Topoisomerase levels determine chemotherapy response in vitro and in vivo.

@article{citeulike:2966770, abstract = {Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic.}, address = {Cold Spring Harbor Laboratory and Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, NY 11724.}, author = {Burgess, Darren J J. and Doles, Jason and Zender, Lars and Xue, Wen and Ma, Beicong and McCombie, W Richard R. and Hannon, Gregory J J. and Lowe, Scott W W. and Hemann, Michael T T. }, citeulike-article-id = {2966770}, doi = {10.1073/pnas.0803513105}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {genetics, medicine, mesophysics}, month = {July}, number = {26}, pages = {9053--9058}, posted-at = {2008-07-06 03:35:52}, priority = {2}, title = {Topoisomerase levels determine chemotherapy response in vitro and in vivo.}, url = {http://dx.doi.org/10.1073/pnas.0803513105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2966770 L3 - citeulike-article-id:2966770 TI - Topoisomerase levels determine chemotherapy response in vitro and in vivo. JF - Proceedings of the National Academy of Sciences of the United States of America VL - 105 IS - 26 SP - 9053 EP - 9058 AD - Cold Spring Harbor Laboratory and Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, NY 11724. SN - 1091-6490 N2 - Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic. KW - genetics KW - medicine KW - mesophysics AU - Burgess, Darren J AU - Doles, Jason AU - Zender, Lars AU - Xue, Wen AU - Ma, Beicong AU - McCombie, W Richard AU - Hannon, Gregory J AU - Lowe, Scott W AU - Hemann, Michael T PY - 2008/07/01/ UR - http://dx.doi.org/10.1073/pnas.0803513105 ER -