Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe combined immune-deficient (SCID) mice accept human cell xenografts. SCID mice inoculated intraperitoneally with human peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors develop a form of disseminated human large cell lymphoma similar to that seen in transplant recipients and AIDS patients. 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. Imexon started 2 weeks after PBMC inoculation significantly reduced the number of animals with lymphoma and the number of lymphomas sites per animal. The lymphoma was widely metastatic in the control animals but limited to the peritoneal cavity in the treated animals. Morphological and molecular parameters were used to confirm the reduced takes in the treated animals. Imexon was not myelosuppressive as determined by measurement of white blood cell counts. Imexon did not significantly suppress human IgG levels in the animals' serum. The tumor growth and lethality of human B lymphoblastoid cell lines in SCID mice was also suppressed by imexon treatment. A relatively nontoxic class of drugs that can suppress the development and/or growth of EBV-related lymphoma should be explored with priority for potential use in patients at high risk of this type of lymphoma.
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PMID:Suppression of human lymphoma development in the severe combined immune-deficient mouse by imexon therapy. 839 8

Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) microM for a 48 h exposure with a range of 64-358 microM. Cell killing was schedule-dependent, favoring exposure times > or =48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations < or =200 microM for 48 h. When concentrations were increased to 300 microM for > or =48 h, the MiaPaCa-2 cells arrested in G2 phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of > or =400 microM were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards. The levels of imexon that are cytotoxic in human PCC's are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G2 arrest, accumulation of ROS, and the induction of apoptosis.
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PMID:Induction of apoptosis and cell cycle arrest by imexon in human pancreatic cancer cell lines. 1622 32

The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium. For a selection of compounds (Clofibrate, Gefitinib, Sirolimus, Imexon and Dexamethasone) their ability to restore ciliogenesis was confirmed in a panel of human cancer cell line models representing different cancer types (pancreas, lung, kidney, breast). Most compounds attenuated cell proliferation, at least in part through induction of the primary cilium, as demonstrated by cilium removal using chloral hydrate. These findings reveal that several commonly used drugs restore ciliogenesis in cancer cells, and warrant further investigation of their antineoplastic properties.
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PMID:Identification of drugs that restore primary cilium expression in cancer cells. 2686 38