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Schedule-dependence of C-CAM1 adenovirus gene therapy in a prostate cancer model.

BACKGROUND
C-CAM1 functions as a tumor suppressor in prostate cancer. Thus C-CAM1 recombinant adenovirus therapy may be a promising treatment for prostate cancer. Understanding the time course of C-CAM1's antitumor activity is essential for designing an optimal schedule for C-CAM1 gene therapy.


MATERIALS AND METHODS
PC3 cells were exposed to Ad-C-CAM1 and the time course of C-CAM1 expression was monitored by flow cytometry. Tumors generated in nude mice by subcutaneous injection of PC-3 cells were used for in vivo testing of C-CAM1's antitumor activity. Intratumoral injections of viruses (either Ad-C-CAM1 or Ad-beta-gal) or buffer only (control) were performed according to two different schedules. Mice in Schedule A received a single injection, while mice in Schedule B received the same total amount of viruses in 3 equal doses at 2-week intervals.


RESULTS
After single exposure to Ad-C-CAM1, PC-3 cells expressed abundant C-CAM1 protein which reached the highest level on day 3 and persisted for up to 5 days. PC-3 tumors in nude mice exhibited 2 to 3-week lag in tumor growth curves after a single Ad-C-CAM1 injection. In contrast, 14 of the 18 tumors receiving 3 fractionated Ad-C-CAM1 injections regressed completely, while the other 4 tumors shrank to significantly smaller sizes.


CONCLUSIONS
Sustained expression of C-CAM1 is required for optimal tumor suppression. The schedule-dependence of C-CAM1's antitumor activity should be taken into account in optimizing gene therapy in clinical settings.