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Nutritional Supplements & IL-2
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Nutritional Supplements and Interleukin-2

This article is about substances available as "Nutritional Supplements" which may be helpful to take with IL-2 therapy. This article is not about "boosting the immune system" in general. It is limited to things which may be useful with Interleukin-2.

That I have listed something here does not mean I automatically recommend you take it with IL-2. It means I've found something interesting on relating to that substance and IL-2. I recommend you talk to your doctor about any of these substances before taking them. Having said that, these are things that many doctors may be unaware of and which you can do for yourself.

At the same time, if your doctor is skeptical, you might take that with a grain of salt and require a specific reason to believe it would be a bad idea. Many doctors still turn up their professional noses at the mention of vitamins and herbs. With classic cytotoxic chemotherapy, which is far more used in cancer treatment than immunotherapy, the drug does the work by killing the cancer cells directly. With immunotherapy, the drug stimulates your own body, your immune system, to destroy the cancer. Your body does the work, and it seems obvious that maintaining adequate nutrition for immune function makes sense. It makes more sense when it turns out that the immunotherapy taxes the body's reserves of some nutrients known to be important in immune function. The situation here is entirely different from the typical "chemo" (though I'm not excluding that nutrition can make a difference with chemo - that's a different story though). If your doctor is a skeptic, you might share the evidence I present here.

Vitamins and Minerals

Vitamin C

High dose IL-2 severely depletes blood vitamin C levels, often to levels associated with scurvy, the disease caused vitamin C deficiency[Marcus 1987]. The depletion is so severe that often no vitamin C is detectable (the level is below the detection limit of the assay).

In the initial report [Marcus 1987], response to treatment correlated with a lesser depletion of C levels but the entire study was based on only 11 patients of which only three responded to treatment. When they updated their study by adding four more patients [Marcus 1991], the correlation didn't hold up. Three of these four were responders, thus doubling the size of the responder group. These numbers are still so tiny there is no way you could hope to reliably determine whether there was a real correlation or not. Furthermore, even the responders still had severe declines in vitamin C status.

As the authors point out, vitamin C is required for proper function of the immune system, and specifically for cell mediated immunity, which is the arm of the immune system which IL-2 stimulates and which is responsible for response to IL-2.

It makes no sense to allow your vitamin C level to be depleted to the level of clinical scurvy during treatment, so I recommend supplementing with vitamin C before, during and after treatment. It is difficult to know how much to give, since unfortunately no studies have been done on how much vitamin C is required to maintain normal levels, but 500 - 1000mg, while well above RDA levels, is very safe and seems reasonable. I would start supplementing a week before therapy starts and continue for a month afterwards. They did test a few (3) patients and found vitamin C levels had recovered to normal one month post-treatment.

Whether outpatient IL-2 causes similar depletion of vitamin C is not known. While the therapy is less intense than high dose, it's more prolonged. Since modest vitamin C supplementation is non-toxic I think it makes sense even if there's some uncertainty about whether it is really needed.

Other Vitamins

Baker 1992 studied the effect of high dose IL-2 therapy on a number of vitamins and other micronutrients.

Some Were Decreased

  • Vitamin A (Retinol) (60% became deficient)
  • Beta-Carotene (80% became deficient)
  • Vitamin B6 (90% became deficient)
  • Folic Acid (45% became deficient)

Some Were Increased

  • Vitamin B12 (Elevated in all patients)
  • Inositol (Elevated in 90%)

Some Were Unchanged

  • Vitamin E
  • Panthonate (Vitamin B5)
  • Thiamin (Vitamin B1)
  • Riboflavin (Vitamin B2)
  • Niacin (Vitamin B3)
  • Biotin

Not surprisingly given the extreme demands on the immune system imposed by high dose IL-2 therapy, most of the vitamins which are decreased (Vitamin B6 and vitamin A/Beta Carotene, Vitamin C) are specifically known to be necessary for proper immune function. Folic acid isn't known as an immune stimulant but it is required for cell division and would be needed to support proliferation of immune cells. Although again, this study doesn't address whether supplementing these vitamins would either improve response or decrease the side effects, it makes a great deal of sense to support the nutritional demands of IL-2 therapy with supplementation.

Minerals

Magnesium

A group from The National Cancer Institute has recently studied the effects of IL-2 therapy on magnesium levels [McKee 2002]. The resulting picture is complex, but in the end I think don't justify do-it-yourself supplementation.

They found that serum magnesium declined to somewhat low levels while the amount in white blood cells increased dramatically. The decline in magnesium levels was nothing like that for vitamin C, where declines to undetectable levels are common. The body has a large store of magnesium in the bones and magnesium levels are more closely regulated than vitamin C levels.

Magnesium levels in the serum returned to normal levels within three days of stopping IL-2 and they also found that supplementing with modest amounts of magnesium during treatment in patients with low magnesium failed to raise the levels.

I think given the very large rises in magnesium in the lymphocytes they are probably able to get all they need for immune function out of their environment. The resultant low magnesium levels could cause side effects, but the authors note that serious side effects associated with severe magnesium deficiency are rare in IL-2 treatment though more subtle (and more manageable) effects can't be ruled out. Overall though, this doesn't appear a severe concern to me.

One popular but credible reference on magnesium [Hendler 1990]stated that while serious problems from magnesium overdose are rare, they can occur in people with impaired kidney function. Given that the kidneys tend to shut down temporarily over the course of high dose IL-2 treatment, I think supplementing with large amounts of magnesium without careful monitoring of the levels would be highly inadvisable. Don't do it! I wouldn't worry about the small amount in a typical multivitamin.

Overall Recommendations

High dose IL-2 causes nutritional stress that affects a number of important vitamins though not all. Since not all micronutrients have been studied with IL-2, and since vitamins and minerals in reasonable amounts are non-toxic, it seems prudent to take a high quality comprehensive vitamin and mineral supplement with IL-2 treatment plus enough vitamin C to bring you to a total of 500-1000mg per day. The vitamins which had increased levels during IL-2 were presumably being released from body stores, and I presume adding a little more wouldn't be toxic since these vitamins aren't toxic to begin with.

References

Baker H, Marcus SL, Petrylak DP, Frank O, DeAngelis B, Baker ER, Dutcher JP, Wiernik PH.
Effect of interleukin-2 on some micronutrients during adoptive immunotherapy for various cancers.
J Am Coll Nutr. 1992 Oct;11(5):482-6. [PubMed Abstract (will open in new window)]
Sheldon Hendler, M.D, Ph.D.
The Doctor's Vitamin and Mineral Encyclopedia
Simon and Schuster 1990 NY, NY
Lissoni P, Arosio V, Mocchegiani E, Fabris N, Barni S, Pierpaoli W, Tancini G.
Zinc levels in serum during subcutaneous interleukin-2 immunotherapy of cancer.
Int J Biol Markers. 1995 Apr-Jun;10(2):124-5. [PubMed Abstract (will open in new window)]
Marcus SL, Petrylak DP, Dutcher JP, Paietta E, Ciobanu N, Strauman J, Wiernik PH, Hutner SH, Frank O, Baker H.
Hypovitaminosis C in patients treated with high-dose interleukin 2 and lymphokine-activated killer cells.
Am J Clin Nutr. 1991 Dec;54(6 Suppl):1292S-1297S. [PubMed Abstract (will open in new window)]
Marcus SL, Dutcher JP, Paietta E, Ciobanu N, Strauman J, Wiernik PH, Hutner SH, Frank O, Baker H.
Severe hypovitaminosis C occurring as the result of adoptive immunotherapy with high-dose interleukin 2 and lymphokine-activated killer cells.
Cancer Res. 1987 Aug 1;47(15):4208-12. [PubMed Abstract (will open in new window)]
McKee MD, Cecco SA, Niemela JE, Cormier J, Kim CJ, Steinberg SM, Rehak NN, Elin RJ, Rosenberg SA.
Effects of interleukin 2 therapy on lymphocyte magnesium levels.
J Lab Clin Med. 2002 Jan;139(1):5-12. [PubMed Abstract (will open in new window)]

Melatonin

Melatonin is a human neuro-hormone produced by the pineal gland. Astoundingly in the United States, melatonin is available over the counter as a nutritional supplement, although in some other countries it is more closely regulated. Melatonin, which must be taken at night, is non-toxic for most people although some suffer vivid or disturbed dreams, especially at first, and occasionally fatigue is a problem, particularly with very high doses.

Melatonin has important roles in the regulation of your natural night-day cycle and also seems to be an immune regulator. A significant amount of clinical work has been published on combining IL-2 and melatonin claiming either increased efficacy or decreased side effects. All or almost all of it is from one Italian doctor, Paolo Lissoni. Many of these studies are small, and I have qualms about some of them.

Further Details To Come Soon!

Astragalus Herb

This non-toxic herb is a mainstay of Chinese Herbal medicine and is an immune stimulator. It is widely available as a nutritional supplement. Test tube experiments, and possibly clinical work in China, suggest possible synergy with IL-2 treatment.

Further Details To Come Soon!

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This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: July 29, 2003, Last Updated: February 2, 2004