This is the first convincing in vivo evidence to support the use of a tricyclic antidepressant (in this case imipramine). The use of ticlopidine will be problematic, due to it being an antiplatelet drug.
In genetically engineered mice (with deletion of one copy of TP53) the oral administration of imipramine prolonged survival significantly. In the more aggressively growing tumors from mice with double knockout of TP53, imipramine did not make any difference.
From page 2 (see figure 1A):
"Thus, IM treatment was able to delay the progression of incipient low-grade gliomas but not the more aggressive disease,"
Please note that tricyclic antidepressants (like imipramine, clomipramine etc.) shouldn't be combined with SSRI antidepressants (fluoxetine, sertraline etc.), due to pharmacokinetic interactions as well as increased risk for serotonin syndrome.
These mice were genetically engineered to have these p53 abnormalities. In humans, the more common situation is to have one mutant copy of TP53. The other copy may or may not be deleted. This could be determined by copy number analysis (by FISH?) of chromosome locus 17p13.1 (where the TP53 gene is located). This is far from being a standard test for gliomas though.
An even more common occurrence in lower grade IDH1-mutant astrocytomas is to have "copy number neutral loss of heterozygosity" at chromosome 17p, which contains the TP53 gene. This typically means the unmutated copy is deleted and the mutant copy is duplicated. This is also called chromosome 17p "homodisomy".
Surprisingly this is actually associated with longer survival in IDH1-mutant astrocytoma without 1p/19q codeletion.
Thanks Mike!
ReplyDeleteExtended PDF can be downloaded here:
http://www.cell.com/cancer-cell/pdfExtended/S1535-6108(15)00303-7
This is the first convincing in vivo evidence to support the use of a tricyclic antidepressant (in this case imipramine). The use of ticlopidine will be problematic, due to it being an antiplatelet drug.
ReplyDeleteIn genetically engineered mice (with deletion of one copy of TP53) the oral administration of imipramine prolonged survival significantly. In the more aggressively growing tumors from mice with double knockout of TP53, imipramine did not make any difference.
From page 2 (see figure 1A):
"Thus, IM treatment was able to delay the progression of incipient low-grade
gliomas but not the more aggressive disease,"
Please note that tricyclic antidepressants (like imipramine, clomipramine etc.) shouldn't be combined with SSRI antidepressants (fluoxetine, sertraline etc.), due to pharmacokinetic interactions as well as increased risk for serotonin syndrome.
ReplyDeleteHow do we know if we have deletion of one copy of TtP53 or double knockout of TP53?
ReplyDeleteThese mice were genetically engineered to have these p53 abnormalities. In humans, the more common situation is to have one mutant copy of TP53. The other copy may or may not be deleted. This could be determined by copy number analysis (by FISH?) of chromosome locus 17p13.1 (where the TP53 gene is located). This is far from being a standard test for gliomas though.
DeleteAn even more common occurrence in lower grade IDH1-mutant astrocytomas is to have "copy number neutral loss of heterozygosity" at chromosome 17p, which contains the TP53 gene. This typically means the unmutated copy is deleted and the mutant copy is duplicated. This is also called chromosome 17p "homodisomy".
DeleteSurprisingly this is actually associated with longer survival in IDH1-mutant astrocytoma without 1p/19q codeletion.
http://theoncologist.alphamedpress.org/content/early/2016/07/08/theoncologist.2016-0003.abstract