Proc Annu Meet Am Assoc Cancer Res; 35:659-60 1994. Unique Identifier : AIDSLINE ICDB/95606242 Krown SE; Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Abstract:
Although the incidence of Kaposi's sarcoma (KS) the most common neoplastic complication of HIV infection, appears to be declining with time, its prevalence remains high and appears to be growing in importance as a contributor to late morbidity and mortality in profoundly immunosuppressed HIV-infected people. Although the precise mechanisms leading to the appearance of KS lesions are incompletely understood, there is evidence that cytokines, including IL-6, oncostatin M, and bFGF, play important roles in KS development and growth. These recent insights provide the basis for new therapeutic approaches and help to elucidate the mechanisms by which an established agent, IFN-alpha, works. Therapeutic approaches to KS are reviewed. Liposomally encapsulated anthracyclines (doxorubicin and daunorubicin), currently under investigation in patients with KS as first-line chemotherapy (compared to standard therapy with the combination of doxorubicin, bleomycin and vincristine) and as therapy for chemotherapy-intolerant or resistant patients, show relatively low toxicity and a prolonged serum half-life (compared to free doxorubicin). There is evidence that tumor tissue drug levels of doxorubicin are some 5-11-fold higher after administration in a liposomal formulation (Doxil) than after an equivalent dose of free doxorubicin. In determining the optimal conditions for use of interferons in KS and as anti-HIV agents and elucidating their potential mechanisms of action, when combined with zidovudine (AZT) or didanosine (ddI), rIFN-alpha2 appears to have anti-KS activity at significantly (8-30 times) lower doses than when IFN-alpha is given alone. The combination of IFN-alpha with an RT inhibitor also appears to be active in some patients with severe immunosuppression who would be considered unlikely to respond to IFN-alpha2 monotherapy. Recent evidence that IFN-alpha species other than alpha2 may have more potent anti-HIV activity is discussed. Several additional therapeutic approaches, which are based upon the growing understanding of the factors and processes involved in the development of KS lesions, are currently in early clinical trials. For example, rIL-4, which down regulates IL-6 secretion by cultured KS-derived cells, with a coordinate decrease in KS-cell proliferation, is currently in Phase I clinical trials. Trials of other cytokine inhibitors, for example rsTNF-R, pentoxifylline and thalidomide (all of which may inhibit the action or production of TNF), and rsIL-1R and IL-1RA (which may inhibit IL-1 action), are either contemplated or in progress for KS and/or HIV infection. Another class of compounds--angiogenesis inhibitors--currently in the early phases of clinical testing have all been shown to possess significant antiangiogenic activity in the CAM assay and to inhibit the growth of sc implanted tumor cells in mice. PF4, a member of the chemotactic gene family that includes IL8 (an angiogenic molecule), is released from platelet alpha granules during platelet aggregation; its antiangiogenic activity is associated with its heparin-binding domain. DS-4152, as well as other sulfated polysaccharides including pentosan polysulfate (which has been ineffective against KS in early clinical trials), appears to inhibit the function of heparin-binding growth factors (notably bFGF) and may inhibit KS-induced vascular hyperpermeability by inhibition of VEGF, a heparin-binding growth factor of the PDGF family. Similarly AGM-1470 inhibits bFGF-induced endothelial cell growth. Additionally, several other classes of compounds including retinoids (which, among other relevant properties, may inhibit angiogenesis), and sex steroids or their inhibitors, are in early clinical trials in KS. Early results of these clinical trials were updated (9 Refs)
Keywords: Acquired Immunodeficiency Syndrome/*COMPLICATIONS/METABOLISM Antineoplastic Agents/THERAPEUTIC USE Cytokines/*METABOLISM/THERAPEUTIC USE Human Interferons/METABOLISM/THERAPEUTIC USE Interleukins/METABOLISM/THERAPEUTIC USE Sarcoma, Kaposi's/*ETIOLOGY/METABOLISM/THERAPY ABSTRACT 950430
M9541136
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