Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models.
OBJECTIVE
The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.


METHODS
A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis.


RESULTS
ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis.


CONCLUSIONS
ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.
Shoemaker
Alex R
AR
Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, USA. alex.shoemaker@abbott.com
Mitten
Michael J
MJ
Adickes
Jessica
J
Ackler
Scott
S
Refici
Marion
M
Ferguson
Debra
D
Oleksijew
Anatol
A
O'Connor
Jacqueline M
JM
Wang
Baole
B
Frost
David J
DJ
Bauch
Joy
J
Marsh
Kennan
K
Tahir
Steven K
SK
Yang
Xiufen
X
Tse
Christin
C
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
D000814:Aniline Compounds / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax