The role of glucuronidation in 7-ethyl-10-hydroxycamptothecin resistance in vitro.

Although glucuronidation catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) is a major pathway of drug inactivation in humans, glucuronidation in malignant cells has received little attention as a cause of anti-cancer drug resistance. In this study, we tried to elucidate the role of SN-38 glucuronidation in the CPT-11-resistant human lung cancer cell line PC-7/CPT. PC-7/CPT cells possessed an increased activity to glucuronidate SN-38 compared to the parent cells, PC-7. Furthermore, sensitivity of PC-7/CPT cells to SN-38 was improved by inhibiting UGT activity. Western and northern blot analyses demonstrated that this increased activity was due to increased levels of UGT protein and mRNA. These results not only imply that upregulation of UGT activity in PC-7/CPT cells may contribute in part to SN-38 resistance, but also illustrate the important of drug metabolism within malignant cells themselves, as a cause of drug resistance.

uridine 5′‐diphosphoglucuronosyltrans‐ferase

7‐ethyl‐10‐hydroxycamptothecin

7‐ethyl‐10‐[4‐(l‐piperidino)‐1‐piperidin01 carhonyloxycampto‐thecin

camptothecin

7‐ethyl‐10‐hydroxycamptothecin glucuronide

DNA topoisomer‐ase I

dimethyl snlfoxide

uridine 5′‐di‐phosphoglucnronic acid

high‐performance liquid chro‐matography

4‐methylumbelliferone

sodium do‐decyl sulfate

piperazine‐N, N'‐bis‐[2‐ethanesulfouicacid]