Disease relevance of Imexon

• Sensitivity of multiple myeloma to imexon in the human tumor cloning assay [1].
• Imexon inhibited four of seven fresh lymphoma and 11 of 16 fresh myeloma biopsy specimens to less than 40% of the control [2].
• BACKGROUND: Imexon, a 2-cyanoaziridine, is therapeutic and reverses lymphadenopathy and splenomegaly in the LP-BM5 murine retrovirus-induced immunodeficiency disease (murine AIDS) [2].
• This study reports that imexon has cytotoxic activity in other malignant cell lines including NCI-H929 myeloma cells and NB-4 acute promyelocytic leukemia cells, whereas normal lymphocytes and U266 myeloma cells are substantially less sensitive [3].
• Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma [4].

High impact information on Imexon

• Imexon reduced the incidence of lymphoma in severe combined immune deficient mice inoculated with human lymphocytes [2].
• RESULTS: The concentration of imexon that caused 50% inhibition of growth was under 10 micrograms/mL for lymphocytes stimulated with mitogens [2].
• Cells exposed to inhibitory concentrations of imexon were blocked in cell cycle progression [2].
• Antiproliferative and antitumor activity of the 2-cyanoaziridine compound imexon on tumor cell lines and fresh tumor cells in vitro [2].
• Flow cytometric experiments have shown that imexon treatment is associated with the formation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Deltapsi(m)) in imexon-sensitive myeloma cell lines and NB-4 cells [3].

Biological context of Imexon

• Previous studies have shown that imexon induces oxidative stress and apoptosis in the RPMI 8226 myeloma cell line [3].
• Mitochondrial swelling was observed by electron microscopy in RPMI 8226 myeloma cells treated with 180 microM imexon as early as 4 hours [3].
• Imexon-induced apoptosis in multiple myeloma tumor cells is caspase-8 dependent [5].
• Preclinical pharmacokinetics and antitumor activity of imexon [4].
• Using the maximally tolerated dose of imexon, we sought to identify a potential pharmacodynamic biomarker to monitor the mechanistic effect systemically [6].

Anatomical context of Imexon

• PURPOSE: To determine its antitumor activity, we screened imexon against fresh human tumor cells and tumor cell lines [2].
• Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one), a cyanoziridine immunomodulator with a selective inhibitory effect on B cells, was tested for its effect on this lymphoma development [7].
• Imexon was not myelosuppressive as determined by measurement of white blood cell counts [7].
• Phytohemagglutinin-induced blastogenesis and percent of total T cells, T helper cells and T suppressor/cytotoxic cells in the spleens were increased, and the percentage of B cells decreased by imexon treatment of both FV-infected and uninfected mice [8].
• Following a single 150 mg/kg dose of imexon by intraperitoneal injection, glutathione levels decreased by 40% at 3 h in mouse erythrocytes [6].

Associations of Imexon with other chemical compounds

• Treatment of imexon-sensitive RPMI 8226 cells with the antioxidant N-acetyl-L-cysteine (NAC) protects cells against these effects of imexon [3].
• Depletion of intracellular glutathione was documented in RPMI-8226 at high imexon concentrations (>or=225 microM) but not in other cell lines [5].
• We examined the mechanism of imexon cytotoxicity in a diverse panel of dexamethasone and chemotherapy-sensitive and -resistant myeloma cell lines [5].
• Bcl-2:bax was proapoptotic with imexon in C2E3, whereas bcl-2:bax was independent of steroid resistance, chemotherapy sensitivity, and chemotherapy resistance [5].
• These data suggest that imexon perturbs cellular thiols and induces oxidative stress leading to apoptosis in human myeloma cells [9].

Gene context of Imexon

• Although there was a positive correlation between increasing CuZnSOD levels and imexon resistance, no relationship was found for catalase, Bcl-2, mitochondrial thioredoxin or MnSOD levels [10].
• Imexon cytotoxicity was unchanged in three RPMI8226 cell lines with different levels (low, medium and high) of FAS expression [11].
• However, it was unknown whether imexon activates an intrinsic apoptotic pathway that is associated with activation of caspase-9 or an extrinsic pathway that is induced by receptor-mediated signals such as Fas ligand characterized by caspase-8 activation [11].
• Damage to mitochondrial DNA was detected by a semiquantitative polymerase chain reaction assay in imexon-treated RPMI 8226 cells; however, nuclear DNA was not affected [3].
• The following immunomodulators were evaluated, listed in the order of their ability to inhibit the FV disease: imexon > MVE-2 > human recombinant IFN-alpha A/D > AS101 > ampligen > AM-3 = oxamisole > ImuVert > bropirimine [12].

Analytical, diagnostic and therapeutic context of Imexon

• Since Imexon and other cyanoaziridine compounds have been safely administered to humans, we suggest that this class of compounds be further investigated in both large animal models of HIV infection and in patients with HIV-induced disease [13].
• For the scheduled phase I clinical trials a stable, sterile, injectable pharmaceutical dosage form containing 100 mg Imexon was required [14].
• Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines [15].
• Imexon, a novel pro-oxidant, thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid tumors [6].
• Confocal microscopy confirmed that caspase-3 is also activated after treatment with imexon [11].

References