Canadian AIDS Treatment Information Exchange (CATIE) TreatmentUpdate48, Vol. 4, No. 8 - March 1994
Sean Hosein

The standard therapies for treating Kaposi's sarcoma (KS) may reduce the size and spread of lesions in people with AIDS but this relief is usually temporary and is not a cure. Moreover, the side effects from these treatments are not pleasant and can reduce quality of life. Here are some therapies that are being tested either m laboratory experiments or in humans with KS.

VITAMIN A AND RELATED CHEMICALS

Researchers in the USA are testing vitamin A-related compounds, called analogies, such as Accutane, beta-carotene, Retin-A (tretinoin) and Tegison (etretinate), by themselves or in combination with interferon- alpha as potential KS therapies. These vitamin A analogues are normally used by doctors to treat acne or psoriasis. We know a small number of patients with KS who have just started using these analogues (Retin-A, 0.05%) on their lesions. So far they appear to peel the skin and some lesions appear to be getting thinner. As these patients have only just started using these drugs they do not know if the lesions will disappear. Retin-A therapy will not affect lesions inside the body.

BETA-CAROTENE

We know of two patients with KS who are taking large doses of beta-carotene 100,000 iu and 200,000 iu respectively, per day. one plans to do a schedule of 3 weeks on, 1 week off. The other is doing 2 months on, 1 month off. Both of these have just started using high-dose beta-carotene so they don't know if it is having any effect on their lesions.

OTHER IMMUNE BOOSTERS

Earlier in 1993 we reported results from 1 patient who had KS lesions on his foot and ankle injected with GM-CSF (granutocyte-macrophage colony-stimulating-factor). The lesions disappeared completely. Researchers in Canada, under the aegis of the Canadian HIV Trials Networks plan to study the effect of intralesional GM-CSF on KS. Injecting another immune booster interleukin-2 (IL-2) in doses of "3 to 5 million units, 3 times weekly for 4 weeks", directly into the lesions is also supposed to destroy KS lesions. Some patients in Canada and the USA are applying the immune booster DNCB directly onto KS lesions.

ANTI-INFLAMMATORY DRUGS--DEXTRAN AND HEPARIN

Another potential therapy is the use of anti-inflammatory chemicals. These drugs could help restrict the overgrowth of blood vessels that make up KS lesions. In this area potential therapies include Aspirin, Indocid, dextran and heparin sulfates and certain fatty acids found in cod, halibut and other fish oils. In the late 1980s some Canadian patients with KS treated themselves with dextran sulfate but this drug seemed to have no effect on their lesions or survival. A related chemical, pentosan polysulfate, is being tested in clinical trials in the USA. Heparin, a drug used to prevent blood from clotting, has potential but we do not know of any patient who has used it. In the EC heparin is sold in the form of a cream. Heparin may also affect the functioning of cells of the immune system and this may or may not be useful. A dangerous effect of heparin is its ability to allow cuts or breaks in blood vessels to bleed and so trials with this drug or related chemicals may be dangerous.

ANTI-INFLAMMATORY DRUGS--FATTY ACIDS

Oils from the livers of cod and halibut (with the vitamins A and D removed) are sold in health food stores in the EU (European Union) and the USA under brand names such as 'MaxEPA'. These oils contain the fatty acids EPA and DHA (eicosapentaenoic acid and doscosahexenoic acid) commonly called omega-3 lipids. These oils have an anti- inflammatory effect and may be useful for some people with mild acne, arthritis and psoriasis. These fatty acids may suppress the formation of certain chemicals (such as TNF (tumour necrosis factor) and certain prostaglandins) that may impair the immune system. As with dextran and heparin, omega-3 lipids, while not as powerful, may also increase the time it takes blood to clot. Oil from flax seeds also contains omega-3 lipids and is sold in health food stores in North America.

A PILOT STUDY OF FATTY ACIDS

At the V International Conference on AIDS in Montreal, the BioSyn Corporation had an abstract on fatty acids published. This American company conducted a small study on five HIV-infected subjects with KS giving them high doses of essential fatty acids (equivalent to about 6 grams/day of fish oil with added vitamin E and beta-carotene as preservatives). Two subjects had a good response to this therapy with a complete loss of lesions after 6 months of therapy. In patients with many lesions it took at least 6 months before some of the lesions grew smaller or faded. Interviewed at the conference, personnel associated with the study found that most subjects had some improvement in their KS as a result of this therapy. However, they confessed that by the 9th month of therapy all patients had "relapsed" and old as well as new lesions began to appear. At that time they could not explain why this happened.

The failure of the therapy may have occurred because the body adapted to continuous doses of the fatty acids since it was given every day. For trials of drugs that affect the immune system some immunologists are suggesting that these drugs not be given every day. Please see TreatmentUpdate 39 for details.

Perhaps another issue is long-term use. In one study researchers enrolled people without HIV infection. Subjects in this study received a very high dose of MaxEPA 18 grams daily. Researchers did not detect any significant changes in CD4+ or CD8+ cell counts. Some activities of the immune system were enhanced while others were reduced. In another study in women, researchers gave the subjects 2.4 grams/day. Some immunofunctions remained within the normal range in young women while in older women the researchers detected some suppression of the immune system. We know of 1 HIV-infected patient who is using 6 grams/day, 5 days weekly of omega-3 lipids extracted from fish and flax oil as part of a treatment for KS. He is also taking 400 iu of vitamin E and at least 50, 000 iu of beta-carotene as preservatives. After 1 month of using these fatty acids he has not had any new lesions. The problem in evaluating this therapy is that this patient, like many others with HIV, is using a number of drugs that affect the immune system such as DNCB, high-dose beta-carotene and co-enzyme Q10, just to name a few. Another confounding factor is that there may be lesions growing inside his body of which he is not aware. As well, it is possible that this is just part of the natural progression of KS and more lesions might appear in the future.

UNRAVELING THE BLOOD VESSELS

Since KS lesions are an overgrowth of blood vessels, drugs that can cause the collapse of this network are being tested for anti-KS effects in humans. Some of these drugs include:

- an artificial form of fumagillin (AGM-1470, TNP470) is being given to subjects at the National Cancer Institute (NCI, Bethesda, MD)

- PF4 (platelet factor 4) is being injected into the lesions of subjects at San Francisco General Hospital

- Pentosan polysulfate (mentioned earlier)

REFERENCES:

1. Myskowski PL. Kaposi's sarcoma: where do we go from here? Editorial. Archives of Dermatology 1993;129:1320-1323.

2. Katakkar SB. Use of heparin as a topical anti-thrombotic and anti-inflammatory agent. Journal of the National Cancer Institute 1993;85(22):1865-1866.

3. Ihreke NS, Wrenshall LE, Lindman BJ and Platt JL. Role of heparin sulfate in immune system-blood vessel interactions. Immunology Today 1993;14(10):500-505.

4. Golden S. Kahl P and Sears B. Dietary intervention in Kaposi's sarcoma patients. V International Conference on AIDS, Montreal, June 4-9, 1989, abstract ThBP381, page 479.

5. Folkman J. Diagnostic et applications therapeutiques de la recherche sur l'angiogenese. Comptes rendus de l'Académie des sciences, Sciences de la vie 1993;316:909-913.

6. Leventhal LJ, Boyce EG and Zurier RB. Treatment of rheumatoid arthritis with gammalinoleic acid. Annals of Internal Medicine 1993;119(9):867-873.

7. Louthrenoo W. Successful treatment of severe Reiter's syndrome associated with Human Immunodeficiency Virus infection with etretinate: Report of two cases. Journal of Rheumatology 1993;20: 1243-1246.

8. Endres S. Meydani SN, Ghorbalii R. et al. Dietary supplementation with Q-3 fatty acids suppresses interleukin-2 production and mononuclear cell proliferation. Journal of Leukocyte Biology 1993;54:599-603.

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