PubMed · 13926410
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A W VOGEL, J D HAYNES. 1962. Experiences with sequential screening for anticancer agents.. https://pubmed.ncbi.nlm.nih.gov/13926410/
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Endoplasmic reticulum/Golgi-dependent protein secretion depends on signal peptides that mediate membrane translocation of nascent secretory proteins into the lumen of the endoplasmic reticulum. Classical secretory proteins are transported across the membrane of the endoplasmic reticulum in an unfolded conformation, which is similar to protein import into mitochondria. This process is mediated by Sec61, the protein-conducting channel of the endoplasmic reticulum. Employing both FACS-based in vivo transport assays and confocal microscopy, we now show that fibroblast growth factor 2 (FGF-2), a pro-angiogenic mediator exported from mammalian cells by an unconventional secretory pathway, does not need to be unfolded in order to be released into the extracellular space. These findings suggest that the molecular apparatus mediating export of FGF-2 is not only distinct from classical translocation machineries in terms of molecular identity but also operates in a mechanistically distinct manner that allows membrane translocation of FGF-2 in a folded conformation.
PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.
Editing of the amino acid homocysteine (Hcy) by certain aminoacyl-tRNA synthetases results in the formation of an intramolecular thioester, Hcy-thiolactone. Here we show that the plant yellow lupin, Lupinus luteus, has the ability to synthesize Hcy-thiolactone. The inhibition of methylation of Hcy to methionine by the anitifolate drug aminopterin results in greatly enhanced synthesis of Hcy-thiolactone by L. luteus plants. Methionine inhibits the synthesis of Hcy-thiolactone in L. luteus, suggesting involvement of methionyl-tRNA synthetase. Consistent with this suggestion is our finding that the plant Oryza sativa methionyl-tRNA synthetase, expressed in Escherichia coli, catalyzes conversion of Hcy to Hcy-thiolactone. We also show that Hcy is a component of L. luteus proteins, most likely due to facile reaction of Hcy-thiolactone with protein amino groups. In addition, L. luteus possesses constitutively expressed, highly specific Hcy-thiolactone-hydrolyzing enzyme. Thus, Hcy-thiolactone and Hcy bound to protein by an amide (or peptide) linkage (Hcy-N-protein) are significant components of plant Hcy metabolism.