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Sobre Aplidina y VEGF, qué es lo nuevo?

-nada nuevo tampoco

mirate esto que es del año pasado y lo de éste y dime si esa casi indetectable diferencia es lo que te hace darle 2 euros más a zel.

No sé por qué, me viene al coco la noticia de ayer sobre Camelo José Cela ( http://www.labolsa.com/foro/mensajes/1003518827.phtml )

saludos

año pasado:
http://www.aacr.org/newdrugs00/214.html
[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
214 Aplidine blocks VEGF secretion and VEGF/VEGF-RI autocrine loop in a human leukemic cell line. M. Broggini1, S. Marchini1, M. D'incalci1, G. Taraboletti1, R. Giavazzi1, G. Faircloth2, J. Jimeno3 1Oncology Dept., Mario Negri Institute, Milan, Italy; Pharma Mar, 2Cambridge, MA, USA and 3Madrid, Spain.

The new marine compound Aplidine possesses high cytotoxic activity both in vitro and in vivo and is currently at the end of Phase I in clinic. Aplidine was found to induce strong apoptosis in the human leukemic cell line MOLT-4. In the same cell line microarray analysis revealed changes in the expression of different genes at early times after treatment. Among these we found that the VEGF-RI (flt-1) was downregulated by drug treatment and its downregulation was confirmed by northern and western blotting analysis. Further studies showed that treatment of the same cellular system with the compound resulted in a strongly reduction of VEGF secretion in the medium. The decrease in VEGF secretion was associated to a decrease in the mRNA encoding for VEGF in MOLT-4 cells treated with Aplidine. Trying to elucidate the mechanism by which Aplidine blocks VEGF secretion, we found that the compound does not change the half-life of VEGF mRNA. Similarly, using the electromobility shift assay, Aplidine did not change the ability of two transcription factor, HIF-1 and AP-1, to bind their respective consensus sequence present in the promoter of VEGF and did not decrease the transcription of VEGF when a VEGF promoter-luciferase construct was used in transient transfection experiments. The decreased secretion of Aplidine was associated with an increased intracellular accumulation of VEGF strongly suggesting that the compound could act through a block of the secretion of VEGF. Simultaneous treatment of MOLT-4 cells with low concentrations of Aplidine and VEGF partially abolish the activity of Aplidine suggesting that the drug could partially exert its activity in this cellular system by blocking the autocrine loop VEGF/VEGF-RI. These studies are of great potential relevance to conduct ongoing clinical investigations in a rational way and particularly to test the aplidine effects on VEGF levels in phase II clinical trials.

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y lo del próximo congreso:
Aplidine-induced apoptosis in MOLT-4 cells is mediated by its ability to block VEGF secretion.
M. Broggini, S. Marchini, E. Galliera, M. D'Incalci, G. Taraboletti, R. Giavazzi, G. T. Faircloth Jr., J. Jimeno, Inst Mario Negri, Milano, Italy; PharmaMar USA, Cambridge, MA; PharmaMar SA, Tres Cantos, Spain.

The human leukemia cell line MOLT-4 growing in vitro produces and secretes VEGF. In addition, these cells present on their surface one of the VEGF receptors, namely the VEGF-RI (flt-1). The co-existence, in the same cellular context, of the ligand and its receptor, strongly suggest the possibility that in these cells VEGF works as growth factor. To test this hypothesis, we transfected MOLT-4 cells with human VEGF cDNA both in sense and antisense orientation. With the sense construct, we could obtain different colonies, while with the antisense construct, all cells died and no colonies could be obtained. The same constructs transfected in a human ovarian cancer cell line producing VEGF but not expressing any of the receptors, allowed us to recover colonies both with the sense or antisense construct. These results clearly indicate that VEGF is essential for the growth of MOLT-4 cells. The new marine compound Aplidine, a cyclic depsipeptide, possesses high cytotoxic activity both in vitro and in vivo and is currently selected to begin Phase II clinical development. Aplidine was found to induce strong apoptosis in MOLT-4 cells. In the same cell line Aplidine strongly inhibits the secretion of VEGF. The decrease in VEGF secretion was associated with a decrease in mRNA encoding for VEGF. The block of VEGF secretion induced by Aplidine is not due to a change in the half–life of VEGF mRNA and not associated with a direct effect on the transcription of VEGF. The importance of blocking VEGF secretion as a putative mechanism of action of Aplidine was studied further using clones derived from MOLT-4 that overexpress VEGF. One of these clones was able to produce and secrete approximately 10 times more VEGF in 24 hours than the parent cell line. In this clone Aplidine was less active in inducing growth inhibition and apoptosis. Similarly, simultaneous treatment of MOLT-4 cells with low concentrations of Aplidine and VEGF partially abolish the activity of Aplidine. Taken together, these data show that Aplidine exerts its effect(s) on this cellular system by blocking the autocrine loop VEGF/VEGF-RI, which is essential for the growth of these cells. We are currently investigating if Aplidine can utilize this mechanism in other types of leukemia.