Alternative Medicine Review 1999 (Oct); 4 (5): 304–329 ~ FULL TEXT
Davis W. Lamson, MS, ND and Matthew S. Brignall, ND
Introduction
Dietary and endogenous antioxidants prevent cellular damage by reacting
with and eliminating oxidizing free radicals. However, in cancer treatment,
a mode of action of certain chemotherapeutic agents involves the generation
of free radicals to cause cellular damage and necrosis of malignant cells.
So a concern has logically developed as to whether exogenous antioxidant
compounds taken concurrently during chemotherapy could reduce the beneficial
effect of chemotherapy on malignant cells. The importance of this concern
is underlined by a recent study which estimates 23 percent of cancer patients
take antioxidants. [1]
The study of antioxidant use in cancer treatment is a rapidly evolving
area. Antioxidants have been extensively studied for their ability to prevent
cancer in humans. [2] This paper reviews the
use of antioxidants as a therapeutic intervention in cancer patients, and
their potential interactions with radiation and chemotherapy. There has
been significant investigation of this area, with promising findings which
indicate continuing investigation is warranted. For further discussion
of the use of antioxidants as sole cancer therapy, refer to the review
article by Prasad published earlier this year. [3]
A number of reports show a reduction in adverse effects of chemotherapy
when given concurrently with antioxidants. These data are more completely
summarized by Weijl et al. [4]
Conflicting Views of Antioxidant Use in Cancer Therapy
It was suggested in a recent publication that no supplementary antioxidants
be given concurrently with chemotherapy agents which employ a free radical
mechanism. [5] The paper must be commended
for pointing out that the combination of antioxidants and chemotherapy
agents needs more investigation, and should serve as a wake-up call regarding
how much we need further definition of the actions of specific antioxidants
with chemotherapeutic agents. However, it should not serve as scientific
closure on an adjunctive treatment of possible great promise in cancer
therapy.
The present authors are by no means recommending any lack of caution
about use of antioxidants. On the contrary, published research indicates
the cautious and judicious use of a number of antioxidants can be helpful
in the treatment of cancer; as sole agents and as adjuncts to standard
radiation and chemotherapy protocols.
It was suggested that antioxidants might interfere with the oxidative
mechanisms of alkylating agents. [5] These
drugs create substantial DNA damage, resulting in cell necrosis. However,
recent evidence indicates a sizeable amount of chemotherapy damage is by
other mechanisms, which trigger apoptosis. [6]
Antioxidants have been shown to increase cell death by this mechanism. [7,8]
Given this, any argument that antioxidants are likely to interfere with
most chemotherapy is too simplistic and probably untrue.
Numerous animal studies have been published demonstrating decreased
tumor size and/or increased longevity with the combination of chemotherapy
and antioxidants. [7,9-16] A recent study
was conducted on small-cell lung cancer in humans using combination chemotherapy
of cyclophosphamide, Adriamycin (doxorubicin), and vincristine with radiation
and a combination of antioxidants, vitamins, trace elements, and fatty
acids. The conclusion was "antioxidant treatment, in combination with
chemotherapy and irradiation, prolonged the survival time of patients"
compared to expected outcome without the composite oral therapy. [17]
Two human studies found melatonin plus chemotherapy to induce greater tumor
response than chemotherapy alone. [18,19]
The treatments producing these positive results would have been advised
against by those advocating no antioxidant use during chemotherapy. These
studies will be discussed in more detail below.
It is the opinion of the authors of this paper that interactions between
antioxidants and chemotherapeutics cannot be predicted solely on the basis
of presumed mechanism of action. The fact remains that physicians must
be aware of the available research to help their patients take advantage
of positive interactions existing between antioxidants and chemotherapy
or radiation.
Additionally, physicians need to remain aware of the large body of evidence
showing a positive effect of antioxidants in the period following chemotherapy
administration. The general protocol with standard oncologic therapies
is to follow a watch-and-wait strategy after therapeutic administration
is concluded. This is a period when supplemental therapies are highly indicated
and have been demonstrated to result in a higher percentage of successful
outcomes. [20,21]
Overview of Cancer Therapeutic Agents
Chemotherapy agents can be divided into several categories: alkylating
agents (e.g., cyclophosphamide, ifosfamide), antibiotics which affect nucleic
acids (e.g., doxorubicin, bleomycin), platinum compounds (e.g., cisplatin),
mitotic inhibitors (e.g., vincristine), antimetabolites (e.g., 5-fluorouracil),
camptothecin derivatives (e.g., topotecan), biological response modifiers
(e.g., interferon), and hormone therapies (e.g., tamoxifen).The agents
most noted for creating cellular damage by initiating free radical oxidants
are the alkylating agents, the tumor antibiotics, and the platinum compounds.
The agents in these categories demand definition concerning interactions
with antioxidants which might reduce effectiveness of chemotherapy. There
is also the possibility of adverse interaction between antioxidant treatment
and agents that do not act via an oxidative mechanism (e.g., 5-fluorouracil
or tamoxifen).
In addition to the idea that chemotherapy must create a lethal injury
to DNA to produce malignant cell death is the mechanism of apoptosis. A
dose of chemotherapy which does not produce necrosis can trigger apoptosis,
either immediate or delayed. Additionally, anti-apoptotic mutations can
result in drug resistance in human tumors. At least one antioxidant (quercetin)
has been demonstrated to overcome such an anti-apoptotic blockage. [22]
Radiotherapy uses ionizing radiation to produce cell death through free
radical formation. Two mechanisms are involved. The apoptosis mechanism
results in cell death within a few hours of radiation. The second mechanism
is radiation-induced failure of mitosis and the inhibition of cellular
proliferation, which kills cancer cells. Currently, the principal target
of radiation is considered to be cellular DNA. However, studies show the
signal for apoptosis can be generated by the effect of radiation on cell
membranes, apparently through lipid peroxidation. This suggests an alternate
mechanism to the hypothesis that DNA damage is required for cell death. [23]
Categories of Chemotherapeutics
Vitamin A and Carotenoids as Cancer Treatment
Many research reports on the anti-cancer properties of vitamin A and
the related retinoids have been published over the last 20 years. Most
of these studies examined all-trans retinoic acid (RA). RA is formed in
human tissues from beta-carotene and retinol, does not accumulate in the
liver, thus it is not associated with significant hepatotoxicity. [24]
Treatment with RA is associated with many side effects, including headache,
lethargy, anorexia, vomiting, and visual disturbance. [24]
Another retinoid used in cancer treatment is 13-Cis-retinoic acid (cRA),
also known as isotretinoin. [25]
RA in vitro demonstrates growth inhibitory activity against at least
14 types of human cancers. [24] Acute promyelocytic
leukemia (APL) has been shown to respond well to RA, but not to cRA. [26]
In one study, nine of 11 patients with APL entered complete remission after
treatment with 45 mg/m2 daily oral dose of RA. [27]
Similar results are reported elsewhere, [28,29]
and have been confirmed in vitro. [30]
Local application of an RA-containing cream demonstrated low toxicity
and some histological improvement of cervical intraepithelial neoplasia
II (CIN II) in a phase I study. [31]In a phase
III trial, RA led to complete regression of CIN II in 42 percent of women
compared with 27 percent in the placebo group. [32]
No significant effect was noted in severe cervical dysplasia. [32]
After remission induced by conventional therapy, treatment with cRA is
associated with fewer second primary tumors in head and neck squamous-cell
carcinoma. [33]
Retinoic acid decreased the growth rate and increased differentiation
of human small cell lung cancer lines in vitro. [34 ]Daily
oral administration of 300,000 IU vitamin A as retinol palmitate led to
a significant reduction in second primary tumors and an increase in disease-free
survival post-surgery in stage I lung cancer. [35]
However, a small trial of cRA at 200 mg/day found no appreciable benefit
in the treatment of advanced non-small cell lung cancer. Of 23 patients
evaluated in this trial, only one achieved a partial response to treatment. [36]
A trial of oral vitamin A at 100,000 IU/day in patients with resected
malignant melanoma found no survival benefit compared with those taking
placebo. [37] In a trial of oral RA for hormone-refractory
prostate cancer, dosed 45 mg/m2 daily, only a 15-percent response rate
was seen. [38 ]It is clear from these data
that the effects of the retinoids as sole therapeutic agents are limited,
perhaps mainly to hematologic malignancies, which tend to develop RA resistance
over time. [28 ]For further information on
the use of retinoids in cancer therapy, refer to the review by MA Smith,
et al. [24]
In contrast to the retinoids, comparatively little is known about the
use of carotenoids as anti-cancer agents in vivo. The interest in carotenoids
mainly stems from the extensive epidemiological evidence associating dietary
intake with lower incidences of many cancer types. [39]
Alpha- and beta-carotene have been examined for in vitro tumor inhibitory
activity against human neuroblastoma cell lines, and alpha-carotene was
found to have 10 times the anti-tumor activity of beta-carotene. [40]
Currently there is some concern regarding supplementation with carotenoids, [41]
as beta-carotene has been associated with higher risk of lung cancer in
smokers, but not in the general population. [42]
Aside from this concern, high doses of beta-carotene, even over long periods
of time, are not associated with serious toxicity. [39]
There are also promising data showing chemopreventative activity of the
carotenoid lycopene against prostate cancer. [43]
In vitro work suggests lycopene can induce differentiation, with vitamin
D3, in human leukemia cells. [44] One study
showed lycopene to be a stronger inhibitor of human cancer cell proliferation
in vitro than alpha- or beta-carotene. [45]
As yet, human trials are lacking on the use of lycopene.
Vitamin A and Carotenoids with Radiation
Evidence exists to support the use of retinoids concomitantly with radiotherapy.
In vitro studies have shown retinoic acid (RA) causes radiosensitization
in human tumor cell lines at concentrations which do not cause cellular
toxicity. This effect was reversible with removal of RA. [46]
In mice bearing human breast adenocarcinoma tumor lines, the effect of
local radiation was enhanced by supplemental vitamin A (150,000 IU) and
beta-carotene (90 mg/kg) given during treatment. The beneficial effect
of the supplemental treatment was noted as decreased tumor size and increased
survival time. Supplemental vitamin A and beta-carotene plus radiation
had significantly greater anti-tumor effect than radiation or supplementation
alone. The effect of vitamin A was not significantly different from beta-carotene. [9]
In a randomized trial of oral vitamin A (1.5 million IU/day) plus radiotherapy
for advanced cervical cancer, vitamin A plus radiotherapy significantly
increased T-cell response and non-significantly reduced relapse rates compared
with those undergoing radiotherapy only. [46]
A pilot human study of cis-retinoic acid (cRA) with radiotherapy and interferon-a2a
on locally advanced cervical cancer noted a 47-percent tumor response and
33-percent complete remission rate, with no grade 3 or 4 toxicity noted.
Historical controls without cRA treatment had a 42-percent tumor response
rate and only 17-percent complete remissions. [47]
The ability of vitamin A to increase tumor response to radiation while
reducing toxicity has been theorized to be due to the stimulation of immune
response to tumor tissue. [48]
In a human study, beta-carotene at 75 mg daily during radiation treatment
for advanced squamous cell carcinoma of the mouth significantly reduced
the incidence of severe mucositis reactions without causing noticeable
side effects. The remission rate was unchanged by beta-carotene treatment.49
In vitro evidence suggests synthetic beta-carotene does not have the radioprotective
effect noted with the natural form. [50] The
meaning of this finding is as yet unclear.
Vitamin A and Carotenoids with Chemotherapy
Perhaps more than any other antioxidant treatment, retinoids are increasingly
being pursued as adjunctive treatment to standard chemotherapeutics. Most
evidence suggests an increased cytotoxic effect with reduced toxicity.
In vitro studies using human small cell lung cancer lines demonstrated
that incubation with retinoic acid (RA) led to an increased sensitivity
to etoposide, but more resistance to doxorubicin. [51]
Human synovial sarcoma cells exposed to RA in vitro were found to have
enhanced response to doxorubicin, vincristine, and especially cisplatin. [52]
Although the potential adverse interaction with doxorubicin was not confirmed
in the latter study, this is an area that merits further definition.
In studies of mice with transplanted human breast tumor tissue, concurrent
treatment of either vitamin A or beta-carotene with cyclophosphamide led
to a significantly greater tumor response and survival time compared to
cyclophosphamide treatment alone. The effect of beta-carotene was roughly
equivalent to that of vitamin A.9 Also in mice, co-administration of vitamin
A with methotrexate ameliorated intestinal damage, without inhibiting its
in vivo anti-tumor activity. [53 ]
In a phase I human trial of cisplatin with 13-cis-retinoic acid (cRA),
the two agents were noted to have strong synergism against head and neck
squamous cell carcinoma. Of 10 evaluable patients, all had complete tumor
response at the primary site. Dosages of 20 mg/day cRA were well tolerated,
but severe toxicities were seen at 40 mg/day.54 Extremely high oral doses
of RA (150 mg/m2 daily) showed no inhibitory effect on the activity of
cisplatin and etoposide on small cell lung carcinoma in humans. This dose
also was not associated with any therapeutic benefit, and needed to be
discontinued in a majority of patients due to side effects . [55]
Vitamin A palmitate at an oral dose of 50,000 IU twice daily, plus b-interferon
and combined chemotherapy (epirubicin, mitomycin C, and 5-fluorouracil)
prolonged symptom palliation in 35 percent of pancreatic cancer patients.
This treatment was associated with severe toxicities in several systems,
but only hepatotoxicity was thought to be associated with the addition
of retinoids. [56] Sequential treatment of
non-lymphocytic leukemia patients with conventional chemotherapy, followed
by 16,000 IU/day of retinol palmitate led to a further induction of maturation
in blast cells than seen with chemotherapy alone. In three of four patients
undergoing this sequential therapy, complete remission resulted. [57]
Addition of 400,000 IU/week vitamin A to a conventional chemotherapy regimen
(doxorubicin, bleomycin, 5-fluorouracil, and methotrexate) led to improved
survival with less than the expected severity of side effects compared
with historical controls. [10]
Although the relative lack of toxicity compared to the retinoids makes
it an attractive option, beta-carotene in combination with chemotherapy
is a largely unexplored area. In mice, beta-carotene co-administration
led to increased tumor growth delay with doxorubicin and etoposide, and
increased tumor cell killing with cyclophosphamide in solid tumors. The
co-administration of beta-carotene and 5-fluorouracil, however, reduced
tumor growth delay in murine fibrosarcomas, but not in squamous cell carcinomas. [58]
Data on other carotenoids is lacking.
Vitamin A Summary
Vitamin C as Cancer Treatment
The use of vitamin C in the treatment of cancer has been the source
of many claims and controversies over the last 25 years. Initial reports
from Drs. Pauling and Cameron were promising, and gained much notoriety.
They reported 100 cases of terminal cancer, independently assessed and
refractory to conventional treatment, who lived on average four times longer
than 1000 age- and disease-matched controls. [59]
The protocol included intravenous and oral administration, and is described
in detail elsewhere. [60]Prospective randomized
trials held at the Mayo Clinic were unable to replicate these results,
finding negligible difference between treated patients and controls in
survival time. [61,] [62
]These results were criticized on a number of grounds, including
the noticeable difference between the vitamin C and placebo, lack of intravenous
administration, and termination of treatment with tumor progression. [60
]Later in vitro and in vivo research, and well documented case
reports, 63 suggest a vitamin C dose much higher than that used in the
Pauling/Cameron studies can actually be cytotoxic to tumors without damaging
normal cells. The required tissue concentrations are thought to only be
reachable with intravenous doses over long periods of time. This research,
as well as the proposed mechanism of action, is examined elsewhere. [64]
Vitamin C is generally well-tolerated by healthy people, even in doses
as high as 200 g/day IV. [64,] [65
]Dr. Cameron has noted that a small percentage of cancer patients
will respond to vitamin C with rapidly proliferating and disseminating
tumors. [66] Other investigators have not
noted this effect.
Vitamin C with Radiation
Quite surprisingly, no published studies have looked at the effect of
doses over five grams of oral or intravenous vitamin C on radiotherapy
in humans. It has been shown, however, that cancer patients have a significant
elevation in plasma and leukocyte ascorbate levels after radiotherapy compared
with pretreatment levels without any change in dietary intake. [67]
In mice, vitamin C (1 g/kg), given intraperitoneally with vitamin K3
(10 mg/kg), increased the therapeutic effect of radiation on solid tumors
without causing any signs of toxicity due to the vitamins. [68]
In another mouse study, a single intraperitoneal dose of 4.5 g/kg vitamin
C was not cytotoxic to normal tissue and did not change the radiation effect
on tumor tissue. The lethal dose of radiation increased and skin desquamation
reaction was reduced by ascorbate treatment. It should be noted that these
vitamin C doses are much greater than have been used historically in humans. [69]
The radioprotection of healthy tissue and radiosensitizing effect in tumors
with use of ascorbate were confirmed in two other mouse tumor models. [70,]
[71]
A randomized trial with 50 human subjects looked at the effect of concurrent
vitamin C (five daily doses of 1 g each) and radiotherapy on different
tumor types. More complete responses to radiation were noted in the vitamin
C group at one month (87% to 55%) and four months (63% to 45%) post treatment.
Side effects tended to be fewer in the ascorbate-treated subjects as well.
Plasma levels of ascorbate in the treatment group were greater than control
subjects, but less than the mean of 20 healthy subjects tested. [72]
It remains to be investigated whether continuing treatment beyond the end
of radiotherapy or use of a higher dose would improve these results. A
double-blind trial of topical vitamin C solution for the prevention of
radiation dermatitis failed to find any beneficial effect. The trial did
not examine the absorption of the aqueous preparation, although previous
trials showed about 12 percent of the vitamin C penetrated into the epidermis. [73]
Vitamin C with Chemotherapy
Vitamin C has been extensively tested in vitro and in vivo for its ability
to prevent the adverse effects of, decrease resistance to, and increase
the effects of chemotherapeutic agents. Co-treatment with doxorubicin and
vitamin C (2 mg/kg) led to a reduction in the toxicity seen with doxorubicin
alone in mice and guinea pigs. The prevention of cardiomyopathy was confirmed
by electron microscopy. Treatment with ascorbic acid was not associated
with decreased effect of doxorubicin, and was associated with an increased
life span compared with doxorubicin treatment alone. [11]
In vitro experiments do suggest, however, that vitamin C does enhance doxorubicin
resistance in human breast cancer cell lines already known to be resistant.
It did not lead to resistance in cells which were doxorubicin-sensitive. [74]
Vitamin C at non-cytotoxic concentrations (1 mM) increased the activity
of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells
in vitro. This effect was particularly marked and synergistic with doxorubicin.
The authors note that since vitamin C has already shown an ability to reduce
the cardiotoxicity of doxorubicin, ascorbic acid and doxorubicin are an
attractive future treatment for breast cancer. [75]
Vitamin C has been shown to increase the drug accumulation and decrease
resistance to vincristine in human non-small-cell lung cancer cells in
vitro. An ascorbic acid-sensitive uptake mechanism was theorized to explain
these results. [76]
Combined intraperitoneal administration of vitamin C (1g/kg) and vitamin
K (10 mg/kg) given prior to chemotherapy increased survival and the effect
of several chemotherapeutic agents (cyclophosphamide, vinblastine, doxorubicin,
5-fluorouracil, procarbazine, and asparaginase) in a murine ascitic liver
tumor model. The vitamin combination did not increase the toxicity of these
agents to healthy tissue. Splenic and thymic weights of the vitamin-treated
animals were higher than those receiving cytotoxic treatment alone, suggesting
an immune-stimulating action of the vitamins.12 These results have yet
to be confirmed in humans.
Vitamin C Summary
Vitamin E as Cancer Treatment
Vitamin E succinate (VES, alpha tocopherol succinate),has generated
some interest as an adjunctive cancer therapy recently. VES demonstrated
growth inhibition of human B-cell lymphoma77 and estrogen receptor-negative
breast cancer78 cell lines in vitro. Vitamin E at 3 mM concentration arrested
tumor cells in the G1 phase of the cell cycle, leading to apoptosis. [7]
Recent research on human oral squamous carcinoma cells suggests the VES
effect is biphasic; growth stimulatory at physiological concentrations,
while pharmacological concentrations are inhibitory. [79]
A phase I trial of intravenous vitamin E in treatment refractory neuroblastoma
found mild toxicity (tendency toward increased bleeding time was noted)
at doses below 2,300 mg/m2. Five of 13 patients experienced pain relief
and/or tumor regression with treatment. No complete remissions resulted
from treatment. [80] Vitamin E, 200 mg daily,
given together with 18 g/day omega-3 fatty acids from fish oil, prolonged
survival in patients with generalized malignancy in a randomized controlled
trial. Improvement in T-helper/suppressor ratio was also noted with treatment. [81]
Phase I clinical trials are being planned or are underway in patients with
breast and prostate cancers. [82] Vitamin
E and its derivatives are particularly attractive therapeutic agents due
to their remarkable lack of toxicity in vivo. [83]
Vitamin E with Radiation
The picture here is unfortunately far from clear. An initial report
showed mice treated with 1 g/kg of vitamin E had an increased in the lethal
radiation dose (LD50). Unfortunately, squamous cell carcinoma cell lines
treated in this study were less radiosensitive, with 35-percent cell survival
versus 13 percent in controls. [84] A later
experiment was able to replicate this finding in vitro in cells incubated
for several weeks with vitamin E, but not those in which it was added immediately
before irradiation. [85] The latest experiment
to look at this issue actually found that some doses of vitamin E enhanced
mouse sarcoma tumor cell kill. Intraperitoneal pretreatment with 50, 250,
and 500 mg/kg, but not 1000 mg/kg, led to better tumor response than radiation
alone. The authors also noted that intramuscular and oral tocopherol administration
had a similar effect. [86] From these results
it would appear vitamin E doses used in humans increase the effect of radiotherapy,
and super-human doses (above 35,000 IU) may blunt the therapeutic efficacy
of radiotherapy.
Radiation-induced fibrosis is a sequela to irradiation therapy which
does not spontaneously regress. A combination of vitamin E (1000 IU/day)
and pentoxifylline (800 mg/day) completely reversed a case of radiation-induced
cervicothoracic fibrosis in a 67-year-old woman after an 18-month course
of treatment. The findings were confirmed with CT scan. A phase II trial
is currently underway to confirm these results. [87]
Vitamin E with Chemotherapy
There are a few interesting recent reports on the concurrent use of
vitamin E with chemotherapy. Vitamin E, 750 mg/kg intraperitoneally, given
with 5-fluorouracil had a greater anti-tumor effect in mice bearing human
colon cancer lines than either agent alone; treatment led to complete cessation
of tumor growth. The same investigators found in vitro addition of vitamin
E to either 5-fluorouracil or doxorubicin enhances the effect of these
agents on human colon cancer cells. [7] Another
report showed pre-treatment with 85 mg (approximately 4000 mg/kg) alpha-tocopherol
reduced the lethality of a single 15 mg/kg dose of doxorubicin from 85
percent to 10 percent in mice. This dose of tocopherol did not alter the
suppression of tumor cell DNA synthesis by doxorubicin. The tumor-bearing
mice pretreated with vitamin E lived longer on average than those treated
with doxorubicin alone. The authors theorized the vitamin E blocked lipid
peroxidation-mediated toxicity, while not impairing the anti-tumor property
of doxorubicin.14 Both the toxicity prevention effect and the lack of inhibition
of vitamin E toward doxorubicin were confirmed in a later experiment. [89]
In vitro experiments showed VES can enhance the cytotoxic effect of doxorubicin
on human prostate cancer cells at concentrations easily attained in human
plasma (5 mg/ml). This inhibition was found to be dose-dependent. [89
]Oral and intraperitoneal administration of vitamin E (20 mg/kg/day)
enhanced the anti-tumor activity of cisplatin on neuroblastoma in mice. [90]
Vitamin E Summary
Selenium as Cancer Treatment
The use of selenium compounds as a cancer treatment predates most conventional
treatments currently in use. [91] In spite
of this, comparatively little is known regarding the use of selenium as
a cancer therapy in living systems. Subcutaneous injection of 2 mcg/g selenium
into tumor-bearing mice led to a 75-percent reduction in tumor mass compared
to controls. [92] This inhibitory effect of
selenium was confirmed in human breast cancer cells in vitro. [93]
In an open trial of 32 patients with treatment refractory brain tumors,
intravenous infusion of selenium (1000 mcg/day for 4-8 weeks) was associated
with a slight to definite improvement in all participants. Symptomatic
decrease was seen in nausea, emesis, headache, vertigo, and seizure activity.
Although the results are largely credited to the selenium treatment, it
should be noted these patients were concurrently receiving chemotherapy,
oxygen therapy, vitamins E and A, dietary changes, and psychotherapy. [94]
Unpublished research from the 1950s outlines the treatment of over 1000
malignancies with selenium compounds, reportedly with beneficial results. [95]
Unfortunately, a study of this magnitude has yet to appear in the peer-reviewed
literature.
Selenium with Radiation
Little is known about the interaction between selenium supplementation
and radiotherapy. In the one human trial available, patients with advanced
rectal cancer were given daily supplementation with 400 mcg of selenium
after treatment. The selenium was well-tolerated, but the researchers presented
no data regarding interaction between the two treatments. [96]
An animal study suggests that selenium depletion reduces the lethal dose
of radiation. [97] Until more is known regarding
the effect of selenium on radiotherapy, pharmacological doses (above 400
mcg/day) cannot be advised.
Selenium with Chemotherapy
Interactions between selenium and platinum-containing chemotherapy agents
have been extensively studied. In a mouse study, selenium decreased nephrotoxicity
of cisplatin, while simultaneously increasing its anti-tumor activity. [15]
Other animal studies confirmed these findings. [16,98]
A randomized crossover trial in humans looked at the effect of selenium
(4000 mcg/day from four days before until four days post-chemotherapy)
on the toxicity of cisplatin. Selenium consumption was associated with
a higher WBC count, even with less consumption of granulocyte stimulating
factor. Nephrotoxicity, measured by urine enzymes, was also significantly
less in patients taking selenium. No mention is made in this study of any
effect of selenium intake on the therapeutic activity of cisplatin. [99]
One in vitro study suggests a selenium-containing antioxidant compound
called Ebselen (2-phenyl-1,3-benzisoselenazol-3(2H)one) has a mild inhibitory
effect on the anti-tumor effect of bleomycin. The authors did not speculate
on whether dietary selenium would have an adverse effect on therapeutic
use of bleomycin. [100] Perhaps until these
results are followed up, it would be best to avoid this combination.
Selenium Summary
Coenzyme Q10 as Cancer Treatment
A series of case reports from the Institute for Biomedical Research
at the University of Texas at Austin describe the therapeutic benefit of
coenzyme Q10 (CoQ10) in cancer patients. These investigators have noted
tumor regressions and long-term survival associated with oral CoQ10, at
doses from 90 to 390 mg/day. [101,102] This
same group used 90 mg CoQ10/day, combined with other antioxidants (vitamin
C 2850 mg, vitamin E 2500 IU, b-carotene 32.5 IU, selenium 387 mcg) and
3.5 g omega-3 fatty acids, in an open trial in node-positive breast cancer
patients. Patients also underwent conventional treatment. The investigators
observed no distant metastasis in any patient, and partial remission in
six of 32 patients. No patients died during the 18-month study period.
The lack of a control group makes these data hard to interpret. [103]
CoQ10 with Radiation
A 1998 study warns that CoQ10 reduces the effect of radiotherapy on
small-cell lung cancer in mice. This trial did indeed show a significant
inhibition of radiation-induced cell growth delay at 40 mg/kg oral dose,
and a borderline inhibition at 20 mg/kg. However, no inhibitory effect
on radiotherapy was noted at 10 mg/kg CoQ10, a dose roughly equivalent
to 700 mg in an adult human. [104] Based on
this, the normal human dose of CoQ10 of 100-400 mg/day probably has little
inhibitory effect on concurrent radiotherapy.
CoQ10 with Chemotherapy
A number of studies have looked at the capacity of CoQ10 to prevent
the cardiac toxicity associated with doxorubicin. A small study in humans
showed CoQ10 administration at 1 mg/kg led to an over 20-percent reduction
in episodes of ECG change post-treatment compared with doxorubicin alone.
Diarrhea and stomatitis were also significantly reduced. [105]
A mouse study confirms the protective effect of CoQ10 treatment on the
toxicity of doxorubicin. In this study, it was noted that CoQ10 did not
reduce the anti-tumor effect of doxorubicin. Instead, a trend toward better
tumor control was seen. [106] In a study of
20 leukemia patients undergoing treatment with the similar agent daunorubicin,
100 mg CoQ10 twice daily was able to significantly reduce adverse cardiac
events as measured by echocardiography. No mention was made of the effect
of CoQ10 treatment on the therapeutic benefit of daunorubicin chemotherapy. [107]
CoQ10 Summary
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