NEWS

KS Enters Y2K Still Riddled With Many Questions

Mike Miller

Despite many treatment breakthroughs and the decline in incidence of AIDS-related malignancies — Kaposi's sarcoma in particular — there are many perplexing mysteries still surrounding these cancers.

The 1994 discovery of human herpesvirus-8, for example, was a major breakthrough in the etiology of KS. But in the intervening 5 years, scientists have been unable to link HHV-8 solely to KS.

"In [only] 50% of mice injected with HHV-8, KS lesions have developed," a finding that suggests that HHV-8 "is sufficient but not necessary for KS, " noted Kimberly Foreman, Ph.D., an assistant professor of pathology, Loyola University, Chicago, at the recent annual meeting of the Institute of Human Virology in Baltimore. "Thus, a co-factor may be needed for 100% transformation."

A "Peculiar" Growth

Robert Gallo, M.D., director of the institute, said that several growth-promoting genes and several pathways may be implicated in the disease process, although he believes that KS is clearly caused by HHV-8. But Gallo described KS, as he has in the past, as "a peculiar kind of growth" because in its early stages it is more like a lesion, only becoming cancerous in some people in late-stage disease.



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Dr. Robert Gallo

 
Among the more puzzling aspects of KS, Gallo said, are that it is seldom seen in women; its African endemic form is found mainly in children despite the fact that it is thought to be sexually transmitted; and that other factors in addition to HHV-8 might be involved in its development. "I think it is clear now that the KS virus exists at the outset of lesion formation," Gallo said, "but is it in the lesion, or are inflammatory changes needed for its replication to begin?"

Answers to these questions may have implications beyond containing and treating KS in this country, several speakers suggested. Jeffrey Martin, M.D., an assistant professor of epidemiology and biostatistics at the University of California, San Francisco, noted that " other herpesviruses are clearly known to do more than one thing." Martin said that just as herpes zoster causes shingles and varicella zoster causes chicken pox, HHV-8 may be associated with multiple myeloma.

According to Harald zur Hausen, M.D., director of the German Cancer Research Center, Heidelberg, among the agents thought to induce cancer, "there are two known parasites, one bacterium, and five viruses."



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Dr. Harald zur Hausen

 
In fact, he said, an estimated 15% to 20% of global cancer incidence can be linked to some kind of infection. But when it comes to viruses, zur Hausen added, the latency period linked to tumors is about 30 to 60 years. KS, however, presented itself fairly early in the AIDS disease process in the 1980s, creating an anomalous mystery in zur Hausen's latency of viruses schema.

Global Havoc

One example of the potential havoc created by the global spread of human herpesviruses came from Chris Boshoff, M.D., Ph.D., a professor at University College London, England. Boshoff is conducting a study among Ashkenazi and Sephardic Jews in Israel where various diseases associated with HHV-8 are seen, particularly a form of KS in older men that has no known environmental factors contributing to its development.

"In our study," Boshoff said, "KS, Castleman's disease, and primary effusion lymphoma all appear to be related to HHV-8. We now think that Castleman's [disease] may be associated with a subtype of HHV-8."

If, as Boshoff's study suggests, HHV-8 and KS have the potential to cause widespread harm and considerable disease burden, are treatment and control plans for these agents adequate?

One area of cancer treatment, anti-angiogenesis, intersects directly with KS treatments. "KS exhibits lots of angiogenic lesions. For that reason, we have clinical trials of endostatin and angiostatin that are either in early experimental stages, or are recruiting patients that will examine the effects of these agents on KS lesions," said James Pluda, Ph.D., senior clinical investigator, Investigational Drug Branch, National Cancer Institute.

Isaiah Fidler, D.V.M., Ph.D., chairman of the Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, said, "anti-angiogenic therapy has the ability to treat cancer as a chronic biological disease." Fidler explained that KS cells can't survive without an oxygen supply and if the cells are more than 200 microns from a capillary, they die. Thus, cutting off the blood supply to KS could theoretically kill the lesion.



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Dr. Isaiah Fidler

 
Fidler also noted that angiogenesis occurs due to the absence of suppressor genes such as interferon, which down-regulates transcription. Interferon is one of the drugs of choice in several KS treatment regimens. "Each step of angiogenesis is governed by independent genes and their associated proteins" and the search for these genes is an active area of research in his laboratory, he said.

Robert Yarchoan, M.D., chief of the HIV and AIDS Malignancy Branch, NCI, is conducting a clinical trial of interleukin 12 to study its possible anti-angiogenic activity. Yarchoan has found that IL-12 can induce type 1 immune responses, which can then activate interferon gamma. "We have observed a very different response in KS to IL-12 than we see with chemotherapy for other cancers," Yarchoan said. "In KS, the lesions wane gradually over the course of a year, whereas in conventional chemotherapy, if successful, there is often a more immediate response."

Treatment of KS in its earlier stages may be most effective because "in people with aggressive KS, substances like IL-12 may not be effective due to its toxic side effects," said Yarchoan. Other researchers have tried substances like interferon alpha against KS, but Yarchoan claims that IL-12 is less toxic.

When looking at controlling KS before it gains a strong toehold, Paul Zoeteweij, Ph.D., Dermatology Branch, NCI, said that one problem with immunosuppressive therapies is that they may contribute to the development of KS by activating HHV-8 replication. He cautions against using HIV therapies that could be strongly immunosuppressive.

Yarchoan concurred. But, he added, anti-retroviral therapy including protease inhibitors do seem to be effective against KS development.

Eradication of HHV-8 and its attendant diseases is unlikely any time soon. But control of diseases such as KS does seem possible, according to experts in the field.

As Pluda noted of his and Yarchoan's ongoing IL-12 study, "most of the 15 patients enrolled in the trial tolerated the IL-12 quite well, with only some attendant neutropenia. And 12 of the patients showed partial spontaneous resolution of their symptoms after 1 to 2 weeks of treatment." If trials such as these hold up, the morbidity and mortality from KS could be diminished substantially.



             
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