Vitamin E May Protect Against.........

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Vitamin E may protect against cisplatin-induced neurotoxicity

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Publish Date: 04/04/2003

NEW YORK (Reuters Health) - Mounting evidence from both preclinical

and clinical studies suggests that supplementation with the

antioxidant alpha-tocopherol may protect cancer patients from

cisplatin-induced toxicity without interfering with antitumor

efficacy.

The latest study, from an Italian group led by Dr. Carlo Leonetti of

Regina Elena Cancer Institute in Rome, is published in the March 20th

issue of the International Journal of Cancer. " This preclinical study

was performed on the basis of an original observation from physicians

of our institute that neurotoxicity in cancer patients treated with

cisplatin was accompanied by a fall in plasma levels of vitamin E, "

Dr. Leonetti told Reuters Health.

In experiments with the M14 human melanoma cell line, adding alpha-

tocopherol to cisplatin did not reduce the efficacy of cisplatin.

Conversely, the addition of alpha-tocopherol increased survival in

mice treated with high-dose cisplatin.

With cisplatin alone, 70% of mice died, compared with only 30% of

mice treated with cisplatin and alpha-tocopherol. Histologic studies

on peripheral nerve also showed protection against cisplatin-induced

neurologic damage.

The researchers credit the apparent protective role of alpha-

tocopherol against the toxic effects of chemotherapy to its

antioxidant activity.

Dr. Leonetti said a larger randomized study is getting underway on

cancer patients at Regina Elena Cancer Institute. In addition to

cisplatin, alpha-tocopherol supplementation could be useful to reduce

neurotoxicity of other chemotherapeutics such as vincristine, he said.

The Views on the News section is a commentary from a leading cancer

expert on what this story means and why it's important to you.

Two new studies suggest vitamin E may protect against nerve damage

from the chemotherapy drug cisplatin

Author: Ethan Basch, MD, Editor of Natural Standard, CancerSource

Medical Advisory Board Member

Cisplatin toxicity

Cisplatin (Platinol) is a chemotherapy drug used to treat many types

of cancer. Its use is often limited because of its toxic side

effects, which can include nerve damage (neuropathy), kidney damage

(nephrotoxicity), and hearing damage (ototoxicity, tinnitus). These

effects can be irreversible. Neuropathy occurs in almost all patients

who receive a lifetime total dose greater than 300mg/m2 of cisplatin.

Researchers do not fully understand how the toxicity is caused. One

theory is that the toxicity is caused by oxidative damage to nerve

and kidney cells. Some research has linked the side effects of

cisplatin with the formation of oxygen free radicals (1,2).

Experiments in animals suggest that antioxidants such as selenium,

vitamin C, or vitamin E may protect patients from getting kidney

toxicity and hearing damage (ototoxicity) caused by cisplatin

(3,4,5). It has also been suggested that low vitamin E blood levels

in patients taking cisplatin may add to the nerve damage. (6). Other

agents have been tested and found to have some protective effects.

These include adrenocorticotropic hormone analogs, ciliary growth

factor, nerve growth factor, amifostine, and thiols.

Two studies were recently published by an Italian research group. The

studies tested the ability of vitamin E to protect against nerve

toxicity from cisplatin (7,8).

Laboratory/animal study

Leonetti et al. published a two-part study in the International

Journal of Cancer (7). In the first part, the effects of vitamin E on

the anti-tumor properties of cisplatin were tested in human cancer

(M14 melanoma) cells in a laboratory. Cells were placed into a petri

dish with cisplatin, with or without vitamin E. The anti-tumor

effects of cisplatin on these cells were not changed by vitamin E. In

the second part of the study, 40 mice with tumors were treated with

cisplatin for three weeks. Half of the mice were given vitamin E, and

the other half received no protective therapy. After 20 days, 70

percent of the non-vitamin E treated mice died, while only 35 percent

of the vitamin E treated mice died. Examination of nerves under a

microscope found less nerve damage (demyelination) in the vitamin E

treated mice. The authors suggested that vitamin E might be a useful

protective agent that does not lower the anti-tumor effects of

cisplatin. These results are promising, but findings in the

laboratory and in animals do not always mean they will work in

humans.

Human study

A second study, by Pace et al. was done in humans (8). This trial

included 47 patients who were 28 to 74 years old, had solid tumors,

and were to receive cisplatin. Cancer types included lung, ovarian,

nose/throat, urethral, gastric, testicular, esophageal, ethmoidal,

and tongue. Participants were randomly picked to either receive

vitamin E or not. The dose of vitamin E used was 300mg/day (Ephynal,

Roche, Milan, Italy) beginning several days before chemotherapy and

continuing for three months after treatment was finished. The average

dose of cisplatin given was 420mg/m2.

Out of the 47 participants, 20 dropped out and 18 stopped

chemotherapy after two to three cycles because their cancers

progressed. In the remaining 27 patients, there was no difference

between groups in the growth of tumors or in the amount of kidney

damage seen. There was no nerve damage or neuropathy in any patient

at the beginning of the study. After six months of treatment, 86

percent of patients not taking vitamin E showed symptoms of nerve

damage (peripheral neuropathy), while only 31 percent of patients who

took vitamin E had this toxicity. Survival data was not provided.

Antioxidants in cancer

Vitamin E (a-tocopherol) is a fat-soluble vitamin found naturally in

many vegetables, including asparagus, corn and corn oil, nuts,

spinach (and other green leafy vegetables), sunflower oil, and

soybean oil. Vitamin E acts as an antioxidant in the body, and it has

been proposed in the treatment of many illnesses.

The role of antioxidants in cancer remains controversial. Oxidative

damage has been linked with the development of many cancer types.

However, it is not yet clear if antioxidant therapy prevents cancer.

Population studies suggest that intake of antioxidants such as

lycopene may lower the rate of cancer. However, well-designed

prospective controlled trials are not available, and this evidence is

not conclusive. It has also been suggested that high-dose

antioxidants may actually interfere with the effects of chemotherapy

or radiation therapy. Therefore, cancer patients are often

discouraged from taking these supplements during chemotherapy or

radiation therapy.

Analysis

These two new studies have been published by the same research group,

based at the Regina Elena Cancer Institute and San Gallicano

Institute, Rome, Italy. The publication by Leonetti et al. provides

laboratory and animal evidence that vitamin E does not interfere with

the effects of chemotherapy. Pace et al. wanted to show that the rate

of nerve damage can be lowered in humans with the use of vitamin E.

Although impressive results were reported for the 27 patients

remaining in the study, the conclusion is limited because so many

other patients dropped out of the study. It is not clear why patients

dropped out, and it is possible that subjects either with the best or

worst symptoms failed to finish the study. No analysis or follow-up

of the dropouts was presented. The study was not blinded, which is a

potential source of bias. Due to these methodological weaknesses, the

results cannot be considered conclusive.

Conclusion

Patients taking cisplatin should be watched carefully for signs and

symptoms of toxicity. Intravenous hydration, anti-nausea medications,

and monitoring of urine output and creatinine are standard. Mannitol

is given with some doses. In patients at risk of developing nerve

damage or neuropathy, or those approaching a lifetime cumulative dose

of 300mg/m2, neuroprotective agents can be considered. There is

compelling initial evidence supporting the use of vitamin E as a

neuroprotective agent. However, the evidence remains preliminary, and

a firm conclusion cannot be reached without more high-quality human

research.

References

Smoorenburg GF, De Groot JC, Hamers FP, et al: Protection and

spontaneous recovery from cisplatin-induced hearing loss. Ann N Y

Acad Sci 1999; 884:192-210.

Weijl NI, Hopman GD, Wipkink-Bakker A, et al: Cisplatin combination

chemotherapy induces a fall in plasma antioxidants of cancer

patients. Ann Oncol 1998;9(12):1331-1337.

Sugihara K, Gemba M. Modification of cisplatin toxicity by

antioxidants. Japan J Pharmacol 1986;40(2):353-355.

Appenroth D, et al: Protective effects of vitamin E and C on

cisplatin nephrotoxicity in developing rats. Arch Toxicol

1997;71:677.

Rybak LP, Husain K, C, et al: Effect of protective agents

against cisplatin ototoxicity. Am J Otol 2000;21(4):513-520.

Bove L, Picardo M, Maresca V, Jandolo B, Pace A. A pilot study on the

relation between cisplatin neuropathy and vitamin E. J Exp Clin

Cancer Res 2001;20:277-280.

Leonetti C, Biroccio A, Gabellini C, et al. a-Tocopherol protects

against cisplatin-induced toxicity without interfering with antitumor

efficacy. Int J Cancer 2003;104:243-250.

Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of

vitamin E supplementation in patients treated with cisplatin

chemotherapy. J Clin Oncol 2003;21(5):927-931. Breast Cancer News is

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