Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro macrophage- or TNF-alpha-mediated selection procedures on 3LL tumor cells have led to the selection of 3LL variants manifesting a highly reduced sensitivity towards the cytotoxic effects of both TNF-alpha and tumoricidal macrophages, while retaining the parental sensitivity to the cytolytic activity of (i) H2O2, (ii) macrophage-ADCC reactions and (iii) NK cells. A correlation was observed between the TNF-alpha binding capacity of the 3LL cell lines and their susceptibility towards macrophage- and TNF-alpha-mediated cytotoxicity, indicating that macrophage and TNF-alpha sensitivity may partially be regulated at the TNF-alpha receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-alpha receptor by interferon-gamma (IFN-gamma) or 5'-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-alpha. The resistance of the 3LL variants to macrophage- and TNF-alpha-mediated cytotoxicity in vitro was reflected by a higher tumorigenic and metastatic potential in vivo. Therefore, the generation of TNF-alpha- and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.
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PMID:TNF-alpha mediated selection of macrophage-resistant gene-regulatory tumor variants. 247 62

CCR4 is one of the receptors for chemokines and is expressed on Th2, Th17, skin-homing T cells and regulatory T cells (Tregs). Activated Tregs highly express CCR4 and are induced into tumor environment by M2 macrophages-producing CCL22. Tregs show strong suppres- sive functions in cancer immunity, resulting in tumor progression. On the other hand, moga- mulizumab is a humanized anti-human CCR4 monoclonal antibody with a defucosylated Fe region which markedly enhances ADCC activity, and the antibody has been shown to effi- ciently deplete CCR4-positive cells. Therefore, a phase Ia clinical study of mogamulizumab was conducted in the treatment of solid cancers. Mogamulizumab almost depeleted activated Tregs in peripheral blood, and then re-activated CTL function with low grade of adverse events. However, no clinical responses were observed in ten patients. A phase lb study is now on-going, and further clinical studies may be needed in combination with other anti- tumor drugs.
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PMID:Basic and clinical evaluation of anti-CCR4 mAb in cancer immunotherapy. 3056 54