3192 Background: Doc is an effective chemotherapeutic agent for CaP. It stabilizes the β-subunit of tubulin, phosphorylates and inactivates the anti-apoptotic protein Bcl-2, and stabilizes the tumor suppressor protein p27 resulting in cell cycle arrest at M-phase and apoptosis. PS-341 is an inhibitor of the proteasome, which is necessary for the degradation of cellular proteins. By preventing degradation of proteins such as p27 or p53, PS-341 causes G1 and G2 cell cycle arrest. Because PS-341 inhibits cell cycling, it may be antagonistic to or limit the activity of taxanes, which show their greatest activity in M-phase. Our previous work with Doc plus erlotinib showed that intermittent delivery was more effective than either drug alone or given concurrently. We hypothesized that the combination of Doc and PS-341 would show similar sequence dependence to achieve the greatest cell kill. Methods: Flow cytometric analysis of DNA content was done to estimate the proportion of PC3 (p53 null) or LNCaP (p53 wild-type) cells in each cell cycle phase as well as sub-G1. Western blot analysis was used to evaluate protein levels. Results: In PC3 cells, as single agents Doc was more effective than PS-341 (sub-G1: 21.8% and 7.3%, respectively). In combination, the sequence of Doc→PS-341 (sub-G1: 47.4%) was more effective than either PS-341→Doc (sub-G1: 25.7%) or PS-341 + Doc (sub-G1: 6.3%). In LNCaP cells, there was little difference between Doc and PS-341 as single agents (sub-G1: 18.8% and 14.7%, respectively). However, Doc + PS-341 (sub-G1: 39.3%) given concurrently was more effective than either PS→Doc or Doc→PS (sub-G1: 14.7 and 14.4%). p27 was shown to be up-regulated in all treatment groups, as expected. Initial PC3 xenograft studies showed slightly greater inhibition of tumor growth in combination treatments versus single agents. Conclusions: LNCaP (p53 wild-type) cells showed greater sensitivity to PS-341, particularly when given concurrently with Doc, than PC3 (p53 null) cells. These data support further studies into the role of p53, cell cycle arrest, and sequencing of treatment with PS-341 and Doc in CaP. (U01-CA-62505, N01-CM-17101, ACS-CRTG-0019701-CCE) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Millenium Aventis, Millenium