There are concerns that antioxidants may facilitate metastasis. That they may have this effect in some situations should not be surprising, given the above discussions. In one of the few animal studies that tested combined antioxidants, metastasis increased.192 In this study, high and very high doses of antioxidants were given in drinking water to rats with established, carcinogen-induced tumors. The high doses were about 2.4 grams of vitamin C and 1,200 I.U. of vitamin E per day (as scaled to humans). The very high doses were 10fold greater. Both groups received selenium (at 2 mg/kg) and a thiol antioxidant compound (2-MPG, at 15
mg/kg). The high-dose therapy was not effective in increasing life span nor was tumor size greater, but secondary metastases increased. Life span was increased 1.4fold in the very high dose group, but again secondary metastases increased equal to the high-dose group. The results suggest the antioxidants may have protected me-tastasizing cells from apoptosis. Perhaps metastasizing cells are under greater oxidative stress than tumor cells and require additional antioxidants. They are certainly under great oxidative stress while they travel through the lungs during circulation. Another study also reported that synthetic antioxidants increased metastasis of lung cancer cells injected into mice but did not affect growth of the primary tumor that formed. Moreover, other studies have reported metastasizing cells are protected from apoptosis by high intracellular glutathione levels in vivo.
As we will see in Chapter 18, some antioxi-dants, including vitamins C and E, increase intracellular glutathione concentrations.
The above discussions indicate that primary antioxi-dants have the potential to promote metastasis, another reason to avoid their sole use. If they are used in combination with other cancer inhibitors, any assistance an-tioxidants may give to metastatic cells should, in theory, be negated by the effects of the other active compounds. Along these lines, secondary antioxidants could be expected to inhibit cancer more potently than primary ones.
Antioxidants may be more useful in preventing cancer than treating established cancers. A recent large clinical trial reported that prostate cancer rates were lowered in smokers who took vitamin E supplements.198 A mixture of natural compounds is likely to be even more effective. Even mixtures of primary antioxidants may be more useful than single ones, as reported recently for a combination of vitamin C and ^-acetylcysteine (NAC)
Antioxidant supplements also seem to be useful in preventing recurrence after treatment. For example, they were a prominent part of a protocol used in a randomized, double-blind study of 65 postsurgical patients with bladder cancer.40 All patients were treated with the immunostimulating bacterial compound BCG. Those who received RDA doses of multivitamins plus 40,000 I.U. vitamin A, 100 milligrams vitamin B6, 2 grams vitamin C, 400 I.U. vitamin E, and 90 milligrams zinc per day had a 41 percent recurrence rate after five years. In comparison, those receiving only BCG plus RDA multivitamins had 91 percent recurrence.
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