ammonium-trichloro(dioxoethylene-o-o--)tellurate and Neoplasms

Tellurium is a rare element, which has been regarded as a toxic, non-essential trace element; its biological role, if any, has not been clearly established to date. The investigation of therapeutic activities of tellurium compounds is rather limited in the literature, despite the relative abundance of tellurium in the human body. Nevertheless, the varied activities of tellurium agents in both malignant and normal cells are extremely exciting, though very complex. Not surprisingly, an increased interest in tellurium among biological chemists and pharmacists has fuelled the search for more and more diverse tellurium compounds. The present review will focus on two small inorganic tellurium complexes, ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) and Octa-O-bis-(R,R)-tartarate ditellurane (SAS), thoroughly investigated by us, converging at their anti-cancer properties, and elucidating their mechanism of action. AS101 is probably the most extensively studied synthetic tellurium compound from the standpoint of its biological activity. It is a potent immunomodulator (both in vitro and in vivo) with a variety of potential therapeutic applications. It is probably the only tellurium compound to be tested in phase I/II clinical studies in cancer patients. The effects of AS101 and SAS are primarily caused by their specific Te(IV) redox-modulating activities enabling the inactivation of cysteine proteases such as cathepsin B, inhibition of specific tumor survival proteins like survivin, or obstruction of tumor IL-10 production. All of these have profound consequences regarding anti-tumor activity or sensitization of tumors to chemotherapy. These properties, coupled with the excellent safety profile of the compounds, suggest promising anti-cancer therapeutic potential for tellurium compounds such as AS101 or SAS.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Cysteine Proteinase Inhibitors; Dogs; Ethylenes; Humans; Immunologic Factors; Immunomodulation; Interleukin-10; Mice; Neoplasms; Organometallic Compounds; Rats; Tartrates

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.

Topics: Animals; Antineoplastic Agents; DNA-Binding Proteins; Ethylenes; Humans; Interleukin-10; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasms; Oligonucleotides, Antisense; Paclitaxel; Phosphorylation; STAT3 Transcription Factor; Trans-Activators

Several studies have recently suggested that the immune response to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymphocyte response in patients with advanced cancers, may be associated with disease progression. Evidence suggests that the T Helper 1 (TH1) and T Helper 2 (TH2) types of reaction are reciprocally regulated in vivo. The immunomodulator AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on cancer patients are now in progress.. The aim of this study was to evaluate the ability of AS101 to modulate TH1 and TH2 responses in tumor-bearing mice and in patients with advanced cancer. In addition, we investigated the association between the predominance of each type of response with the antitumoral effects of AS101.. Mice into which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and cancer patients (n = 13) were treated with AS101 on alternate days, at 10 micrograms/mouse intraperitoneally, or for the patients, at 3 mg/m2 intravenously. The types were sarcoma, melanoma, and colon, lung, ovarian, and renal cancers. Cytokine levels were determined by immunoassay kits and compared with the paired Student's t test: in mice, they were tested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants. The chi-squared test was used to compare tumor volumes. All P values represent two-sided tests of statistical significance.. Our results show that treatment of mice and patients with AS101 results in a clear predominance in TH1 responses, with a concomitant decrease in the TH2-type response. This was reflected by a significant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN gamma) levels (P < .01) paralleled by a substantial decrease in IL-4 and IL-10 (P < .01). Moreover, the concentration of IL-12 was significantly increased (P < .01) in AS101-treated patients who also showed enhanced levels of natural and lymphokine-activated killer cell-mediated cytotoxicity. The statistically significant increases in IL-2 and IFN gamma levels, paralleled by the pronounced decrease in IL-4 and IL-10 in the AS101-treated mice, were associated with its antitumoral effects. In addition, systemic cotreatment of 3LL-transplanted mice with AS101 and anti-IL-12 antibodies partly abrogated the antitumoral effect of AS101.. Immunotherapy with AS101 enhances TH1 function while interfering with the TH2 response. This TH1 trend may be related to the antitumor effects of AS101.. Isolation and characterization of a distinct cytokine pattern in patients with advanced cancer treated with AS101 may contribute to the development of intervention strategies using this compound.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Division; Cytokines; Ethylenes; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-4; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Spleen

AS101 [ammonium trichloro(O,O'-dioxyethylene)tellurate] is a new immunomodulator previously shown to stimulate the production of different cytokines in vitro and in vivo. We report here our results of a phase I clinical trial conducted on 47 cancer patients with advanced malignancies. AS101 was administered intravenously at escalating doses from 1 to 10 mg/m2, twice or thrice a week. The maximal tolerated dose has not yet been determined. However, significant immunologic responses were noted at dose levels of 1-3 mg/m2 administered three times a week. At these doses statistically significant rises in gamma-interferon, natural killer cell activity, tumor necrosis factor and interleukin-2 (IL-2) levels as well as the expression of IL-2 receptors were noted. In most of the immunologic parameters the maximal response was seen at 3 mg/m2. Throughout the study toxicity was minimal. In view of these results phase II studies are currently being initiated.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Drug Evaluation; Ethylenes; Female; Humans; Male; Middle Aged; Neoplasms

AS-101 (ammonium trichloro[dioxoethylene-O,O'-]tellurate) is a newly developed synthetic compound with immunomodulating properties and minimal toxicity. We evaluated the effects of AS-101 on various parameters of the activation and function of immunocompetent cells. AS-101 induced IL-2 receptor expression, IL-2 production and proliferation by human and mouse lymphocytes in vitro and enhanced the production colony-stimulating factor (CSF) by mouse spleen cells. In vivo treatment of Balb/c mice with AS-101 caused a significantly increased production of IL-2 and CSF in vitro in the presence of mitogen. When administered systemically to mice, AS-101 mediated antitumor effects in vivo. These results suggest that AS-101 is an active biological response modifier, which might have potential use in the treatment of conditions such as malignancy, AIDS and some types of immune deficiency.

Topics: Adjuvants, Immunologic; Animals; Colony-Stimulating Factors; Ethylenes; Humans; Immunotherapy; Interleukin-2; Lethal Dose 50; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Neoplasms; Rats; Receptors, Interleukin-2