antioxidants, chemo, & Cory

January 30, 2000

First of all, my apologies to anyone who was inconvenienced by my last post

regarding charging for e-mail. Hopefully you read the second message I sent

moments later which identified it as a hoax. I assumed the information was

reliable since it came from an MD.

And speaking of MDs...for the longest time there's been--at best--a debate

about the effectiveness or harm of antioxidants used in conjunction with

oncologic treatments (chemo, etc.). If this issue concerns you or a loved

one you may want to copy the following article (posted to another list) and

show it to your oncologist or MD. Thus far the medical establishment has

been--at best--grudgingly accepting of antioxidants and more typically

dismissive if not hostile to their use.

The following article would seem to be especially relevant for Cory's

impending bone marrow transplant...

Bill

Bill Asenjo, MS, PhD©, CRC

http://www.tell-us-your-story.com/asenjostory.html#ARCHIVES

http://www.tell-us-your-story.com/_disc68b/00000005.htm#ARCHIVES

Date: Fri, 28 Jan 2000 12:32:36 -0500

>Subject: Detailed Study of Anti-Oxidants and Chemotherapy and Radiation

>

>A number of people have been concerned about the POSSIBLE intference of

antioxidants with chemotherapy and radiation. Some of the warnings have been

tentative and a large formal review of the medical literature was done by

Drs Lamson and Brignall both Naturopathic Doctors and published in

Alternative Medicine Reviews,1999;4(5):304-329. The results showed that

there were actually only 3(Three) specific chemotherpy treatments that

interfered with the conventional chemotherapy, usually they actually

helped..I 'll list this conluding section first since its a long article and

not everyone will want to read it in its entirety.

>

>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.

>

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>Antioxidants in Cancer Therapy; Their Actions and Interactions With

Oncologic Therapies

>

> W. Lamson, MS, ND and S. Brignall, ND

>

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>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

>

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>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

>

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>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

>

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>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

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>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.31In 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 , 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.

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>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.

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>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

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>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.

ing 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.60Prospective

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 ing/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.

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>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

>

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>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

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>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

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>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

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>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

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>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.

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>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.

>

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>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

>

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>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

>

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>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.

>

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>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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>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 cells, and

therefore significantly reduces cell proliferation.8 Impaired p53 expression

is associated with many human cancers.109 Melatonin is also known to modify

many cytokines, including TNF, IL1, IL-2, IL-6, and gamma-interferon, 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 non-small 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 disease.115 The latter study stressed that based in its effects

on the immune system, melatonin could be tested in association with other

anti-tumor 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

>

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>Melatonin with Radiation

>

>In a randomized trial including 30 patients with glioblastoma, the effect

of radiotherapy plus 20 mg/day of melatonin was compared to that of

radiotherapy alone. At the end of one year, six of the 14 patients receiving

melatonin were still living, compared to one of the 16 undergoing

radiotherapy alone. The authors also noted fewer side effects from

radiotherapy in patients taking melatonin.118

>

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>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 (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 was

noted in five of the 12 patients.120 A randomized trial investigated the

difference between melatonin (20 mg/day), cisplatin, and etoposide, and

treatment with cisplatin and etoposide alone in advanced non-small cell lung

cancer. One-year survival was significantly higher in patients receiving

adjunctive melatonin compared to standard chemotherapy alone (15 of 34 vs. 7

of 36). There was a non-significant trend toward greater tumor 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

>

>Melatonin Summary

>

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>N-acetylcysteine as Cancer 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

>

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>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.126An in vitro experiment showed that NAC is not likely to block

the tumor cell killing effect of radiation.127 Application of gauze soaked

in 10-percent NAC solution to the skin 15 minutes before radiotherapy was

tested in an unblinded trial. Topical NAC appeared to be associated with

more rapid healing and less use of analgesics compared with those in the

control group.128

>

>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 that it is often used in clinical trials as an

adjunct to the therapy being tested. Animal studies have shown NAC protects

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

>

>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.137As data on the subject of doxorubicin with NAC are currently

conflicting, this combination might best be avoided at this time.

>

>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.

>

>N-acetylcysteine Summary

>

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>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

>

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>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.

>

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>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% response, compared to

52% in controls) was comparable.151

>

>A double-blind trial studied the neuroprotective effect of intravenous

glutathione (1500 mg/m2) during cisplatin treatment for gastric cancer.

After nine weeks, no patient of the 24 receiving glutathione, 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 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.

>

>Glutathione Summary

>

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>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 anti-cancer 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 curcumin (from turmeric),158 silibinin (from milk

thistle),159 and quercetin (from many yellow vegetables). The authors are

presently preparing a review of the use of quercetin as cancer therapy.

>

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>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.

>

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>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 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 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

receptor-negative 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.

>

>Flavonoid Summary

>

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>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 beta-carotene 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 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 the end of the study (mean

survival time for survivors = 32 months). No side effects from nutritional

treatment were noted.17 Hopefully these promising results will be followed

up with larger and more well-controlled studies.

>

>Combinations of Antioxidants Summary

>

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>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 appears a theoretical concern, the evidence reviewed

here shows that this proposed interaction 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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>Potential Mechanisms of Antioxidants in Cancer

>

>Therapy How could antioxidant therapy protect normal cells against damage

from cancer therapies, while often increasing their cytotoxic effect against

malignant cells? While the answer to this question is not entirely mapped

out, there are concepts which might help us understand. One is the recent

evidence that radiation and chemotherapy often harm DNA to a relatively

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

>

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>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 N-acetylcysteine 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.58The nature of this interaction is not

clear. Until this is clarified, the combination would best be avoided.