International journal of cancer. Journal international du cancer
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We previously reported that DX-8951f, a novel water-soluble camptothecin analog, significantly inhibits the growth of various human and murine tumors in vitro and in vivo. The antitumor effects and topoisomerase I inhibitory activity of DX-8951f are stronger than those of other current camptothecin analogs. In this study, we established an SN-38-resistant cell line, PC-6/SN2-5, from the human oat cell carcinoma PC-6 cell line by a stepwise selection system, investigated the mechanism of resistance of this cell line and then compared the antitumor activity of camptothecin analogs against the cell line. ⋯ Determination of the cellular drug concentration by either flow cytometric analysis or the high-performance liquid chromatography method confirmed that the cellular accumulation of SN-38 and topotecan was significantly reduced in PC-6/SN2-5 cells, whereas that of DX-8951f was only slightly reduced. Furthermore, DX-8951f stabilized the cleavable complex formations in intact PC-6/SN2-5 cells as well as in parental cells, but SN-38 and topotecan did not in the resistant cells. Our data suggest that PC-6/SN2-5 cells may have acquired resistance to camptothecin analogs by a decrease in intracellular drug accumulation and that DX-8951f may have the potency to overcome such a type of resistance mechanism induced by camptothecin compounds.
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The present report describes the in vitro and in vivo profile of CEP-751, a novel receptor tyrosine kinase inhibitor. CEP-751 at 100 nM inhibits the receptor tyrosine kinase activity of the neurotrophin receptors trkA, trkB and trkC. CEP-751 has no effect on activity of receptors for EGF, IGF-I, insulin or on erbB2; inhibition of receptors for PDGF and bFGF was observed but occurred with lesser potency than inhibition of trk. ⋯ Inhibition of trk phosphorylation could also be measured in these tumors, suggesting that anti-tumor efficacy of CEP-751 is related to inhibition of trk receptor tyrosine kinase activity. CEP-751 was found to be without effect when administered to nude mice bearing SK-OV-3 tumors, which overexpress erbB2 receptors, providing further evidence that inhibition of tumor growth may be related to inhibition of trk receptor tyrosine kinase activity. Our data indicate that CEP-751 is a potent trk inhibitor which possesses anti-tumor activity.
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We have investigated the effect of Fab oligomerization on imaging efficacy in a pancreatic-carcinoma xenograft model in mice. Recombinant mouse/human chimeric Fab of the anticarcinoembryonic antigen (CEA) monoclonal antibody A10, which has been shown to react specifically with gastrointestinal cancers, was used in this study. Fab homo-oligomers (dimers and trimers) were prepared by linkage of chimeric Fab with N-succinimidyl-3-(2-pyridyldithio)-propionate. ⋯ At 18 hr after injection, clear scintigraphic detection of the pancreatic-carcinoma tumors was obtained with 123I-labeled S-S Fab dimers. At 24hr, improved tumor imaging was shown for 123I-labeled S-S Fab oligomers with slightly visible uptake in normal tissues, similar to that of F(ab')2. S-S oligomers of chimeric A10 Fab may be useful as rapid diagnostic tools of pancreatic carcinomas.
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Rat ascites hepatoma cell (MM1) invade a mesothelial cell monolayer in vitro in assay medium containing serum, but not in serum-free medium. Serum could be completely replaced by 1-oleoyl lysophosphatidic acid (LPA) in inducing invasion. LPA-induced invasion was inhibited by genistein, a tyrosine-kinase inhibitor. ⋯ Invasion of MCL by MM1 cells induced by serum and that by B16FE7 cells induced by LPA were inhibited by genistein or C3 as well. By immunoprecipitation, we detected p 125 focal adhesion kinase (FAK) as a major protein of 110- to 130-kDa tyrosine phosphorylated in response to LPA. Tyrosine phosphorylation of paxillin by LPA was also detected.
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The data of the Australian Paediatric Cancer Registry on childhood cancer incidence in Australia for the 10-year period 1982-1991 are presented. The crude average annual incidence of cancer in children under the age of 15 years was 13.8 per 100,000. The incidence of childhood cancer in Australia is rising. ⋯ Of particular interest is malignant melanoma, whose incidence in Australia is more than 5 times that in the UK, as a result of excessive UV exposure. Australia has a higher incidence of Ewing's tumour than osteosarcoma, nearly twice that of the UK. International comparative studies may help to elucidate the aetiology of these tumours.