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In view of the unclear prognostic and diagnostic role of interleukin 2 (IL-2) and its receptor in human tumours, we examined the cellular expression of IL-2 and of the subunit α of its receptor (IL-2Rα, CD25) in relation to the proliferative activity of various subtypes of lung tumours. The immunocytochemical ABC technique was applied to archival tissue material of neuroendocrine lung tumours: lung carcinoids, including typical carcinoids (TC), atypical carcinoids (AC) and small-cell lung cancers (SCLC) and squamous cell lung cancers (non-small cell lung cancers, NSCLC). Expression of IL-2 was detected in all types of lung tumours. The highest frequency of IL-2 expression (93%) was noted and the most pronounced semi-quantitatively evaluated expression of IL-2 was detected in AC tumour cells. The expression was more pronounced as compared to neoplastic SCLC (p = 0.01) and NSCLC cells (p = 0.005). The results suggest a negative correlation between IL-2 expression and the proliferative activity of tumour cells (evaluated by expression of Ki-67) in AC. The frequency of detection of IL-2 receptor (IL-Rα, CD25) was the highest in NSCLC (94%). Semi-quantitative expression of IL-2R, like that of IL-2, also dominated in the group of atypical lung carcinoids but manifested a significant difference only as compared to typical carcinoids (p = 0.014). Within the groups of tumours studied no correlation could be detected between cellular expressions of IL-2 and IL-2R. Our results demonstrate variable expression of IL-2 and its receptor in various types of lung tumours, but no simple relationship could be detected between tissue expression of the markers and proliferative activity. Appraisal of the diagnostic and/or prognostic significance of the results requires further study.
The phosphatidylinositol-3-kinases (PtdIns-3-kinase) are a family of enzymes involved in the control of cell replication. One member of the family, the mammalian pll0/p85 PtdIns-3-kinase, is a potential target for anticancer drug development because of its role as a component of growth factor and oncogene activated signalling pathways. There are a number of inhibitors of this PtdIns-3-kinase, the most potent being wortmannin (IC50 4 nM). Wortmannin inhibits cancer cell growth and has shown activity against mouse and human tumor xenografts in mice. Other inhibitors of the PtdIns-3-kinase are halogenated quinones which also inhibit cancer cell growth and have some in vivo antitumor activity. Some D-3-deoxy-3-substituted mt/o-inositol analogues and their corresponding Ptdlns analogues have been synthesized. They may act as mi/o-inositol antimetabolites in the PtdIns-3-kinase pathway and they can inhibit cancer cell growth.
The verotoxin receptor globotriaosyl ceramide (Gb3) is overexpressed in an ovarian tumour resistant to chemotherapy. An overlay of frozen tumour sections shows extensive staining of the tumour cells with verotoxin B subunit. In addition, blood vessels within the tumour mass are stained. The sensitivity of ovarian tumour cells in vitro to verotoxin can be modulated by culturing the cells in sodium butyrate to obtain an approximatly 5000-fold increase in susceptibility. This increased susceptibility is correlated with the intracellular targeting of verotoxin as monitored by using FITC-VT B subunit, in that prior to sodium butyrate treatment the toxin is internalized to a juxtanuclear (likely) Golgi location whereas, following butyrate treatment the intracellular toxin is distributed around the nucleus, consistent with endoplasmic reticulum and nuclear envelope location. This perinuclear location is similar to that found for drug-resistant variants of ovarian tumour cell lines. These results suggest that intracellular targeting of verotoxin to the perinuclear area results in increased cytotoxicity. Potentially such targeting may also occur in other human tumours.
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