Summary In a variety of adult and childhood leukaemia cell samples collected at different states of the disease, we analysed in a series of sequentially performed slot-blot or Northern-blot hybridisation experiments the expression of genes possibly involved in multiple drug resistance (MDR) (mdrl/P-glycoprotein, DNA topoisomerase II, glutathione-S-transferase x), and the expression of the DNA topoisomerase I and histone 3.1 genes. Occasionally, P-glycoprotein gene expression was additionally examined by indirect immunocytofluorescence using the monoclonal antibody C219. No significant difference in mdrl/P-glycoprotein mRNA levels between primary and relapsed state acute lymphocytic leukaemias (ALL) was seen on average. Second or third relapses, however, showed a distinct tendency to an elevated expression of this multidrug transporter gene (up to 10-fold) in part well beyond the value seen in the moderately cross-resistant T-lymphoblastoid CCRF-CEM subline CCRF VCR 100. Increased mdrl/P-glycoprotein mRNA levels were also found in relapsed state acute myelogeneous leukaemias (AML), and in chronic lymphocytic leukaemias (CLL) treated with chlorambucil and/or prednisone for several years. Topoisomerase I and topoisomerase II mRNA levels were found to be very variable. Whereas in all but one case of CLL topoisomerase II mRNA was not detected
The initial clinical experience of using multi-colour fluorescence imaging has shown that the technique has the potential to reveal malignant tumour tissue, including non-invasive early carcinoma and also precancerous tissue. Further investigations are needed to fully develop the method.
The two tripeptide antibiotics ~-2-amino-4-methylphosphinobutyryl-alanyl-alanine (L-phosphinothricyl-alanyl-alanine) and L-(Ns-phosphono)methioiiine-S-sulfoximinyl-alanyl-alanine, both inhibitors of the glutamine synthetase, are transported into the cell of Escherichia coli K 12 via the oligopeptide transport system. The uptake by this system is proved first of all by cross-resistance with tri-L-ornithine using oligopeptide-transport-deficient mutants, and secondly by antagonism tests demonstrating competitive reversal of the action of the antibiotic by several peptides which have been shown to be transported via the oligopeptide transport system, e. g. tri-L-alanine, tetra-L-alanine, tri-L-lysine, tri-L-serine, tri-glycine, glycyl-glycyl-L-alanine and the synthetic tripeptide L-azaadenylaminohexanoyl-alanyl-alanine. On the other hand, there is no effect on the action of the antibiotic in antagonism tests with compounds which use different transport systems, such as L-alanyl-alanine, L-lysyl-lysine, glutathione and the synthetic amino acid azaadenylaminohexanoic acid, i.e. 2-amino-6-(7-aniino-3H-n-triazolo-[4,5-d]-pyrimidin-3-yl)hexanoic acid.Another inhibitor of the glutamine synthetase, L-methionine-S-dioxide (methioninesulfone) could be converted into a tripeptide form by linkage to L-alanyl-alanine analogously to the tripeptide antibiotics described above. Whereas the free L-methionine-S-dioxide seems to be transported v b the methionine transport system, the tripeptide form is transported via the oligopeptide transport system. Thus, this glutamine synthetase inhibitor can be taken up by the cell via two different transport mechanisms. Our results indicate that this could provide a synergistic effect.The syntheses of the new tripeptides L-azaadenylaminohexanoyl-alanyl-alanine and L-methionine-S-dioxidyl-alanyl-alanine were performed by dicyclohexylcarbodiimide couplings of the unusual N -protected L-a-amino acids azaadenylaminohexanoic acid and L-methionine-S-dioxide to L-alanylalanine-tert-butyl ester followed by common deprotection steps. Tri-L-ornithine was synthesized without carboxyl protection via two successive couplings of hydroxybenzotriazol esters of Nu-butoxycarbonyl-N'-benzyloxycarbonyl-L-orni thine to N6-benzyloxycarbonyl-L-ornithine.
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