Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies

摘要: Thymidylate synthase (TS) is responsible for the de novo synthesis of thymidylate, which required DNA and repair an important target fluoropyrimidines such as 5-fluorouracil (5-FU), antifolates Tomudex (TDX), ZD9331, multitargeted antifolate (MTA). To study importance TS expression in determining resistance to these agents, we have developed MDA435 breast cancer-derived cell line with tetracycline-regulated termed MTS-5. We demonstrated that inducible increased IC 50 dose TS-targeted therapeutic agents 5-FU, TDX, ZD9331 by 2-, 9- 24-fold respectively. An MTA was unobtainable when overexpressed cells, indicated toxicity highly sensitive levels. The growth inhibitory effects chemotherapeutic CPT-11, cisplatin, oxaliplatin, Taxol were unaffected up-regulation. Cell cycle analyses revealed doses TDX caused S-phase arrest cells did not overexpress TS, this overcome up-regulated. Furthermore, accompanied 2- 4-fold regulatory genes cyclin E , A dependent kinase 2 ( cdk2 ). These results indicate acute increases levels play a key role cellular sensitivity TS-directed drugs modulating degree agents. Moreover, remain cytotoxic TS.