Antioxidants in cancer therapy; their actions and interactions with oncologic therapies

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Content: Antioxidants in Cancer Therapy; Their Actions and Interactions With Oncologic Therapies by Davis W. Lamson, MS, ND and Matthew S. Brignall, ND
Abstract There is a concern that antioxidants might reduce oxidizing free radicals created by radiotherapy and some forms of chemotherapy, and thereby decrease the effectiveness of the therapy. The question has arisen whether concurrent administration of oral antioxidants is contraindicated during cancer therapeutics. Evidence reviewed here demonstrates exogenous antioxidants alone produce beneficial effects in various cancers, and except for a few specific cases, animal and human studies demonstrate no reduction of efficacy of chemotherapy or radiation when given with antioxidants. In fact, considerable data exists showing increased effectiveness of many cancer therapeutic agents, as well as a decrease in adverse effects, when given concurrently with antioxidants. Altern Med Rev 1999;4(5):304-329 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
Davis W. Lamson, MS, ND Private practice, Tahoma Clinic- Kent, WA. Coordinator of Oncology, Bastyr University- Kenmore, WA. Correspondence Address: 9803 17th Ave. NE, Seattle, WA. 98115. Matthew S. Brignall, ND 1999 graduate, Bastyr University. Currently doing a research fellowship at Tahoma Clinic in Kent, WA. e-mail: [email protected]
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Antioxidants & Cancer
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 chemo-
therapy 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 sci-
entific 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 re-
search 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 chemo-
therapy 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 necro-
sis. However, recent evidence indicates a size-
able 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),
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CATEGORIES OF
CHEMOTHERAPEUTICS
biological response
modifiers (e.g., inter-
feron), and hormone
therapies
(e.g.,
tamoxifen). The agents
Alkylating agents (e.g., cyclophospamide, ifosamide) Antibiotics affecting nucleic acids (e.g., doxorubicin, bleomycin) Platinum compounds
DNA damage is required for cell death.23
most noted for creating cellular damage by initiating free radical oxidants are the alkylating
(e.g., cisplatin) Mitotic inhibitors (e.g., vincristine) Antimetabolites (e.g., 5-fluorouracil)
Vitamin A and Carotenoids as Cancer
agents, the tumor anti-
Camptothecin derivatives
Treatment
biotics, and the plati-
(e.g., topotecan, etoposide)
Many research
num compounds. The
Biological response modifiers
reports on the anti-
agents in these catego-
(e.g., interferon)
cancer properties of
ries demand definition
Hormone therapies (e.g., tamoxifen) vitamin A and the
concerning interactions
related retinoids
with antioxidants which
have been pub-
might reduce effective-
lished over the last 20 years. Most of these
ness of chemotherapy. There is also the possi-
studies examined all-trans retinoic acid (RA).
bility of adverse interaction between antioxi-
RA is formed in human tissues from beta-caro-
dant treatment and agents that do not act via
tene and retinol, does not accumulate in the
an oxidative mechanism (e.g., 5-fluorouracil
liver, thus it is not associated with significant
or tamoxifen).
hepatotoxicity.24 Treatment with RA is asso-
In addition to the idea that chemo-
ciated with many side effects , including head-
therapy must create a lethal injury to DNA to
ache, lethargy, anorexia, vomiting, and visual
produce malignant cell death is the mechanism
disturbance.24 Another retinoid used in cancer
of apoptosis. A dose of chemotherapy which
treatment is 13-Cis-retinoic acid (cRA), also
does not produce necrosis can trigger
known as isotretinoin.25
apoptosis, either immediate or delayed. Addi-
RA in vitro demonstrates growth in-
tionally, anti-apoptotic mutations can result in
hibitory activity against at least 14 types of
drug resistance in human tumors. At least one
human cancers.24 Acute promyelocytic leuke-
antioxidant (quercetin) has been demonstrated
mia (APL) has been shown to respond well to
to overcome such an anti-apoptotic blockage.22
RA, but not to cRA.26 In one study, nine of 11
Radiotherapy uses ionizing radiation
patients with APL entered complete remission
to produce cell death through free radical for-
after treatment with 45 mg/m2 daily oral dose
mation. Two mechanisms are involved. The
of RA.27 Similar results are reported else-
apoptosis mechanism results in cell death
where,28,29 and have been confirmed in vitro.30
within a few hours of radiation. The second
Local application of an RA-containing
mechanism is radiation-induced failure of mi-
cream demonstrated low toxicity and some his-
tosis and the inhibition of cellular prolifera-
tological improvement of cervical
tion, which kills cancer cells. Currently, the
intraepithelial neoplasia II (CIN II) in a phase
principal target of radiation is considered to
I study.31 In a phase III trial, RA led to com-
be cellular DNA. However, studies show the
plete regression of CIN II in 42 percent of
signal for apoptosis can be generated by the
women compared with 27 percent in the pla-
effect of radiation on cell membranes, appar-
cebo group.32 No significant effect was noted
ently through lipid peroxidation. This suggests
in severe cervical dysplasia.32 After remission
an alternate mechanism to the hypothesis that
induced by conventional therapy, treatment
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Antioxidants & Cancer
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, as beta-carotene has been associated with higher risk of lung cancer in smokers,41 but not in the general population.42
Aside from this concern, high doses of betacarotene, 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 betacarotene (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 cisretinoic acid (cRA) with radiotherapy and interferon-a2a on locally advanced cervical cancer noted a 47-percent tumor response and
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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, 5fluorouracil, and methotrexate) led to improved survival with less than the expected severity of side effects compared with historical controls.10
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Antioxidants & Cancer
VITAMIN A SUMMARY
Retinoic acid has been shown to be a
Although the relative lack of toxicity compared to the retinoids makes it an attractive option, betacarotene 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
promising treatment for acute promyelocytic leukemia. Vitamin A and beta-carotene increase radiation's effect in vivo, and vitamin A improves response rate in humans. Vitamin A and beta-carotene increase the effect of cyclophosphamide in vivo. Addition of vitamin A to combined chemotherapy has led to increased response in two human studies. Vitamin A has been shown in vivo not to interfere with methotrexate, cisplatin, and etoposide. No in vivo evidence suggests that vitamin A reduces the effect of chemotherapy. Beta-carotene has been shown in vivo not to interfere with doxorubicin or etoposide. Beta-carotene has been shown to reduce the effect of 5-fluorouracil on one tumor type in vivo.
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 actu-
killing with cyclo-
ally be cytotoxic
phosphamide in
to tumors without
solid tumors. The co-administration of beta-
damaging normal cells. The required tissue
carotene and 5-fluorouracil, however, reduced
concentrations are thought to only be reach-
tumor growth delay in murine fibrosarcomas,
able with intravenous doses over long periods
but not in squamous cell carcinomas.58 Data
of time. This research, as well as the proposed
on other carotenoids is lacking.
mechanism of action, is examined elsewhere.64
Vitamin C is generally well-tolerated by
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.
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.
They reported 100 cases of terminal cancer, independently assessed and refractory to con-
Vitamin C with Radiation
ventional treatment, who lived on average four
Quite surprisingly, no published stud-
times longer than 1000 age- and diseasematched controls.59 The protocol included in-
ies have looked at the effect of doses over five grams of oral or intravenous vitamin C on ra-
travenous and oral administration, and is described in detail elsewhere.60 Prospective ran-
diotherapy in humans. It has been shown, however, that cancer patients have a significant
domized trials held at the Mayo Clinic were
elevation in plasma and leukocyte ascorbate
unable to replicate these results, finding neg-
levels after radiotherapy compared with pre-
ligible difference between treated patients and controls in survival time.61,62 These results were
treatment levels without any change in dietary intake.67
criticized on a number of grounds, including
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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 noncytotoxic 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 VITAMIN C SUMMARY Vitamin C increases the effect of radiotherapy in humans and in mice. Vitamin C increases the effect of cyclophosphamide, vinblastine, doxorubicin, 5-fluorouracil, procarbazine, and asparaginase in vivo. Co-administration of vitamin K may increase both of the above activities of vitamin C. Vitamin C has been shown to increase the effect of cisplatin and paclitaxel in vitro. No in vivo evidence suggests that vitamin C decreases the effect of chemotherapy. Vitamin C may increase the resistance to doxorubicin in resistant breast cancer cells.
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Antioxidants & Cancer
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 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 G phase of the cell cycle, lead- 1 ing 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 radiationinduced cervicothoracic fibrosis in a 67-yearold woman after an 18-month course of treatment. The findings were confirmed with CT
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VITAMIN E SUMMARY
Vitamin E induces apoptosis in
scan. A phase II trial is currently underway to confirm these results.87 Vitamin E with Chemotherapy
experimental tumor lines. Vitamin E with omega-3 fatty acids increased survival time in terminal cancer patients. Vitamin E in doses below 500 mg/kg (approximately 35,000 IU human dose) may increase the effect of radiotherapy in mice. Vitamin E increases the activity of 5fluorouracil, doxorubicin, and cisplatin in
intraperitoneal
administration of
vitamin E (20 mg/
kg/day) enhanced
the anti-tumor
activity
of
cisplatin on
neuroblastoma in
mice.90
There are a few interesting recent reports on the concurrent use
vivo. No evidence exists that vitamin E reduces the effect of chemotherapy in vivo.
Selenium as Cancer Treatment
of vitamin E with
The use of
chemotherapy.
selenium
Vitamin E, 750 mg/kg intraperitoneally, given
compounds as a cancer treatment predates
with 5-fluorouracil had a greater anti-tumor
most conventional treatments currently in
effect in mice bearing human colon cancer
use.91 In spite of this, comparatively little is
lines than either agent alone; treatment led to
known regarding the use of selenium as a
complete cessation of tumor growth. The same
cancer therapy in living systems.
investigators found in vitro addition of vitamin
Subcutaneous injection of 2 mcg/g selenium
E to either 5-fluorouracil or doxorubicin
into tumor-bearing mice led to a 75-percent
enhances the effect of these agents on human
reduction in tumor mass compared to
colon cancer cells.7 Another report showed pre-
controls.92 This inhibitory effect of selenium
treatment with 85 mg (approximately 4000
was confirmed in human breast cancer cells
mg/kg) alpha-tocopherol reduced the lethality
in vitro.93 In an open trial of 32 patients with
of a single 15 mg/kg dose of doxorubicin from
treatment refractory brain tumors, intravenous
85 percent to 10 percent in mice. This dose of
infusion of selenium (1000 mcg/day for 4-8
tocopherol did not alter the suppression of
weeks) was associated with a slight to definite
tumor cell DNA synthesis by doxorubicin. The
improvement in all participants. Symptomatic
tumor-bearing mice pretreated with vitamin E
decrease was seen in nausea, emesis, headache,
lived longer on average than those treated with
vertigo, and seizure activity. Although the
doxorubicin alone. The authors theorized the
results are largely credited to the selenium
vitamin E blocked lipid peroxidation-mediated
treatment, it should be noted these patients
toxicity, while not impairing the anti-tumor
were concurrently receiving chemotherapy,
property of doxorubicin.14 Both the toxicity
oxygen therapy, vitamins E and A, dietary
prevention effect and the lack of inhibition of
changes, and psychotherapy.94 Unpublished
vitamin E toward doxorubicin were confirmed
research from the 1950s outlines the treatment
in a later experiment.88 In vitro experiments
of over 1000 malignancies with selenium
showed VES can enhance the cytotoxic effect
compounds, reportedly with beneficial
of doxorubicin on human prostate cancer cells
results.95 Unfortunately, a study of this
at concentrations easily attained in human
magnitude has yet to appear in the peer-
plasma (5 mg/ml). This inhibition was found
reviewed literature.
to be dose-dependent.89 Oral and
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Antioxidants & Cancer
SELENIUM SUMMARY
Data are incomplete regarding
Selenium with
interaction between selenium and
Radiation Little is known about the interaction between selenium supplementation and radiotherapy. In the one human trial available,
radiotherapy. Selenium increased the activity of cisplatin in mice, and decreased its toxicity in humans. No in vivo evidence exists to suggest that selenium reduces the effect of chemotherapy.
patients with advanced
rectal cancer were
given daily supplemen-
tation with 400 mcg of selenium after treat-
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.
ment. 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.
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
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 stimu-
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
lating 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 seleniumcontaining antioxidant compound called Ebselen (2-phenyl-1,3-benzisoselenazol3(2H)one) has a mild inhibitory effect on the
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
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CoQ10 SUMMARY
Doses of CoQ10 commonly used
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
in humans do not appear to inhibit the effect of radiotherapy in vivo. CoQ10 has been shown not to inhibit the effect of doxorubicin in vivo. No in vivo evidence suggests CoQ10 inhibits the effect of chemotherapy.
proliferation.8 Impaired p53 expression is associated with many human cancers.109 Melatonin is also known to modify many cytokines, including
concurrent radiotherapy.
TNF, IL1, IL-2, IL-
6, and gamma-inter-
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 20percent 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
feron, in ways consistent with increased host defense against cancers.110 Melatonin, perhaps through reduction of TNF secretion, has been shown to reduce cachexia in patients with metastatic solid tumors. Patients taking melatonin (20 mg/day) were found to have significantly less weight loss (3 kg vs. 16 kg) and disease progression (53% vs. 90%) than those treated with supportive care alone.111 In another study, 63 patients with nonsmall cell lung cancer refractory to cisplatin therapy were randomized to receive either 10 mg/day of melatonin or supportive care alone. Patients receiving melatonin lived longer on average than those receiving supportive care alone (6 vs. 3 months) and were more likely to survive for one year (8/31 survivors vs. 2/ 32). No drug-related toxicity was noted by the authors.112 Treatment with melatonin (20 mg/ day) was also associated with greater one-year survival than supportive care alone in patients with brain metastases.113 Other studies have noted increased survival in malignant melanoma114 and patients with metastatic
Melatonin as Cancer Treatment Although it is not usually considered a standard antioxidant, melatonin, the hormone secreted by the pineal gland in response to cycles of light and dark, has exhibited potent free radical-scavenging properties against hydroxyl and peroxyl radicals.108 Melatonin has also been found to have some interesting anti-tumor properties in vitro. It increases p53 expression in breast cancer
disease.115 The latter study stressed that based in its effects on the immune system, melatonin could be tested in association with other antitumor treatments.115 The DiBella multitherapy of cancer, of which melatonin is a part (along with many other agents), was found not to have sufficient efficacy against advanced cancer to warrant further investigation.116 Animal Experiments suggest doses as high as 250 mg/ kg are non-toxic.117
cells, and therefore significantly reduces cell
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Antioxidants & Cancer
MELATONIN SUMMARY
Melatonin increases tumor cell
Melatonin
apoptosis.
was noted in five
with Radiation
Melatonin decreases cachexia
of the 12 pa-
dcwttmntttstmoadhhhohiilufiioeuixeegeoneetttmndlhh/trtheraedhwhaoiotaneitfnaesgpfzaorfpdagyr1selyetnsayitIo6coda3iphrontonfaclbe0uyfespooofltlcnowopramnimfla1ednirnsuaeenari4aeetptesraopovlyilrrdea.deagtameaipreiinit2ntAosaenonooadiattrid0ges------it,,nfnllgetwslriatveadirknisoigintd,hgssittmeencuaeyofmofmermemhleamefleNaupfcooMpleMpMaytmtaoxrcto.atgeoitearorefaniseelelemnlnalnoiadanfsnnitnrstvsnptot,ootoe.di.oovnim1ci.nnnn1eoniTi8ioniscnnrtshhnepeareiueeeim-virlnnammaiicdncptsiraiernrenepeonn,saaaavscalsstce.eniceeehnttwsdihasssinevafesnuetmisesrrusccgaautamareoopgdtrvnnrryvtpeeiitehaovlilposvaayaenatatstailt-rlosohoetisaldtniinnidetitpggmieiehnnmhyen.waete(ifcsetff1rieoit.a5ichamcnsantonppdftaattr3rieee4dnnvtdtsostdvfmdetceascstir.erutmaaetidooseoeeeosrryns7wtmvcnlpaevapatp)caieaoa,nttniloilgetoimsvnlzcraosdcvfards.iaiect.naeti1sdeii3clden2reigpdneOnn0d6degbdrlwetat)elan(eAcart.,ltaal2heiithdotsTna0we-eejnnlwl,yruhrumaamseeodaaeneiiitnnneninnngtuoarigcfddndghner--------/
Melatonin with Chemotherapy Melatonin has been studied a number of times as an adjunct to standard chemotherapy in humans. A phase II study used tamoxifen plus melatonin (20 mg/day) in the treatment of metastatic breast cancer which had progressed under treatment with tamoxifen alone. Four of the 14 patients tested had partial response to this combination, with a median of eight months before disease progression. Treatment was well-tolerated and relief of anxiety or depression was noted by many patients.19 A similar study was conducted using the same combination of treatments in patients with metastatic solid tumors other than breast cancer which had not responded to previous chemotherapies. Partial response or stable disease was seen in 16/25 patients. One year survival was seen in 7/25 patients.119 In another phase II study, melatonin
mor response in melatonin-treated patients as well (11 of 34 vs. 6 of 36). Myelosuppression, neuropathy, and cachexia were noted less frequently in patients receiving melatonin than in those that were receiving only chemotherapy.121 A double-blind trial was unable to replicate this protective effect of melatonin on the myelosuppression mediated by carboplatin and etoposide. This may reflect the effect higher doses of chemotherapeutic agents given in the second trial. The authors concluded that potentiation of the effect of chemotherapy by melatonin was unlikely.122 Concomitant therapy with melatonin (40 mg/day) has been found to increase the effect of interleukin-2 against a variety of solid cancers.123 The combination of melatonin (40 mg/day) and interleukin-2 has been found to be a more effective treatment than cisplatin and etoposide in non-small cell lung cancer.124
(20 mg/day) led to a normalization of platelet
counts in nine of twelve breast cancer patients
who acquired thrombocytopenia during
epirubicin therapy. Objective tumor regression
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N-acetylcysteine as Cancer
Animal studies have shown NAC protects
Treatment We were unable to locate research demonstrating N-acetylcysteine (NAC) as an anti-tumor agent. NAC is known to be safe in doses well above that used in most human trials. Diarrhea is the most commonly reported side effect of higher doses.125
against hematuria resulting from cyclophosphamide therapy without reducing its tumoricidal effect.129-131 A phase I human trial found 6 g/day NAC completely protected against hematuria, which is a dose-limiting side effect of ifosfamide (an analogue of cyclophosphamide).132 Another human study found similar results.133
N-acetylcysteine with Radiation The effect of NAC on radiotherapy was observed in 10 patients with non-small cell lung cancer. NAC was administered by IV (100 mg/kg over 30 minutes) before the first radiation session, followed by 30 mg/kg IV over the next seven hours. They then inhaled a nebulized solution containing 600 mg NAC 30 minutes prior to and after each subsequent radiation treatment. Patients receiving NAC had tissue reactions and tumor responses from radiotherapy judged to be similar to a control group. Average survival time was similar between patients receiving NAC treatment and those who underwent radiation only. The authors concluded the treatment outcome did not justify the expense.126 An in vitro experiment
Human trials with dosages as high as 140 mg/kg NAC were unable to show any prevention of cardiomyopathy due to treatment with doxorubicin. One of these trials also noted that NAC treatment was not associated with a reduction of the anti-tumor action of doxorubicin,134,135 and a mouse study concurred. This study also noted prevention of cardiotoxicity, which as noted above, was not replicated in human studies.136 Another animal study raises the possibility of a reduction of the anti-neoplastic action of doxorubicin by NAC. NAC did, however, lead to a significant reduction in cardiac toxicity.137 As data on the subject of doxorubicin with NAC are currently conflicting, this combination might best be avoided at this time.
showed that NAC is not likely to block the
tumor cell killing effect of radiation.127
Application of gauze soaked in 10-per-
cent NAC solution to the skin 15 minutes before radiotherapy was tested in
N-ACETYLCYSTEINE SUMMARY
an unblinded trial. Topical NAC ap-
NAC does not appear to block the therapeutic
peared to be associated with more rapid
effect of radiation in humans or in vitro.
healing and less use of analgesics com-
NAC does not block the therapeutic effect of
pared with those in the control group.128
cyclophosphamide in vivo.
NAC appears to be associated with limited
N-acetylcysteine with Chemotherapy NAC has been employed with a number of chemotherapy agents as a means of reducing toxicity. It has gained such recognition in this regard
benefit in cancer therapy. One of two animal studies shows NAC to reduce the efficacy of doxorubicin. This finding was not replicated in human studies. NAC has been shown in vitro to reduce the efficacy of cisplatin.
that it is often used in clinical trials as
an adjunct to the therapy being tested.
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Antioxidants & Cancer
It has been shown in two separate in vitro studies that NAC inhibits the cytotoxic activity of cisplatin.138,139 NAC may have a role, however, in the reversal of renal toxicity due to cisplatin.140 Other than use in salvage therapy, the combination of cisplatin and NAC should also probably be avoided at this time. Glutathione as Cancer Treatment Glutathione is a tri-peptide thiol (sulfhydryl-containing) compound which is the major intracellular antioxidant in the body. A human study suggests oral glutathione is poorly absorbed, with negligible plasma concentrations found after administration of a single 3 g oral dose.141 This conclusion is contradicted by a rat study which found dietary glutathione was absorbed in a dose-dependent manner, and remained elevated in the plasma for three hours after administration.142 Aerosol administration of glutathione is an effective means of delivery to the plasma143, as is intravenous administration.144 Glutathione is thought to be non-toxic to humans,144 although one study found a 5 g oral daily dose was associated with GI irritation and sulfur odor.145 A case report from Japan in 1984 raised the possibility that glutathione might be an effective treatment for hepatocellular carcinoma. A trial of six hepatocarcinoma patients on 5 g oral glutathione daily found regression or stagnation of tumor growth in three patients. One patient also had a reduction in alpha-fetoprotein (a tumor marker) from 496 to 5. Two patients of the six survived for one year. These patients were both women, raising the possibility of a sex-dependent effect.145 In a rat study, oral administration of glutathione caused regression of liver tumors, and increased survival of tumor-bearing animals.146 The usefulness of glutathione as an anti-tumor agent may be limited to the liver, kidney, and peripheral neurons, as these are the only tissues believed to have sufficient transport enzymes for cellular uptake.144 For further discussion
of glutathione as an antioxidant, refer to the review article by Kidd.147 Glutathione with Radiation A randomized pilot trial with 45 participants investigated the radioprotective effect of glutathione. Patients were administered 1200 mg glutathione or saline placebo intravenously 15 minutes prior to pelvic radiotherapy. Patients receiving glutathione suffered less from post-therapy diarrhea (28%, compared to 52% of controls) and were more likely to complete the treatment cycle (71% to 52%). Although the sample size was too small to show significance, the authors concluded glutathione was unlikely to interfere with the effect of radiation on neoplasms.148 The argument was not based on patient outcome. Glutathione with Chemotherapy Increased cellular concentrations of glutathione have been associated with resistance to both anthracyclines and platinum agents.149 Given the suggestion of the inability of most cell types to take up exogenous glutathione,144 decreased chemotherapy efficacy due to glutathione administration may be limited to liver, kidney, and neurological tumors. The use of cisplatin and glutathione concurrently has been studied in several small human trials. One human trial found 3 g/m2 intravenous glutathione given 20 minutes prior to cisplatin (100 mg/m2) led to a significant reduction in nephrotoxicity in patients with ovarian cancer compared with those receiving cisplatin alone. There was a trend toward greater tumor response in the glutathione group--73 percent, compared to 62 percent in the control group.150 A similar trial using smaller doses of glutathione (2500 mg/m2) and cisplatin (50 - 75 mg/m2) did not find the reduction in nephrotoxicity reported above. However, the trend toward greater tumor response with glutathione treatment (72%
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GLUTATHIONE SUMMARY
Glutathione is not thought to interfere with
response, compared to 52% in controls) was comparable.151 A doubleblind trial studied
radiotherapy. Glutathione decreases toxicity, and appears to increase the anti-tumor effect, of cisplatin in humans. Glutathione/chemotherapy interactions are poorly explored.
curcumin (from turmeric),158 silibinin (from milk thistle),159 and quercetin (from many yel-
the neuroprotective
low vegetables).
effect of intrave-
The authors are
nous glutathione (1500 mg/m2) during
presently preparing a review of the use of quer-
cisplatin treatment for gastric cancer. After
cetin as cancer therapy.
nine weeks, no patient of the 24 receiving glu-
tathione, but 16 of 18 patients receiving placebo, had developed neuropathy symptoms. Again, a trend toward greater tumor response (76%, compared to 52% in controls) was seen with glutathione treatment.152 An open trial with 79 ovarian cancer patients found i.v. administration of 2500 mg glutathione prior to treatment with a cisplatin / cyclophosphamide combination led to greater tumor response and reduced toxicity compared to that found in other trials using these chemotherapeutic agents.153 Another trial using the same glutathione dose with the same combination chemotherapy found no cases of nephrotoxicity in 20 patients. The authors reported, based on their experience, that the effect of the chemotherapy was not interfered with, and may have been enhanced.154 These results have
Flavonoids with Radiation Little is known about the effects of flavonoids on radiotherapy. An in vitro experiment showed post-treatment application of quercetin caused greater cell death in radiation-treated hepatoma cells than radiation alone. In the same experiment, genistein was showed to be associated with increased cell death from radiation when applied during or after treatment.160 Many different rutosides (flavonoids with similar structures to quercetin) were found to have neither a protective nor sensitizing effect on radiotherapy in experimental mouse tumors.161 There is not enough evidence currently to support or argue against the use of therapeutic doses of flavonoids together with radiation.
not been followed up in controlled trials, however. The interactions between glutathione and chemotherapy agents other than cisplatin and cyclophosphamide have not been explored in human trials.
Flavonoids with Chemotherapy Recent research has focused on the ability of flavonoids to increase the concentration of chemotherapeutics in tumor cells. Resistance to many chemotherapy agents is
Flavonoids as Cancer Treatment Flavonoids are plant compounds known to have antioxidant properties in vitro and in vivo. Many of the thousands of flavonoids in nature have been studied for anticancer properties. Space does not permit a detailed discussion of this work. The most well characterized anti-tumor flavonoids are epigallocatechin gallate (from green tea),155 genistein (from soy and red clover),156,157
thought to be due to reduced accumulation in tumor cells.162 Oral administration of green tea in mice to increased the concentration of doxorubicin in two tumor types, but not in normal tissue. The anti-tumor activity of doxorubicin was enhanced 2.5 times.163 Another report confirmed this action of green tea, finding the tumor inhibition of doxorubicin increased from negligible to 62 percent. This report, however, determined the activity of green tea to be due
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Antioxidants & Cancer
FLAVONOID SUMMARY Several flavonoids increase radiosensitivity of tumor cells in vitro. Green tea, quercetin, and genistein increase the concentration of chemotherapy agents in some resistant cell lines. Quercetin increases the anti-tumor activity of cisplatin and busulfan in vivo, and does not interfere with the activity of doxorubicin or etoposide. Tamoxifen activity has been reduced in vivo by tangeretin and in vitro by genistein. to an amino acid, theanine, rather than its flavonoid content.164 Quercetin has been shown in vitro to increase the concentration of doxorubicin in multidrug-resistant human breast cancer cells.165 Conversely, quercetin decreased the concentration of doxorubicin in a resistant human colon cancer cell line.166 Quercetin and genistein both increased the concentration of daunorubicin in some multidrug-resistant cell lines, but had no effect in others.167 Genistein in vitro increased the concentration of cisplatin in resistant cell lines.168 Other than the green tea studies, none of these studies analyzed cell death due to flavonoid administration. In mice with transplanted human tumors, quercetin (20 mg/kg) given with cisplatin reduced tumor growth to a greater degree than cisplatin alone.169 In a separate experiment, quercetin enhanced the effect of cisplatin and busulfan in vitro and in vivo. No enhancement or reduction of the anti-tumor activity of doxorubicin or etoposide was seen.170 An in vitro study found quercetin increased the effect of doxorubicin against resistant breast cancer cells.165 It should be cautioned, however, that a recent study showed a potential adverse interaction. Tangeretin, a flavonoid found in citrus fruits, completely blocked the inhibitory effect of tamoxifen on mammary cancer in mice.171 One in vitro study suggests attenuation
of tamoxifen may be a concern with genistein as well.172 Another in vitro study, however, shows tamoxifen and genistein synergistically inhibit the growth of estrogen receptornegative breast cancer cells.173 Until the flavonoid-tamoxifen interactions are investigated more completely, it may be best to avoid using therapeutic doses of flavonoid compounds in breast cancer treated with tamoxifen. Combinations of Antioxidants Given that many antioxidants have been shown to have anti-tumor properties, it is worth exploring their use in combination. A study in mice found co-administration of betacarotene and alpha-tocopherol led to much greater tumor regression than either agent alone. The effect was synergistic, being much greater than the sum of the mild tumor inhibition of beta-carotene and alpha-tocopherol.174 Other studies have shown multivitamin supplements were associated with fewer recurrences of solid tumors after remission following standard oncologic therapies.20,21 A small double-blind trial of a mixture of antioxidants, including 600 mg vitamin E, 1 g vitamin C, and 200 mg NAC taken only during treatment, looked at the potential of this mixture to prevent cardiotoxicity during chemo- and radiotherapy. No patient taking the antioxidant mixture had a fall in ejection fraction greater than 10 percent. In patients taking placebo, four of six patients undergoing radiotherapy and two of seven patients treated with chemotherapy had an ejection fraction reduction of 10 percent or more. Treatment outcomes in patients taking antioxidants versus placebo were not discussed.175 An open trial of combination antioxidant treatment along with chemotherapy and radiation in patients with small-cell lung cancer had encouraging results. Patients taking the supplement, which contained at least 15,000 IU vitamin A, 10,000 IU beta-carotene, 300
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COMBINATION
IU alpha-tocopherol, 2 g vitamin C, and 800 mcg selenium, were able to tolerate chemotherapy and radiation well. Their two-year survival rate was greater than that of historical controls (>33% to <15%), with 44 percent still alive at
ANTIOXIDANT SUMMARY Combinations of antioxidants have been shown to have synergistic anti-tumor effects in vivo. Combinations of antioxidants with chemotherapy and radiation have been shown to increase survival time and reduce toxicity in humans.
Potential Mechanisms of Antioxidants in Cancer Therapy How could antioxidant therapy protect normal cells against damage from cancer therapies, while
the end of the study
often increasing their
(mean survival time for
cytotoxic effect against
survivors = 32 months). No side effects from
malignant cells? While the answer to this
nutritional treatment were noted.17 Hopefully
question is not entirely mapped out, there are
these promising results will be followed up
concepts which might help us understand. One
with larger and more well-controlled studies.
is the recent evidence that radiation and
chemotherapy often harm DNA to a relatively
Current Attitudes and New Approaches to Treatment Cancer therapy has been remarkably consistent for the last 50 years. Surgery, radiation, and chemotherapy have been the cornerstones of conventional treatment. Not surprisingly, the clinical success of these treatments has reached a plateau.176 Some authors have even questioned the validity of chemotherapy as a treatment for most cancers.177 Clearly, there is a need for new therapies which can increase the efficacy of cancer treatment. Careful application of antioxidants may be a means helping to raise cancer therapy to a new level of success.4 The attitude of many conventional practitioners toward antioxidant therapy for cancer has been hostile.178 Others have raised the argument that antioxidants could blunt the effect of standard therapies, particularly alkylating, platinum, and tumor antibiotic agents, which are oxidative in nature.5 While this ap-
minor extent, which causes the cells to undergo apoptosis, rather than necrosis.6 Since many antioxidant treatments stimulate apoptotic pathways,7,8 the potential exists for a synergistic effect with radiation or chemotherapy with antioxidants. A second concept is that the defensive mechanisms of many cancer cells are known to be impaired. This presumably makes tumor cells unable to use the extra antioxidants in a repair capacity; this has been illustrated in vitro. An experimental murine ascites tumor cell line was found to have 10 -100 times less catalase than comparable normal cells. This led to a build-up of hydrogen peroxide in the cells upon treatment with vitamin C, in turn leading to cell death. The cytotoxic effects of vitamin C were completely eliminated by addition of catalase to the cell culture.179 Since publication of these findings, most human tumor cell lines studied have proved to be similarly low in catalase.180
pears a theoretical concern, the evidence reviewed here shows that this proposed interac-
tion of anti- and pro-oxidant therapies is not
generally of primary importance in vivo. It is time to put this argument in perspective.
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Antioxidants & Cancer
Caveats When Considering Using Antioxidants in Cancer Treatment We wish to emphasize three concerns regarding the use of antioxidants raised in this paper. One is the routine use of Nacetylcysteine with certain chemotherapeutic agents, namely cisplatinum and doxorubicin. Given the limited therapeutic benefits associated with NAC in cancer treatment, and the number of other antioxidants shown above to help reduce the toxicities of these two chemotherapeutic agents, there appears little reason to consider NAC a first-line adjunct with either agent. Since the potential for adverse interaction with chemotherapy appears to be greater with NAC, perhaps it should be used only in situations where it has clearly been shown to not interfere with other therapies. The second concern we wish to reiterate is the interaction between tangeretin and tamoxifen. Except in cases where interactions with specific flavonoids are clearly defined, it seems prudent to avoid treatment with flavonoids in therapeutic doses concurrently with tamoxifen. It is unknown currently if there is any reduction in tamoxifen activity associated with dietary flavonoids, which are ubiquitous in the plant kingdom. The third area of concern is the potential reduction of 5-fluorouracil (5-FU) activity by beta-carotene.58 The nature of this interaction is not clear. Until this is clarified, the combination would best be avoided. Conclusion Frequently, the effects of using antioxidants concurrent with chemotherapy and radiation are synergistic. Except for three specific interactions outlined above (flavonoids with tamoxifen, NAC with doxorubicin, and beta-carotene with 5-fluorouracil), there is no evidence to date showing that Natural Antioxidants interfere with conventional cancer therapeutics in vivo. Studies have shown patients
treated with antioxidants, with or without chemotherapy and radiation, have many benefits. Patients have been noted to tolerate standard treatment better, experience less weight loss, have a better quality of life, and most importantly, live longer than patients receiving no supplements. It is time to research the role of these agents in conventional oncologic treatment, rather than dismiss them as a class based on theoretical concerns. The authors wish to thank the Smiling Dog Foundation for Financial support of this project and to Bastyr University for its administration. References 1. VandeCreek L, Rogers E, Lester J. Use of alternative therapies among breast cancer outpatients compared with the general population. Altern Ther Health Med 1999;5:71-76. 2. Singh DK, Lippman SM. Cancer chemoprevention part 1: retinoids and carotenoids and other classic antioxidants. Oncology 1998;12:1643-1660. 3. Prasad KN, Kumar A, Kochupillai V, Cole WC. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr 1999;18:13-25. 4. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy induced toxicity. Cancer Treat Rev 1997;23:209-240. 5. Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology 1999;13:1003-1012. 6. Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999;187:127-137. 7. Chinery R, Brockman JA, Peeler MO, et al. Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21 via C/ EBP-beta. Nat Med 1997;3:1233-1241. 8. Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 1999;65:415-420.
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Antioxidants & Cancer
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79. Elattar TMA, Virji AS. Biphasic action of vitamin E on the growth of human oral squamous carcinoma cells. Anticancer Res 1999;19:365-368. 80. Helson L. A phase I study of vitamin E and neuroblasoma. In: Prasad ed. Vitamins, Nutrition, and Cancer. New York: Karger Press; 1984:274-281. 81. Gogos CA, Ginopoulos P, Salsa B, et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy. Cancer 1998;82:395-402. 82. Kelloff GJ, Crowell JA, Boone CW. Clinical development plan: vitamin E. J Cell Biochem Suppl 1994;20:282-299. 83. Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr 1988;48:612-619. 84. Sakamoto K, Sakka M. Reduced effect of irradiation on normal and malignant cells irradiated in vivo in mice pretreated with vitamin E. Br J Radiology 1973;46:538-540. 85. Fonck K, Konings AWT. The effect of vitamin E on cellular survival after X irradiation of lymphoma cells. Br J Radiology 1978;51:832-833. 86. Kagreud A, Peterson HI. Tocopherol in irradiation of experimental neoplasms. Acta Radiol Oncol 1981;20:97-100. 87. Delanian S. Striking regression of radiationinduced fibrosis by a combination of pentoxifylline and tocopherol. Br J Radiology 1998;71:892-894. 88. Sonneveld P. Effect of alpha-tocopherol on the cardiotoxicity of adriamycin in the rat. Cancer Treat Rep 1978;62:1033-1036. 89. Perez Ripoll EA, Rama BN, Webber MM. Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro. J Urol 1986;136:529-531. 90. Sue K, Nakagawara A, Okuzono SI, et al. Combined effects of vitamin E (alphatocopherol) and cisplatin on the growth of murine neuroblastoma in vivo. Eur J Cancer Clin Oncol 1988;24:1751-1758. 91. von Oefele F. Some remarks on the treatment of cancerous growths with selenium compounds. American Medicine 1912;18:216-219. 92. Watrach AM, Milner JA, Watrach MA. Effect of selenium on growth rate of canine mammary carcinoma cells in athymic nude mice. Cancer Lett 1982;15:137-143.
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126. Maasilta P, Holsti LR, Blomqvist P, et al. NAcetylcystine in combination with radiotherapy in the treatment of non-small cell lung cancer: a feasibility study. Radiother Oncol 1992;25:192-195. 127. Wanamarta AH, van Rijn J, Blank LECM, et al. Effect of N-acetylcysteine on the antiproliferative action of X-rays or bleomycin in cultured human lung cancer cells. J Cancer Res Clin Oncol 1989;115:340-344. 128. Kim JA, Baker DG, Hahn SS, et al. Topical use of N-acetylcysteine for reduction of skin reaction to radiation therapy. Sem Oncol 1983;10:S86-S88. 129. Levy L, Vredevoe DL. The effect of Nacetylcysteine on cyclophosphamide immunoregulation and antitumor activity. Semin Oncol 1983;10:S7-S16. 130. Harrison EF, Fuquay ME, Hunter HL. Effect of N-acetylcysteine on the antitumor activity of cyclophosphamide against Walker-256 carcinosarcoma in rats. Semin Oncol 1983;10:S25-S27. 131. Palermo MS, Olabuenaga SE, Giordano M, Isturiz MA. Immunomodulation exerted by cyclophosphamide is not interfered with by Nacetylcysteine. Int J Immunopharmac 1986;8:651-655. 132. Slavik M, Saiers JH. Phase I clinical study of acetylcysteine's preventing ifosfamide-induced hematuria. Semin Oncol 1983;10:S62-S65. 133. Holoye PY, Duelge J, Hansen RM, et al. Prophylaxis of ifosfamide toxicity with oral acetylcysteine. Semin Oncol 1983;10:S66-S71. 134. Myers C, Bonow R, Palmeri S, et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983;10:S53-S55. 135. Unverferth DV, Jagadeesh JM, Unverferth BJ, et al. Attempt to prevent doxorubicin induced acute human myocardial morphologic damage with acetylcysteine. J Natl Cancer Inst 1983;71:917-920. 136. Olson RD, Stroo WE, Boerth RC. Influence of N-acetylcysteine on the antitumor activity of doxorubicin. Semin Oncol 1983;10:S29-S34. 137. Schmitt-Graff A, Scheulen ME. Prevention of adriamycin cardiotoxicity by niacin, isocitrate, or N-acetylcysteine in mice. Path Res Pract 1986;181:168-174.
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173. Shen F, Xue X, Weber G. Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells. Anticancer Res 1999;19:1657-1662. 174. Shklar G, Schwartz J, Trickler D, Reid S. Regression of experimental cancer by oral administration of combined alpha-tocopherol and beta-carotene. Nutr Cancer 1989;12:321-325. 175. Wagdi P, Fluri M, Aeschbacher B, et al. Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. Jpn Heart J 1996;37:353-359. 176. Braverman A. Medical oncology in the 1990's. Lancet 1991;337:901-902. 177. Braverman A. Chemotherapeutic failure: resistance or insensitivity? Lancet 1980;2:1343-1346. 178. Greenberg DM. The vitamin fraud in cancer quackery. West J Med 1975;122:345-348. 179. Benade L, Howard T, Burk D. Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. Oncology 1969;23:33-43. 180. Oberley TD, Oberley LW. Antioxidant enzyme levels in cancer. Histol Histopathol 1997;12:525-535.
NOTICE OF INTENT The American Academy of Ophthalmology's Committee on Ophthalmic Procedures Assessment Complementary Therapies Task Force will develop a Complementary Therapies Assessment (CTA) on Antioxidant Vitamin and Mineral Supplements for AMD. CTAs evaluate complementary therapies in eye care and develop an opinion on their safety and effectiveness, based on the best available evidence and scientific data. If you are interested in bringing to the Academy's attention pertinent, scientifically-sound and evidencebased reports, references and articles (other than those which are readily available in the scientific literature) for these subjects, please forward this information to Nancy Collins in the Quality and Clinical Care Department of the American Academy of Ophthalmology, 655 Beach Street, San Francisco, CA 94109. The Academy requests the receipt of any information by November 1, 1999, for timely consideration
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Title: Antioxidants in Cancer Therapy; Their Actions and Interactions With Oncologic Therapies
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Subject: Antioxidants in Cancer Therapy
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