Kaposi's sarcoma will never be the same.
The rare "classical" disease used to consist of non-malignant tumorson the legs of elderly Russian Jews and Italians. Then suddenly, withonset of the AIDS epidemic, Kaposi's sarcoma became the mostprevalent HIV-associated cancer, affecting fully 50 percent of thevirus's victims.
Late last year, virologists discovered that AIDS-related Kaposi'ssarcoma clearly implicated a new type of herpes virus. (SeeBioWorld Today, Dec. 16, 1994, p. 1.) Now researchers are allegingthat Kaposi's sarcoma is apparently a sexually transmitted disease,which a hormone secreted by pregnant women can reverse.
In today's Nature, National Cancer Institute virologist Robert Gallo,co-discoverer of the AIDS virus, reports that "Tumorigenesis andmetastasis of [a] neoplastic Kaposi's sarcoma cell line inimmunodeficient mice [is] blocked by a human chorionicgonadotropin (hCG), a pregnancy hormone."
Field studies by two of the paper's co-authors, Philippe Hermans ofthe Free University of Brussels, Belgium, and Jacques Besnier of theOB/GYN Medical Center in Paris, tend to bear out the hypothesisthat besides supporting the first two trimesters of gestation, hCGtakes part in the hormonal regulation of local angiogenesis (newblood-vessel formation) and blood flow in menstruation. This wouldexplain why Kaposi's sarcoma attacks so few women.
Hermans followed up on a 35-year-old African women with a two-year history of AIDS-related Kaposi's sarcoma, marked by 14growing lesions. She conceived, and five months into her pregnancy,none of the lesions had progressed. They all disappeared within fivemonths of her giving birth to a baby free of Kaposi's sarcoma, butseropositive for HIV-1.
Besnier reported a Caucasian women, age 27, who owed her AIDS-Kaposi's sarcoma infection to six months on intravenous drugs.Within the first two months of her pregnancy, all five of her Kaposi'ssarcoma tumors had vanished.
Gallo's team showed in vitro that the beta chain of hCG killedAIDS-Kaposi's sarcoma cells that caused malignant metastatictumors in nude mice, presumably by apoptosis. The pregnancyhormone also did away with another neoplastic Kaposi's sarcoma cellline unrelated to HIV.
In their experiments, the scientists inoculated Kaposi's sarcoma cellsinto four female and two male newborn nude mice (which aregenetically immunodeficient). Another 39 adult mice, 20 female and19 male, got similar injections. All adults, and the two neonatalmales, contracted malignant metastatic tumors. Their four femalelitter mates who became pregnant remained tumor-free.
Mice gestate their fetuses for 19 days on average. Females injectedduring the first 10 days of pregnancy, when the CG hormone is mostactive, did not develop Kaposi's sarcoma tumors; those inoculatedlate in gestation generated small but non-metastatic lesions.
In vitro, Kaposi's sarcoma cells bathed in hormone-containing mouseand human sera from early-stage pregnancies showed "markedinhibition of growth." Later-stage sera produced "minimal"inhibition; sera from non-pregnant rodents and humans no effect atall.
Gallo and his co-authors conclude: "To our knowledge, this is thefirst demonstration of an anti-tumor property of beta human chorionicgonadotropin, and offers a new strategy for treating patients withKaposi's sarcoma."
Accordingly, Hermans and Besnier in Europe, and co-author ParkashGill, a research hematologist/oncologist at the University of SouthernCalifornia (USC) in Los Angeles, have already begun clinicaltherapeutic trials. Results of these trials will be available soon.
Since last October, Gill's lab at USC injected native human chorionicgonadotropin into the Kaposi's sarcoma lesions of 25 AIDS patients."We did this," Gill told BioWorld Today, in a dose-escalatingscheme with increased doses of the hormone in each of four patientgroups."
Herpesvirus Kaposi's Sarcoma Causality?
Molecular biologist Yuan Chang, whose paper in Science (Dec. 16,1994) disclosed the connection between AIDS-Kaposi's sarcoma andherpesvirus, has read Gallo's report implicating human chorionicgonadotropin. "I don't really know," she told BioWorld Today, "thatthere's an open-and-shut case there. The only comment I can make atthis point is that I very strongly feel the central etiologic factor forKaposi's sarcoma is the herpes virus. There many be othercofactors," Chang added," such as cytokines and hormones thatcertainly alter or make an impact on the expression of the disease."
Chang and her husband Patrick Moore, both of Columbia University,in New York, co-authored the lead article in today's New EnglandJournal of Medicine (NEJM). Its title: "Detection of herpesvirus-likeDNA sequences in Kaposi's sarcoma in patients with, and thosewithout, HIV infection."
Its findings purport to clear up a key question of herpesvirus causalityin Kaposi's sarcoma. As Chang explained to BioWorld, "Everybodywas asking whether the herpes may be associated with Kaposi'ssarcoma, and with AIDS, perhaps as just another opportunistic orpassenger infection in someone who's immunocompromised."
A leading herpesvirologist, Bernard Roizman of the University ofChicago, is not so sure. "The presence of [this new herpesvirus] in avery large fraction of Kaposi's sarcomas, both AIDS-related andclassic," Roizman wrote in an NEJM editorial, points to [theherpesvirus] as either a highly preferred passenger or an etiologicagent, but the available data do not permit discrimination between thetwo alternatives."
Chang's NEJM paper describes "six classical Kaposi's sarcomapatients, and four HIV-negative homosexuals who also had Kaposi'ssarcoma," she said. She explained the increased risk of Kaposi'ssarcoma run by gay men as "having to do in part with certain sexualpractices and behaviors," which are also risk factors for AIDS. "So itappears to be a sexually transmitted disease, in parallel with the HIVorganism."
As circumstantial evidence supporting her thesis that herpesviruscauses Kaposi's sarcoma, Chang cited independent case reports thatthe cancer resolved, or failed to develop, in patients treated withfoscarnet, a potent across-the-board anti-herpesviral drug. "So acouple of intriguing things have come up since our [December]Science paper," she observed, "suggesting that there may be someinterventional strategies.
"The next question, of course," Chang concluded, "is to explore thebiological properties of the Kaposi's sarcoma-associated herpesvirus,and we're very much interested in pursuing that." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.