfan, and cytosine
arabinoside.
Drugs that are used to reduce chemotherapy-induced
side effects (dexrazoxane for doxorubicin-induced cardiotoxicity,
amifostine for the nephrotoxicity induced by cisplatin, mesna for
ifosfamide-induced hemorrhagic cystitis) have adverse effects of
their own. Dexrazoxane can reduce the effectiveness of doxorubicin
and may increase the risk of a patient’s eventually developing a
secondary cancer. Amifostine can cause hypotension, hypocalcemia, or
nausea, and mesna can cause nausea, vomiting, and diarrhea. The
author points out that supplementation with antioxidants at proper
dosages may also alleviate side effects without these adverse
consequences, and points specifically to CoQ10 as a substance that
may eventually become an important adjunct in the reduction or
prevention of doxorubicin-induced cardiotoxicity.
Conklin KA.
Dietary antioxidants during
cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer
2000;37:1-18.
In vivo studies of human breast cancer cells demonstrated
that curcumin inhibited camptothecin-induced apoptosis in a time-
and dose-dependent manner. Similarly, curcumin inhibited the ability
of an alkylating agent (mechlorethamine) and an anthracycline
(Adriamycin) to induce apoptosis in a dose-dependent manner, in a
number of breast cancer cell lines. This effect was seen even at
concentrations (1 µM) achieved with curcumin doses used in Phase I
chemoprevention trials; for BT-474 cells, the decrease in apoptosis
was 19.3% for mechlorethamine and 27.5% for
camptothecin.
The formation of reactive oxygen
species is thought to be an important mechanism by which
chemotherapeutic drugs such as camptothecin and alkylating agents
induce apoptosis. Curcumin inhibits ROS formation by camptothecin or
mechlorethamine in a dose-dependent manner, at 1 µM, the decrease
was 35.0% for mechlorethamine and at 10 µM, levels of ROS in
camptothecin- or mechlorethamine-treated cells were the same as
those in vehicle-treated cells. Curcumin administration also
decreased the activity of pathways that lead to apoptosis,
presumably by decreasing ROS levels.
In studies in mice
with xenografts of human breast cancer tissue, tumor size did not
decrease with cyclophosphamide administration when the mice were
also given curcumin at 25 g/kg of feed; in fact, in the
curcumin-supplemented group, the tumors grew faster than in the mice
consuming the control diet. Examination of the tumors later
indicated that apoptosis in the mice consuming the standard diet was
1.6 times greater than in the curcumin-supplemented
animals.
A review of the literature shows that curcumin
does seem to induce apoptosis in some cell lines but not in others
(although research with the same cell line by different study groups
has led to different results in at least one case). Curcumin levels
in many of these studies were higher than could be achieved by
dietary intake; the authors of this study designed a protocol in
which curcumin concentrations were achievable under normal, in vivo
conditions. They found that drugs which lead to apoptosis by
increasing ROS formation and certain metabolic pathways (i.e., the
c-Jun NH2–terminal kinase [JNK] pathway and cytochrome c release
from mitochondria into the cytoplasm) are affected by curcumin
administration. However, the effectiveness of agents that do not
affect JNK, such as methotrexate and 5-fluorouracil, should not be
affected by curcumin, and some research has borne this out, although
there is the possibility that curcumin alters other pathways other
than the ones focused on in this study; the authors name paclitaxel
(which activates NF-?B) as a drug that may be inhibited by
curcumin.
The authors suggest that patients being treated
with chemotherapy not be included in chemopreventive trials
involving curcumin, and that this warning may also apply to patients
being treated for prostate cancer. They also suggest that because of
the way in which curcumin is absorbed, its effects may be even
greater in some patients with colon cancer.
Somasundaram S et al.
Dietary curcumin inhibits chemotherapy-induced apoptosis in models
of human breast cancer. Cancer Res 2002;62:3868-3875.
The reduction of plasma levels of several antioxidants due
to chemotherapy can, if the antioxidant defense systems of the cell
are overwhelmed, lead to an increase in lipid peroxidation, which in
turn leads to a decrease in cellular proliferation and therefore to
a decrease in the effectiveness of chemotherapeutic agents. Patients
with an impaired antioxidant status may become relatively resistant
to chemotherapy, and there is evidence that antioxidants improve the
antitumor response to antineoplastic agents.
In vitro
studies indicate that vitamin C increases the activity of
doxorubicin, cisplatin, and paclitaxel, but it may increase
resistance to doxorubicin in cells that are already resistant to the
drug.
The results of studies showing that ß-carotene may
actually promote cancer formation are probably due to the use of the
synthetic form of the nutrient as well as to its use as a single
antioxidant. When used alone, synthetic ß-carotene suppresses uptake
of other carotenoids (of which there are more than a thousand) and
acts as a pro-oxidant. Natural mixed carotenoids have been found to
act synergistically with cisplatin.
Tocotrienols decrease
the growth and proliferation of some human cancer lines, and vitamin
A seems to increase the activity of various inhibitory pathways as
well as having an ability to induce differentiation in some
epithelial tumors.
Drisko JA et al. The use of antioxidant
therapies during chemotherapy. Gynecol Oncol 2003;88:434-439.
Mice with lung carcinoma were treated with cisplatin and
fed diets containing either fish oil (alone or with supplemental
vitamins E and C) or soybean oil. (Basal levels of vitamins E and C
were present in the nonsupplemented diets.) Both groups fed fish oil
had less tumor development than did the mice fed soybean oil;
however, of these mice, those given only basal levels of
antioxidants had significantly slower tumor growth and lower
metastatic load than those given supplemental vitamins E and C. The
mice given fish oil also had no anorexia or cachexia; those given
soybean oil suffered these effects. Because supplementation with
antioxidants had a relatively detrimental effect compared with what
was seen in the mice given fish oil alone, the authors of this study
suggest that oxidized omega-3 fatty acids accumulate in the
membranes and cytosol of tumor cells and eventually lead to the
cells’ death. They also note that the best results were seen with a
fish oil diet followed by cisplatin treatment and a fish oil diet
supplemented with vitamins E and C after the primary tumor was
resected.
Yam D et al. Suppression of tumor growth and metastasis
by dietary fish oil combined with vitamins E and C and cisplatin
(abstract). Cancer Chemother Pharmacol 2001;47:34-40.
There is increasing evidence that the nephrotoxicity, lung
toxicity, and cardiotoxicity of certain antitumor agents are caused
by oxidative stress due to the generation of free radicals, although
their antineoplastic effects are due to non-oxidative damage to DNA
and other cell components. There is also evidence that the use of
antioxidants can alleviate some of side effects without decreasing
the antitumor activity of the drugs.
Not only do some
antineoplastic drugs have the side effects listed above, various
types also increase the likelihood that a secondary malignancy will
develop. Although cisplatin has been seen to be highly mutagenic in
vitro, in vivo studies have not shown that it leads to a
significantly increased risk of secondary cancers. However, the
alkylating agents melphalan and cyclophosphamide, also highly
mutagenic, do induce other malignancies. The patients in the
following study were on a cisplatin single agent or a combination
chemotherapy regimen.
Study patients were given a drink, to
be consumed twice a day for 7 days before the start and until 3
weeks after the end of chemotherapy, containing 1000 mg vitamin C,
400 mg vitamin E, and 100 µg selenium to see whether parameters of
genotoxicity or chromosomal damage, renal function, or hearing would
be affected. Control patients were given a placebo drink.
Consumption of the antioxidant drink did not lead to significant
differences between the study group and the control group in any of
the parameters measured. The authors point out that the antioxidant
system consists of more than these three components, suggesting
specifically that ß-carotene might have helped reduce the observed
genotoxicity. They also note that the higher levels of antioxidants
that were seen at one point in the supplemented patients were not
maintained during chemotherapy, and that compliance was a problem
because the drink was not palatable.
Elsendoorn TJ et al.
Chemotherapy-induced chromosomal damage in peripheral blood
lymphocytes of cancer patients supplemented with antioxidants or
placebo. Mutat Res 2001;498:145-158.
Bleomycin, a antineoplastic drug used in the treatment of
head and neck carcinoma, Kaposi’s sarcoma, testicular carcinoma,
lymphoma, and other germ cell tumors, causes pulmonary fibrosis in
varying degrees in approximately 10% of the people who take it. At
least some of its toxic as well as its neoplastic effects are due to
the production of active oxygen species.
Amifostine
(WR-2721), an aminothiol, is taken up rapidly by normal tissues but
slowly to negligibly by cancer cells, and protects normal tissues
from chemotherapy or radiation without attenuating any antitumor
effect. The free thiol can bind to and detoxify alkylating or
platinum agents, and can also act as a free radical
scavenger.
In hamsters, lung fibrosis due to bleomycin was
reduced by intraperitoneal injection of amifostine just before and
for 7 days after intratracheal administration of bleomycin. This
effect may be due to the binding of amifostine’s active metabolite
to DNA and nuclear proteins, making them less vulnerable to
degradation, or to inhibition of oxidative damage: other
antioxidants (taurine, niacin, NAC, or a form of superoxide
dismutase that contains manganese) have, like amifostine, been shown
to modulate bleomycin injury, and thiols like GSH can scavenge
hydrogen peroxide. Levels of GSH that are normally found in the
epithelial lining fluid of the lung can decrease fibroblast
proliferation, suggesting that low GSH can contribute to
fibrosis.
The authors make no claims about the use of
antioxidants other than amifostine in this article, although they
state that further research on the effects of bleomycin on
antioxidant enzymes and active oxygen species is important.
Nici
L et al. Modulation of bleomycin-induced pulmonary toxicity in the
hamster by the antioxidant amifostine. Cancer 1998;83:2008-2014.
Many antioxidants have been shown to decrease the
ototoxicity of cisplatin that is caused by the production of
reactive oxygen species. Rats given cisplatin once and then treated
daily with a mixture of antioxidants, with melatonin, or with a
combination of the antioxidant mixture and melatonin had responses
to distortion product otoacoustic emissions similar to those of
control animals at 15 days after cisplatin administration, whereas
rats given cisplatin alone had significantly affected hearing. The
authors of this study note that the question of whether melatonin or
the other antioxidants affect cisplatin’s effectiveness was not
addressed.
Lopez-Gonzalez MA et al. Ototoxicity caused by
cisplatin is ameliorated by melatonin and other antioxidants. J
Pineal Res 2000;28:73-80.
The nephrotoxicity of
cisplatin is one of the drug’s dose-limiting side effects; cisplatin
administration is accompanied by depletion of renal GSH and an
increase in lipid peroxidation. Melatonin is an effective scavenger
of free radicals that has been shown to reduce lipid
peroxidation.
Kidney peroxidation was found to be significantly
higher after 5 days in mice given a single injection of cisplatin
than in mice given cisplatin plus melatonin for either 5 days before
and after or only 5 days after the cisplatin. Creatinine and BUN
were also higher in the mice given cisplatin alone than in mice
given either of the melatinon plus cisplatin protocols. Kidney GSH
concentration was higher in the mice given either of the melatonin
plus cisplatin protocols than in those given cisplatin
only.
Sener G et al. The protective effect of melatonin on
cisplatin nephrotoxicity. Fundam Clin Pharmacol 2000;14:553-560.
The peripheral neuropathy induced by cisplatin is
indistinguishable, clinically and neurophysiologically, from vitamin
E deficiency neuropathy. Animal models and examination of human
tissue suggest that the dorsal root ganglia are most affected by
cisplatin treatment, as they are in vitamin E
deficiency.
After an animal study revealed that vitamin E
administration did not decrease the effectiveness of cisplatin,
patients with various types of cancer were assigned to receive
either vitamin E supplementation (300 mg/day) plus cisplatin
treatment or cisplatin alone. After six cycles of cisplatin, there
were no significant differences between the groups in terms of
clinical response to cisplatin, of renal toxicity, of neutrophil
counts, or of thrombocytopenia. The incidence and intensity of
neuropathy in the patients who did not receive vitamin E was
significantly higher than in those who did receive the supplements,
and the response to chemotherapy was not significantly
different.
Pace A et al. Neuroprotective effect of vitamin E
supplementation in patients treated with cisplatin chemotherapy. J
Clin Oncol 2003;21:927-931.
