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Lorus describes anti-cancer effects of two programs
2006-04-03 08:34 ET - News Release
Ms. Grace Tse reports
SMALL MOLECULE SERIES AND INTERLEUKIN-17E SHOW POTENT ANTICANCER ACTIVITY
Lorus Therapeutics Inc. has released data showing novel anti-cancer activity from two of its lead preclinical programs.
"Lorus is a leader in the development of drug candidates from a broad range of technologies, and our in-house research facility allows us to advance new lead compounds efficiently from discovery to formal drug development, adding significantly to the value of Lorus's drug pipeline. These presentations describing novel agents with strong anti-cancer properties are excellent examples of this strategy at work," said Lorus chief executive officer Dr. Jim Wright.
Series of small molecules suppress tumour cell growth
In a presentation entitled "Novel series of small molecules suppress in vitro and in vivo tumour cell growth of colon carcinoma cells through the induction of Kruppel-like factor 4 (KLF4)," Lorus provides data regarding a series of compounds (2-indolyl imidazol 4, 5-d phenanthroline derivatives) developed by Lorus that demonstrate potent and novel anti-cancer activity. The studies presented describe the characterization of the anti-cancer activity and molecular mechanism of action of these compounds. A pattern of tumour-type selectivity was shown in an in vitro anti-tumour screen at the National Cancer Institute (NCI) developmental therapeutics program, and lead compounds showed potent as well as selective growth inhibition of colon cancer, leukemia, non-small-cell lung cancer and prostate cancer. The compounds exhibited in vivo activity in both the hollow-fibre assay, and in mouse models of human colon and lung tumour growth. In addition, dose-schedule studies defined effective therapeutic dose ranges with no signs of apparent toxicity.
The studies on the mechanisms of action focused on changes in gene expression in response to treatment in human tumour tissue implanted into mice. Results indicate that the compounds target the metal-responsive transcription factor-1 or MTF1, a zinc-dependent protein that modulates expression of genes involved in zinc homeostasis. Drug-mediated displacement of zinc associated with MTF-1 resulted in MTF-1 downregulation leading to a strong induction of the tumour suppressor Kruppel-like factor No. 4 (KLF4), a transcription factor with an emerging role in the development and progression of colon carcinoma as well as other types of cancers. KLF4 is a negative regulator of cell growth through mechanisms that include suppression of cyclin D1 expression, leading to cell cycle arrest at the G1 phase. Critical involvement of KLF4 has been validated in siRNA-mediated knockdown experiments, in which KLF4 downregulation resulted in the loss of drug-mediated cell growth inhibition.
IL-17E demonstrates significant anti-tumour activity
In a presentation entitled "IL-17E, a proinflammatory cytokine, has a novel anti-tumour function in vivo," Lorus examines the role of IL-17E as an anti-tumour agent, a previously unrecognized function of IL-17E.
IL-17E belongs to a larger family of cytokines (proteins that function as part of the immune system) and has potent inflammatory effects in vitro and in vivo. Expression of high levels of IL-17E in mice results in a T helper-2 (TH2) type of immune response, characterized by the expansion of eosinophils, and upregulation of specific TH2 type cytokines including IL-5, IL-4 and IL-13.
IL-17E demonstrated significant anti-tumour activity against a variety of human tumours, including melanoma, pancreatic, colon, lung and ovarian tumours grown in mice. In addition, combinations of IL-17E with chemotherapeutic agents showed enhanced anti-tumour efficacy against human colon, lung, melanoma and ovarian tumour models in mice.
The anti-tumour activity was dose-dependent and was observed using three different routes of administration. Consistent with the observed binding of both human and mouse IL-17E to the mouse IL-17E receptor, human IL-17E also exhibited anti-tumour activity against human tumours grown in mice. Studies on the mechanism of action showed that treatment with IL-17E resulted in increased serum levels of IL-5 and increased percentages of eosinophils in peripheral blood. Spleen cells isolated from IL-17E-treated mice showed increases in eosinophils and B-cells, as well as an increase in the percentage of activated B cells. Furthermore, treatment with IL-17E resulted in phosphorylation of kinases and activation of transcription factors involved in immune stimulation. Taken together, the data support further investigation of the potential clinical application of IL-17E, placing IL-17E in a growing class of anti-cancer immunotherapeutic drugs.
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