期刊
CANCER RESEARCH
卷 70, 期 18, 页码 7232-7241出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-0766
关键词
-
类别
资金
- NIH [R01-CA120439]
- UIUC
- NIH Chemistry-Biology Interface [NRSA 1-T32-GM070421]
- Medicinal Chemistry Division of the American Chemical Society
- National Research Service [F31-CA130138-01S1]
A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase autoactivating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted s.c. as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous i.v. infusion of S-PAC-1 in dogs led to a steady-state plasma concentration of similar to 10 mu mol/L for 24 to 72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well tolerated and that the treatments induced partial tumor regression or stable disease in four of six subjects. Our results support this canine setting for further evaluation of small-molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic. Cancer Res; 70(18); 7232-41. (C)2010 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据