What Makes Tumors Multidrug Resistant?
Volume 6, Issue 22
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November 15, 2007
Pages 2782 - 2787http://dx.doi.org/10.4161/cc.6.22.4936
Authors: Piet Borst, Jos Jonkers and Sven Rottenberg View affiliations
Tumors arising spontaneously in genetically modified mice now make it possible to study mechanisms of drug resistance in animal tumors resembling their human counterparts. We have studied mouse mammary tumors induced by conditional deletion of Brca1 and p53. These tumors respond to monotherapy with the maximal tolerable dose of doxorubicin, or docetaxel, but eventually always become resistant to the drugs. Resistance in most tumors is caused by upregulation of drug transporters and not by interference with apoptosis/senescence. The tumors also respond to cisplatin, but do not become resistant, even after repeated treatments at the maximum tolerable dose. We conclude that resistance due to interference with cell death effector pathways (apoptosis/senescence) is not an option in these tumors, re-emphasizing doubts that such mechanisms play a role in epithelial tumors. Tumors responding to drug may shrink to less than 5% of their volume before relapsing. We argue that this resistant remnant fraction may provide a test for the tumor stem cell hypothesis and, more generally, that spontaneous mouse tumors resembling their human counterparts provide a useful new tool for drug development and for improving treatment regimens.