Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos

Authors: Izbicka E.; Nishioka D.¹; Marcell V.¹; Raymond E.; Davidson K.²; Lawrence R.; Wheelhouse R.³; Hurley L.³; Wu R.⁴; Von Hoff D.

Source: Anti-Cancer Drug Design, Volume 14, Number 4, 1999 , pp. 355-365(11)

Publisher: Cognizant Communication Corporation

Abstract:

Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomere-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.

Keywords: G quadruplex; porphyrin; sea urchin; telomerase; telomere

Document Type: Research article

Affiliations: 1: Department of Biology, Georgetown University, Washington, DC 20057, USA 2: University of Texas Health Science Center, San Antonio, TX 78229, USA 3: Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA 4: National Institutes of Health, Bethesda, MD 20892, USA

Publication date: 1999-08-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Pharmacology
• By this author: Izbicka E. ;  Nishioka D. ;  Marcell V. ;  Raymond E. ;  Davidson K. ;  Lawrence R. ;  Wheelhouse R. ;  Hurley L. ;  Wu R. ;  Von Hoff D.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers