Abstract
1824
Telomerase is required for cell immortality, a hallmark of cancer, and is expressed in essentially all cancer types, but not in most normal adult tissues. Therefore, inhibition of telomerase is a promising anti-cancer treatment strategy. GRN163L is a lipidated oligonucleotide with potent telomerase inhibitory activity, and is currently in Phase I/II clinical trials in solid tumors and hematological cancers. A challenge in monitoring target effects during clinical trials is that the target tissues, especially solid tumors, are not easily accessible for sampling. For telomerase inhibition in xenograft studies, measuring target inhibition in tumor samples is difficult in part due to tissue sample heterogeneity, and the presence of factors in tissue extracts that may interfere with the telomerase assay. Recently, we developed an assay for using human hair follicles as a surrogate tissue for monitoring telomerase inhibition in patients (see abstract “Detection of telomerase inhibition by GRN163L, a potent telomerase inhibitor, in human hair follicle," E. Bassett, M.A. Genzer, C. Harley, R. Tressler, and N. F. Go). Therefore, we chose to investigate the effect of GRN163L on telomerase activity in mouse and rat vibrissa follicles. We found that plucked rodent vibrissa follicles from rats, wild-type mice, and nude mice contained robust telomerase activity, readily detectable by an acrylamide gel-based TRAP assay. Our studies showed that GRN163L inhibited both xenograft tumor growth and telomerase activity in the vibrissa follicles of treated animals. Furthermore, telomerase inhibition in rat vibrissa follicles was dose-dependent, and the target inhibitory effect persisted for several days after a single dose treatment with GRN163L. With their easy accessibility, rodent vibrissa follicles, especially those from nude mice commonly used in xenograft tumor models, can be used as a convenient surrogate tissue to monitor telomerase inhibition in in vivo.
Footnotes
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA
- American Association for Cancer Research