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Old 11-06-2005, 04:27 AM   #1
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Herceptin mechanism - questions as to - for the technical

My very limited knowledge does not reach to undestanding the implications of this.

It does demonstrate the wider point as to the current limitations of scientific certainties in the very complex area of cancer mechanisms.

Can anybody explain the potential implications of this study.

RB

http://www.ncbi.nlm.nih.gov/entrez/q...44&query_hl=55



1: Int J Cancer. 2005 Sep 1;116(3):359-67. Related Articles, Links


Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2.

Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH.

Institute of Pathology, The University of Oslo, Rikshospitalet, Oslo, Norway.

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.

PMID: 15800944 [PubMed - indexed for MEDLINE]
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Old 11-06-2005, 08:28 AM   #2
Becky
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Simplistically - the traditional thought was that Herceptin worked by decreasing the amount of HER 2 receptors on the surface of cells by binding with the receptor (and "disabling" it). Since Herceptin was bound and on the surface of the cells, it was further thought that the Herceptin (a foreign antibody) attracted killer T cells (a type of white blood cell) and the T cells would attack the Herceptin (which is attached to a cancer cell) and destroy both.


However - in this article the researchers are suggesting a different mechanism based on PTEN. PTEN up regulation stimulates p53 and other "cell death" regulators that are present in all cells but may be disabled in cancer cells. In a nutshell, this article is suggesting that Herceptin stimulates the cell to kill itself.

I hope this helps - it is more complicated than that because it is explained that one thing causes another thing which causes another thing which causes the cell to self destruct.

If you think about it, no matter which mechanism is right (the first or this new suggestion) the bottom line is cancer cell death.

Warm regards,

Becky
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Old 11-06-2005, 12:00 PM   #3
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Question Herceptin NSABBP trial - LVEF a cancer outcome probability factor?

I admit to being totally out of my depth, and realise that this suggestion could be very contentious, but here it is.

In the NSABBP trial dated october 20 2005 of 1833 randomly assigned women (p.7) 1159 appear to have completed the therapy (p.8). The reasons for exclusion were primarily decline in LVEF.

My question is has it ever been clinically determined if there is a link between cardiac health and cancer - not in the sense of a direct link but an underlying communality of cause - for example diet and an indicator of general health - e.g. omega three six balance in tissue.

Higher levels of omega three are known to be benificial to cardiac health, AND trials show that high levels of omega three correlate to very significantly lower cancer risks 70%, and impact on cell death both in vitro and in vivo.

SK-Br3 featured both in the fish oil trial referred to in the previous post and above.

THE QUESTION

Could exclusion of low LVEF patients in the treatment arm, but not in the control arm result in skewing of results data in favour of Herceptin consequent on low LVEF patients having a higher inherent predisposition to early recourence or spread - say due to lower omega three or wider general health factors that impact both on LVEF and onward cancer developement.


Food for thought,

RB
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Old 11-09-2005, 04:42 AM   #4
BCHusband
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Control by taking low LVEF out of Control Group

Interesting question. The Herceptin trials could easily control for weak hearts and link to cancer recurrence (and may have as I haven't studied the trials in depth). I wonder if the trials controlled for this factor?
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