This article originally appeared in the April 1995 issue of ForeFront--Health Investigations. The illustrations mentioned in the text have not yet been installed.

Medical Forefronts:

Thalidomide for
AIDS, KS and Cancer

by Charles Davidson

Thalidomide was developed in Germany in the 1950s by Chemie Grunenthal for use as a sedative. One of its attractive features was that it was not lethal when people took large overdoses. For several years, thalidomide was widely marketed in Europe. In 1961, thalidomide was found to cause serious birth defects (when used during early pregnancy) and was withdrawn from the European market. It never gained approval in the U.S. because of the snail's pace at which the FDA works. Since then, the American public has been peddled the idea that thalidomide is a demon drug that was kept off the US market by FDA vigilance.

The truth, then and now, is that thalidomide is an invaluable drug that is safe when used properly. In 1965, it was found to be an effective inhibitor of ENL, a complication of leprosy. In Brazil, where leprosy is a significant problem, thalidomide has been readily available.{9} During the 70s and 80s, a variety of autoimmune diseases began to be successfully treated with thalidomide: rheumatoid arthritis,{14} lupus,{15} and many others. In 1989, non-microbial aphthous ulcerations of the mouth and throat that sometimes occur in people with AIDS were reported to be successfully treated with thalidomide.{16,17} Now, six years later, thalidomide is receiving attention as a therapy for other aspects of HIV disease and cancer because of its ability to suppress tumor necrosis factor{6} and angiogenesis (the growth of new blood vessels).{5,13} This therapeutic approach will be tested clinically in the early part of 1995.

Tumor Necrosis Factor

Tumor necrosis factor (TNF) is a cytokine, a class of chemical messenger that facilitates communication between cells. Cytokines can also serve as vital growth factors. A number of cytokines, including TNF{3} and IL-6 (interlukin-6), are over-produced during HIV infection. Not only do HIV-infected cells (T-cells and macrophages) produce particularly high amounts of TNF, but TNF (and other cytokines) increase viral replication in HIV-infected cells.{18,19} By inhibiting TNF production, thalidomide produces an antiviral effect. Both TNF and IL-6 are believed to be involved in angiogenesis and Kaposi's sarcoma (KS), {2,4,20} which is the most common tumor occurring in HIV-infected individuals.

Angiogenesis and KS

Angiogenesis is the process by which small blood vessels (capillaries) are formed in new tissue. This process may be essential to expanding tumors that need new blood vessel growth to obtain needed nourishment. Angiogenesis also appears to become uncontrolled in KS lesions (the extensive new vascularization giving them their characteristic purplish or dark coloration). The ability of thalidomide to inhibit angiogenesis provides a scientific rationale for its use in KS and cancer.

Growth Factors for Kaposi's Sarcoma

Capillaries are composed of a microscopic tubule made from a continuous layer of endothelial cells surrounded by a layer of connective tissue for support. In arteries, the contractile outer layer is formed by vascular smooth muscle cells. These smooth muscle cells contribute to regulating blood pressure in the capillaries. Capillaries also contain a ring-like sphincter of smooth muscle at their opening which regulates blood flow into the capillaries.

Capillary beds are optimized for blood/tissue exchange of nutrients, gases (such as oxygen) and migrating immune cells. The smaller diameter of capillaries and the slower blood flow through them means that nearly all of the blood comes into contact with the walls of the tubule. Capillary endothelial cells thus have greater access to circulating cytokines than the endothelial cells of the larger arteries and veins. During inflammation, elevated levels of IL-6, like TNF, induce vascular relaxation, leakiness of plasma fluids, and increased migration of immune cells into the extravascular spaces.{5,6}

KS cells are not HIV-infected. They go through several developmental stages, each dependent on a possibly different group of secreted cytokines.{5,21-24} In early stages, KS cells transplanted into tissue culture need additional cytokines and growth factors to proliferate. Cells derived from more advanced KS lesions produce their own growth factors and proliferate independently, thus taking on a cancer-like growth quality.{24}

The administration of TNF alone to HIV-infected persons with KS causes a consistent and significant worsening of their KS lesions. TNF causes AIDS-KS cells to proliferate.{4} (AIDS-KS cells are from a specific cell-line standardized for research purposes which were originally derived from an AIDS patient with KS.)

Since 1991, several studies have shown that thalidomide therapy reduces blood levels of TNF in people with leprosy or HIV. Cell-culture experiments have shed light on the mechanism for this effect: thalidomide accelerates the breakdown of messenger RNA molecules that contain information needed by cells to produce TNF.{25}

TNF is angiogenic, in part, by promoting the expression of enzymes secreted from endothelial cells and macrophages which degrade the underlying extracellular matrix that surrounds blood vessels. Such enzymes are required for new vessels to elongate, branch and invade the surrounding tissues.{2,4,5,26,27}

When degraded, the extracellular matrix releases growth factors such as basic fibroblast growth factor (FGF). FGF is released by wounding and promotes healing by inducing the proliferation of blood vessel cells{28} and nearby fibroblasts (cells specialized to produce connective (structural) tissue).

FGF is one of the prominent cytokines expressed by AIDS-KS cells. When it is injected into mice, FGF causes KS-like lesions by excessive capillary proliferation. Genetic engineering techniques which block FGF expression inhibit both KS cell growth in culture and lesion formation in mice.{11} The ability of FGF to induce these lesions is augmented (in a synergistic fashion) by the HIV protein tat, which is secreted by HIV-infected cells.{12}

Tat stimulates the proliferation of both normal endothelial cells and KS- lesion-derived cells.{29} When combined with a small amount of TNF, tat causes normal endothelial cells to take on KS-like qualities.{6,30,31}

Tat increases TNF production and works synergistically with low amounts of TNF to induce IL-6 secretion byendothelial cells. IL-6 is an important growth factor for KS cells and is secreted by AIDS-KS cell cultures.{6,20,30,32}

Thalidomide and KS

Given the central role of TNF and other cytokines in angiogenesis and KS,{33} it is especially fortuitous that thalidomide not only decreases TNF production (in people),{9,34} but also inhibits FGF-induced angiogenesis (in rabbits).{13}

Oxidative Stress and KS

Increased oxidative stress (from free radicals) and reduced antioxidant defenses are characteristic of both HIV infection{35-37} and Kaposi's sarcoma (KS).{24} One of the body's key antioxidant molecules is glutathione, a scavenger of highly reactive molecules (free radicals) which would otherwise alter or damage important cellular constituents. Low glutathione levels occur in AIDS and ARC, and this deficiency causes a buildup of free radicals, an increase in TNF activity, and inhibition of T-cell proliferation.{37,38}

In normal endothelial cells, low glutathione levels are associated with diminished proliferation. However, in endothelial-like cells derived from advanced KS lesions, decreased levels of glutathione are associated with increased KS-cell proliferation.{25} Thus, free radicals (such as superoxide and related molecules) may function as growth factors for AIDS-KS cells.

The development of KS depends on natural repair processes evolved for coping with injury. As an example, when blood vessels are damaged in a tissue injury (thereby reducing oxygen levels), the damaged tissue responds by forming new blood vessels to bring in more oxygen.{39} After heart attacks (occlusion of coronary arteries), collateral vessels are formed to help bring blood to oxygen-starved tissues. In cell culture experiments, even a partial oxygen deficiency (hypoxia) promotes the replication of endothelial cells and tubule formation by stimulating the production of free radicals{40-42} and cytokines, including TNF.{43} Severe blood loss in mammals, which diminishes oxygen supply, also results in a rise in TNF levels.

During inflammation and infection, TNF induces the generation of superoxide, an oxidizing free radical used by certain immune cells to destroy engulfed microorganisms.{44,45} Massive systemic bacterial infections result in extremely high levels of TNF that can influence capillary tone and cause low blood pressure, septic shock, and even death. Chronic infection (as in AIDS or ARC) leads to long-term exposure of blood vessels to a variety free radicals and cytokines produced by activated immune cells.{44-46}

Significantly, TNF and FGF induce superoxide production in endothelial cells (and fibroblasts).{47,48} Contributing to the buildup of superoxide is the HIV protein tat, which has been reported to decrease synthesis of the antioxidant enzyme superoxide dismutase (SOD).{47} Low glutathione levels (and corresponding high free radical levels) are immunosuppressive because they decrease T-cell response to T-cell growth factor (IL-2). Low glutathione levels also promote inflammation by enhancing T-cell response to TNF.{35,37} Similarly, low glutathione levels in KS cells augment cytokine-induced angiogenesis. In cell culture, the production of macrophage-derived angiogenic factors is decreased by anti-oxidant nutrients, which scavenge free radicals.{49} This may define a preventive role for antioxidants in KS.{43}

Thalidomide and Birth Defects

The cytokines and growth factors expressed during hypoxia-induced angiogenesis are complex and involve additional cell types. For example, hypoxia induces the production of vascular endothelial growth factor (VEGF) by vascular smooth muscle cells.{50} Although normal endothelial cells do not produce it, AIDS-KS cells secrete VEGF and thereby stimulate their own growth and proliferation.{27}

In another example of cytokine synergy, small doses of VEGF and FGF (which separately do not promote endothelial cell growth) together induce marked angiogenesis.{51} The production of VEGF and FGF by vascular smooth muscle cells is also regulated indirectly by other cytokines that are associated with HIV infection, AIDS, KS and hypoxia.{21,52,53}

The value of thalidomide in the treatment of KS may be closely related to the birth defects caused by prenatal exposure. As limbs grow out of embryonic limb buds, increased oxygen demands must be met by increased angiogenesis. By inhibiting both the production of and response to certain cytokines, thalidomide prevents the formation of blood vessels{13} required to bring blood and oxygen to the growing limbs. Deprived of blood and oxygen, the limbs cease growing and fail to differentiate into fingers and toes. There is no genetic damage (mutation) involved in this effect.{54}

Cancer and Angiogenesis

In a similar manner, hypoxic conditions in the center of expanding tumors induce the production of new capillary sprouts and tubules.{43,55} Abnormal cytokine levels are required for this process as well. Without angiogenesis, tumor foci would not grow beyond 2-3 mm in diameter. In support of this principle, Judah Folkman et al. have proposed that thalidomide might be valuable as an anti-angiogenic adjunct to standard anti-cancer drug protocols. Damage-induced angiogenic diseases of the eye, such as diabetic retinopathy and age-related macular degeneration, are also candidates for treatment with thalidomide.{27}

Is There a KS Cofactor?

The presence of KS in 25% or more of homosexuals with AIDS but in only 1% of hemophiliacs with AIDS implies the presence of a KS-inducing cofactor in homosexuals with KS that is absent in HIV-infected hemophiliacs. Such a factor could be sexually transmitted. Several previously unidentified genes isolated from KS lesions have recently been identified as DNA sequences from herpes virus. These genes have not been found in blood vessels or other tissues from persons not infected with HIV.{56-58}

In addition to other viruses previously suggested to be involved in the development of KS, researchers have also proposed that certain AIDS-associated bacterial products may function as KS-inducing agents. If a non-HIV infectious agent were found to contribute towards KS in persons with AIDS, such a factor would favor the use of a multiple-drug protocol for KS.

Thalidomide and Cancer

National Cancer Institute-directed clinical trials of thalidomide are intended for KS, and cancers of the breast, brain, prostate and skin (melanoma).{59} Many cytokines that are highly expressed in KS are also excessively produced by cancer cells. Not only do these cytokines promote angiogenesis, but they sometimes act as growth factors for the tumor itself. Under these circumstances, cytokines overstimulate cellular machinery which is normally activated only periodically, and then only just preceding cell division. Cells that usually cease dividing when they come into contact with another cell then grow uncontrollably.

Among other cytokines, FGF is produced by melanomas and by breast and brain cancer cells (that also secrete VEGF{60,61}). Increased FGF levels in an individual's blood and urine are correlated with poor survival in a variety of cancers.{62} FGF functions as a growth factor for melanoma cells by increasing their replication rate;{63-65} when FGF's production is blocked, cell culture growth is suppressed.{66-69} Within solid tumors, FGF also acts on non-cancer cells (such as fibroblasts) to stimulate the production of connective (fibrous) tissue needed for their structural support.

In various cancers cells, as in KS cells, excessive levels of certain free radicals may activate pathways that encourage high rates of replication and that increase the ability of certain cytokines to effect cell growth.{18} Free radicals directly damage (mutate) DNA and may produce a series of lasting alterations in the cellular machinery involved in growth and division.

Higher-than-normal rates of replication of precancerous cells might decrease the ability of these cells to repair their DNA damage prior to the initiation of replication. An accumulation of DNA damage might cause tumors to progress to more advanced stages with increased aggressiveness.{70}

A variety of cytokines promote metastasis (the spreading of cancer cells throughout the body) by inducing the production of extracellular matrix-degrading enzymes and by increasing the permeability of blood vessels. For the same reasons, these cytokines encourage tumor invasion into the surrounding tissues.

TNF, which is often elevated during human cancers,{71} increases the ability of melanoma cells to colonize to distant sites in a recipient animal.{72,73} By producing both TNF and its receptor, melanoma cells (but not their normal progenitors) might stimulate their own growth.{64}

The proportion of cells expressing TNF in breast cancer increases with the aggressiveness of the tumor.{65} TNF production was localized in tumor-associated macrophages immediately adjacent to breast cancer (tumor) cells but not in the tumor cells themselves. The lack of TNF receptors in breast cancer tissue implies the involvement of endothelial activation and tissue-degrading enzymes in invasiveness and metastasis.{74}

By inhibiting both the response to FGF and the production of TNF, thalidomide, might suppress the replication and metastasis of melanoma and perhaps other cancers. Furthermore, thalidomide might undercut the physical requirements of expanding tumors by not only preventing new blood vessel formation but possibly by inhibiting the activity of connective tissue cells like fibroblasts.


We should not let the adverse effects of thalidomide on the human fetus blind us to its potentially valuable role in the treatment of diseases in adults. The FDA's politicization of the thalidomide incident as popular justification for their institution has resulted in a long-standing reluctance to see thalidomide investigated for autoimmune diseases and HIV-associated aphthous ulcers. This prejudice has resulted in shortages of thalidomide and delays of cancer trials.

Beyond birth defects, the next most serious side effect of thalidomide is peripheral neuropathy (pain or numbness in the hands, lower legs, and especially in the feet). Neuropathy typically occurs only after long-term use, but it can also make preexisting neuropathy worse. Permanent nerve damage can be prevented if detected early, and nerve electrical abnormalities may precede clinical symptoms. In some individuals, neuropathy begins after several months of moderate to high use. If peripheral neuropathy does occur, the condition will return to normal more quickly if its use is discontinued as soon as symptoms develop.{75}

Thalidomide's most immediate side effect is drowsiness (for which it was originally developed). Except for the side effects from fetal exposure, thalidomide is less dangerous than a number of drugs presently in common use for a variety of conditions.

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