[chrisy]

Yeah, Becky, I agree with your thinking, that the key to T-Dm1 would be to get the maximum number of molecules binding to the ECD. Not that I'm trying to get you unstuck from your story...

But that's where I think it gets complicated with the oleuropein - because part of it's action seems to be to DECREASE cleavage of the ECD. Doesn't that mean less ECD disconnected from the cell and MORE available for binding to the Herceptin? Of course, the other theorized mechanism is downregulation of Her2. It is interesting to me though that reversal of Herceptin resistance was so significant - which would seem to be a good thing for T-DM1.

Of course, as you say, none of this has any clinical relevance in terms of what it would do in humans, how much would it take, etc. Glad there's no reason to start chugging EVOO!

Thanks for your response Becky, I can always count on you!

"A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression."