Corbeil J, Rapaport E, Richman D, Badel P, Looney DJ; National Conference on Human Retroviruses and Related Infections.
Program Abstr Second Natl Conf Hum Retrovir Relat Infect Natl Conf Hum Retrovir Relat Infect 2nd 1995 Wash DC. 1995 Jan 29-Feb 2; 79.
University of California San Diego.
Rationale: Topical all-trans retinoic acid (retinoin, ATRA) has been reported to be an effective agent for treatment of cutaneous Kaposi's sarcoma(KS). An understanding of the mechanism of action retinoid compounds on KS cells is needed to formulate optimal strategies for the use of retinoids in clinical trials. Methods: Kaposi's sarcoma cells (KSC) were derived from lesion explants from both HIV(+) and HIV(-) patients. A panel of retinoid compounds (ATRA, isotretinoin, acitretin, RO13-1470, other related compounds) was tested for inhibitory activity against KSC, in vitro, using 3H- thymidine uptake. Cell killing was assessed by trypan blue dye exclusion, and cellular DNA fragmentation determined by propidium iodide staining and flow cytometry. Expression of cytokines, oncogenes, and receptors in treated and untreated cells was analyzed by immunohistochemistry and RNA-PCR. Results: ATRA was effective in inhibiting the growth of KSC in vitro at nanomolar to micromolar concentrations, without altering constitutive expression of IL-6 or bF-GF, or their receptors. ATRA selectively inhibited growth of early passage KSC at low concentrations (10(9)M). At higher concentrations (10(6) to 10(5)M), retinoid treatment induced a pattern of DNA degradation and morphological changes in KSC characteristic of apoptosis. Apoptosis in treated KS cells was accompanied by the induction of high levels of expression of fas, myc, and TNFR1 proteins, suggesting the activation of pathways of programed cell death similar to those shown to be involved in growth factor withdrawal, or fas mediated apoptotic death of activated lymphocytes. The inhibitory activity of ATRA on KSC growth was decreased by human serum, and partially restored by removal of serum lipids. Conclusions: These data suggest that retinoids possess potential as therapeutic agents in Kaposi's sarcoma, but that endogenous retinoids, retinoid blinding proteins, or other serum factors may inhibit retinoid action. Further study of the action of retinoids on Kaposi's sarcoma cells is indicated.
Publication Types:
Keywords:
- Acitretin
- Acquired Immunodeficiency Syndrome
- Apoptosis
- Cytokines
- Gene Expression
- Growth Inhibitors
- Growth Substances
- Homicide
- Humans
- In Vitro
- Interleukin-6
- Isotretinoin
- Receptors, Interleukin-6
- Retinoids
- Sarcoma, Kaposi
- Skin Neoplasms
- Tretinoin
- genetics
- immunology
- metabolism
Other ID:
UI: 102213112
From Meeting Abstracts