99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA
New Agents and Therapeutic Approaches: Poster Presentations - Proffered Abstracts |
Abstract #2311
Activity of BSI-201, a potent Poly(ADP-ribose) polymerase (PARP1) inhibitor, alone and in combination with topotecan in human ovarian xenografts
Valeria Ossovskaya,
Lingyun Li,
Charles Bradley and
Barry Sherman
BiPar Sciences, Inc., Brisbane, CA
Introduction: Poly (ADP-ribose) polymerase-1 (PARP1) is an evolutionary conserved enzyme that catalyzes the transfer of ADP-ribose units from NAD+ to target proteins including histones, HMG proteins and topoisomerases I and II. The poly-ADP-ribosylation by PARP1 affects cellular processes such as proliferation, differentiation and response to DNA damage. Inhibition of PARP1 can facilitate the response to alkylating agents and topoisomerase inhibitors. BSI-201 is a novel inhibitor of PARP1.
Experimental design: The human OVCAR-3 ovarian adenocarcinoma utilized in this study was maintained in female CB.17 SCID mice. OVCAR-3 tumor cells were established from the malignant ascites of a patient with adenocarcinoma treated with combination chemotherapy and is resistant to clinically relevant concentrations of adriamycin, melphalan, and cisplatin. BSI-201 was administrated intraperitoneally (i.p, biw), orally (p.o., bid), or subcutaneously (s.c., via osmotic pumps) to SCID mice implanted subcutaneously with OVCAR-3 xenografts. For combination therapies, mice received topotecan concurrently with BSI-201. Mice were sampled for tumor and blood when their tumors attained the endpoint. BSI-201 activity in vitro was measured by inhibition of cell proliferation in BrdU assay. The pharmacodynamic profile of BSI-201 was determined in human PBMCs in a PARP assay. PC-3 prostate adenocarcinoma cells were implanted subcutaneously into nude mice.
Results: Significant inhibition of PARP activity was observed in cancer cell lines and human primary PBMCs after treatment with BSI-201. The antitumor activity of BSI-201 given as a single agent ip, po or sc was assessed as tumor growth delay (TGD) and the logrank test was employed to analyze the significance of the results. All three routes of administration resulted in highly significant antitumor activity, (P < 0.01). BSI-201 was well tolerated and there were no changes in blood counts at the end of treatment. Antitumor activity of BSI-201 was confirmed by Caspace-3 and TUNEL staining of OVCAR-3 tumors. The combination of BSI-201 and topotecan produced significant antitumor activity (P<0.001) and increased the percentage of complete tumor regression compared with topotecan alone. BSI-201 did not exhibit inhibitory activity against PC-3 prostate cancer in cell proliferation assays or in xenograft models indicating tumor selectivity of the compound.
Conclusions: BSI-201 is a promising new cancer therapeutic agent that is well tolerated in preclincial studies and has potent activity against drug resistant ovarian adenocarcinoma xenografts in SCID mice both as a single agent and in a combination with topotecan.
