A new immunomodulating compound (AS-101) with potential therapeutic application

Abstract

There has been interest in the potential of synthetic compounds to modify immune responses by imitation of cytokine action. Direct administration of interleukin 2 (IL-2) in conjunction with adoptive transfer of lymphokine activated killer cells has been used in the treatment of cancer, but there are toxic effects resulting from the high doses of IL-2 required. We have developed a new synthetic compound, ammonium tri-chloro(dioxoethylene-O,O'-)tellurate (AS-101), which has immunomodulating properties and minimal toxicity. The effects of AS-101 on the activation and function of immunocompetent cells have been assessed. We have found that AS-101 induces proliferation and IL-2 production by human lymphocytes in vitro, and enhances the production of IL-2 and colony-stimulating factor by mouse spleen cells. Splenocytes of BALB/c mice injected with AS-101 increased production of IL-2 and CSF in vitro in the presence of mitogen. Mononuclear cells of normal donors acquired responsiveness to recombinant IL-2 and bound monoclonal antibody to IL-2 receptor after incubation with AS-101. Splenocytes of mice treated in vivo with AS-101 expressed high levels of IL-2 receptor. The stimulation of lymphocytes by AS-101 apparently involves an increase in intracellular free calcium. AS-101 administered systemically to mice mediated antitumour effects which could be attributable to its immunomodulatory properties. In addition, AS-101 could directly enhance the ratio of OKT4 to OKT8-positive cells in cultured mononuclear cells from AIDS (acquired immune deficiency syndrome) patients. These results indicate that AS-101 is potentially useful in the treatment of clinical conditions involving immunosuppression.

Driving GDNF expression: The green and the red traffic lights

“…This is further supported by the finding that AS101 increases GDNF production in rat glomerular mesangial cells (Kalechman et al, 2003) and GDNF mRNA levels in peripheral blood leukocytes and head kidney cells (Okun et al, 2006). AS101 is an immunomodulator (Sredni et al, 1987) that directly inhibits the transcription of IL-10 followed by the increase of specific cytokines including IL-1a and TNF-a (Sredni et al, 1987;Kalechman et al, 1995Kalechman et al, , 1997Strassmann et al, 1997). AS101 increases GDNF levels in rat astrocyte cultures and in the human SVG astrocyte cell line, while LPS-induced IL-10 secretion in the presence of AS101 is inhibited in both cell types (Sredni et al, 2007).…”

Ammonium Trichloro(dioxoethylene-o,o′)tellurate (AS101) Sensitizes Tumors to Chemotherapy by Inhibiting the Tumor Interleukin 10 Autocrine Loop

“…Most of its activities have been primarily attributed to the direct inhibition of the anti-inflammatory cytokine interleukin (IL)-10 (15), followed by the simultaneous increase of specific cytokines (16 -18). These immunomodulatory properties were found to be crucial for the clinical activities of AS101, demonstrating the protective effects of AS101 in parasite-and virusinfected mice models (19), in autoimmune diseases (20), in septic mice (21), and in a variety of tumor models in mice and humans where AS101 had a clear antitumoral effect (16,22). Phase I clinical trials with advanced cancer patients treated with AS101 showed increased production and secretion of a variety of cytokines, leading to a clear dominance in TH1 responses with a concurrent decrease in the TH2 responses (22).…”

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

“…The most notable tellurium compound that exerts biological activity is found in the salt ammonium trichlorido (dioxyethylene-O,Oꞌ)tellurate, known as AS-101 ( Figure 1a) [25]. This low-molecular weight organotellurate is a potent immunomodulator [26] that has been in clinical trials for psoriasis [27], topical treatment for human papillomavirus [28], prevention of infertility in chemotherapy patients [29] and for inhibition of angiogenesis [24,30].…”