Re: [ More info on new drug

[Guest guest]

Another good article. Thanks again, Cheryl. The findings of this one (that

certain mutational variants of BCR-ABL are MUCH more sensitive to the new

drug, but that others are more sensitive to IM) suggest that in the

not-too-distant future part of the initial workup for CML may be mutation

testing, which will direct patients to the drug most likely to knock it out.

I'll take it!

R

> Date: Mon, 2 May 2005 19:51:34 -0400

> From: " Cheryl-Anne Simoneau " <cheryl.simoneau@...>

> Subject: More info on new drug

>

> This is interesting as the drug is not even in clinical trials yet cell

> screening strategies are already being studied for a possible combinatory

> strategy with IM.

>

> Happy reading!

>

> Cheers,

> Cheryl-Anne

>

> A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies

> the mutation pattern for PD166326, an alternative Abl kinase inhibitor.

>

> von Bubnoff N, Veach DR, van der Kuip H, Aulitzky WE, Sanger J, Seipel P,

> Bornmann WG, Peschel C, son B, Duyster J.

>

> Department of Internal Medicine III, Technical University of Munich, D-81675

> Munich, Germany.

>

> In Philadelphia-positive (Ph(+)) leukemia, point mutations within the

> Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib

> mesylate. We established a cell-based screening strategy for detection of

> clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells.

> We identified 32 different single-point mutations within the kinase domain

> of Bcr-Abl. The pattern and frequency of mutations in this cell

> culture-based screen resembled the pattern and frequency observed in

> resistant patients. We then applied this screen to an alternative Abl kinase

> inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5

> to 10 times the median growth inhibition (IC50) of PD166326 was

> significantly lower than with imatinib. In addition, PD166326 produced a

> distinct pattern of Bcr-Abl mutations. The majority of mutations that came

> up with both imatinib and PD166326 could effectively be suppressed by

> increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few

> mutations could be suppressed by increasing the imatinib dose to 5 to 10

> microM. However, 3 mutations affecting F317 displayed complete resistance to

> PD166326, but could be effectively inhibited by standard concentrations of

> imatinib. Thus, this robust and simple screening system provides a rational

> basis for combinatorial and sequential treatment strategies in targeted

> cancer therapy.