| 17696516 |
Kalet BT, McBryde MB, Espinosa JM, Koch TH: Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism. J Med Chem. 2007 Sep 6;50(18):4493-500. Epub 2007 Aug 16.
The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. The IC (50) for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase II dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC (50) for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II deficient derivative of HL-60 cells, is 1420-fold lower than the IC (50) for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II independent. |
1(0,0,0,1) |