Modulation of macrophage-lymphocyte interactions by the antiarthritic gold compound, auranofin.

Auranofin (AF), a new oral gold agent effective for treating rheumatoid arthritis (RA) was evaluated for its ability to alter macrophage and lymphocyte functions of immune mediated chronic inflammation. AF (2 microM) inhibited antigen presentation by splenic macrophages to sensitized (DNFB) lymph node cells in vitro and also inhibited production of IL-2 and IL-1 by lymphocytes and macrophages, respectively. When AF suppressed Con-A induced mitogenesis in vitro, there were no inhibitory effects on Con-A induced suppressor T cell functions.

Identification of live cells for flow cytometric analysis of lymphoid subset proliferation in low viability populations.

Combined analysis of single cell DNA content and immunofluorescence by flow cytometry is complementary to tritiated thymidine analysis of cellular proliferation, allowing detailed dissection of particular cell types in a mixed population which respond proliferatively to selective stimuli. However, in vitro culture of primary immune cells (e.g.

Microprocessor-assisted plethysmograph for the measurement of mouse paw volume.

A sensitive and reproducible method of measuring mouse paw volume was developed by interfacing a Mettler DeltaRange top-loading balance with a microcomputer. This methodology combined ease of operation and precision with the advantages of computer-controlled data processing and archivable storage of data.

Inhibition of T suppressor cell expression by histamine type 2 (H2) receptor antagonists.

The effect of histamine type 2 (H2) receptor antagonists, cimetidine and ranitidine, on the induction and expression of hapten-specific suppressor T cells was studied. The activity of DNBSO3 -induced suppressor cells was evaluated after adoptive transfer to naive syngeneic recipients. Treatment with cimetidine or ranitidine markedly inhibited suppressor T cell activity in a dose-related manner and enhanced the contact sensitivity response to DNFB.

Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice.

Following implant of cotton thread-carrying 3-methyl-cholanthrene into the pancreas tissue of 90 C57BL/6 and 60 BALB/c mice, 13 developed ductal adenocarcinomas. Two of these tumors, both of C57BL/6 origin (Panc 02 and 03), were established in serial s.c.

Antiinflammatory activity of 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles. Isomeric 4-pyridyl and 4-substituted phenyl derivatives.

Isomeric 5(6)-(4-pyridyl)- and 6(5)-(4-substituted-phenyl)-2,3-dihydroimidazo[2,1-b]thiazoles were prepared by a mixed benzoin-imidazothione route, and their structures were assigned by spectral comparison to compounds of established substitution pattern. The structural assignment was confirmed by X-ray analysis. Examination of the compounds for antiinflammatory activity by an adjuvant arthritic rat assay revealed strikingly higher potencies for one analogous series than for their isomers.

Biologic actions and pharmacokinetic studies of auranofin.

The preclinical profiles of auranofin (Ridaura), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate, gold thioglucose, and their respective ligands were compared. Auranofin was more effective than gold sodium thiomalate in suppressing inflammation and stimulating cell-mediated immunity. In contrast to gold sodium thiomalate and gold thioglucose, auranofin inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions.

Establishment of cross-resistance profiles for new agents.

Sublines of murine leukemias (L1210 and P388) and solid tumors selected for resistance to representatives of all of the chemical and functional classes of clinically useful anticancer drugs have been isolated and established in serial in vivo passage and, in some cases, in vitro culture. Extensive resistance, cross-resistance, and collateral-sensitivity patterns have been established with most of the sublines of the drug-resistant murine leukemias under treatment with greater than 100 different established and clinically useful anticancer drugs or new candidate anticancer drugs currently under study. Patients selected for inclusion in phase I-II trials usually have tumors that have failed to respond to treatment with established clinically useful drugs, either from the start of treatment or during continuing treatment after initial useful response.

Distribution of gold in rat blood after intravenous administration of auranofin, gold sodium thiomalate and aurothioglucose to rats.

Serum, blood and cell-associated gold were determined at various time periods after intravenous administration of 1 mg Au/kg of auranofin (AF), gold sodium thiomalate (GSTM) and aurothioglucose (GTG). AF gold exhibited an early phase of decay with high levels of cell-association; whereas, after 72 h cell-associated gold was not detectable. In contrast, GSTM and GTG serum gold values were generally higher than blood values since cell-associated gold rarely occurred.

The pharmacological profile of auranofin, an orally active gold compound.

Auranofin (AF; ' Ridaura '), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate (GST) and gold thioglucose (GTG) were evaluated in order to compare their preclinical profiles. AF was found to be more effective than GST and GTG in suppressing inflammation and stimulating cell-mediated immunity. In contrast to GST, AF inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions.

Inhibition of antibody synthesis by histamine in concanavalin A-treated mice: the possible role of glucocorticosteroids.

Administration of histamine (50 mg/kg) to BALB/C mice injected with concanavalin A (Con A) (100 micrograms, i.v.) 24 hr previously, results in a marked decrease in antibody synthesis to sheep red blood cells (SRBC) injected 2 hr later.

A high performance liquid chromatography assay for the rapid analysis of the subunit content of concanavalin A.

A high performance liquid chromatography system is described which provides a rapid and convenient assay for the relative amounts of intact (26000 dalton) and fragmented (14000 and 12000 dalton) subunits present in preparations of concanavalin A. Analyses were performed on an HPLC size exclusion column using either 8M urea or 6M guanidine hydrochloride as denaturing eluents. The efficiency and resolving power of this technique were confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis.

Comparative pharmacology and biological effects of different gold compounds.

Auranofin's (AF) physical, chemical, pharmacological, and pharmacokinetic properties differ from those of gold sodium thiomalate (GSTM). AF is lipid soluble, monomeric, nonconductive and is not a potent sulfhydryl reagent. In further contrast to GSTM, AF gold is orally absorbed, exhibits protracted blood levels, is bound to cellular elements of the blood, excreted mainly in the feces, and exhibits less tissue retention.

Mechanisms of action of auranofin: effects on humoral immune response.

Auranofin (AF) and gold sodium thiomalate (GSTM) were evaluated in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent antibody responses. AF decreased the ability of immune sera to participate in ADCC, whereas GSTM did not. Immune serum from AF-treated rats also exhibited a decreased antibody-dependent complement lysis (ADCL) reactivity.

Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents.

Other investigators have demonstrated that dihydroxyanthracenedione (DiOHA) and anthracenedione acetate (AA) are active against a broad spectrum of transplantable mouse tumors. DiOHA and AA are in clinical trial in the US; AA is in clinical trial in Europe. Because of the broad spectrum of activity of these DNA binders against murine tumors and due to their promising clinical utility, we have evaluated these agents in combination with a variety of clinically useful antitumor drugs.