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¹ Boston VA Health Care System, West Roxbury, MA; ² Dana Farber Cancer Institute, Boston, MA; ³ Harvard Medical School, Boston, MA; ⁴ Departments of Geriatrics, and Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR; ⁵ Central Arkansas Veterans Health Care System, Little Rock, AR; and ⁶ Arizona Cancer Center and College of Pharmacy, University of Arizona, Tucson, AZ

Requests for reprints: Nikhil C. Munshi, Dana Farber Cancer Institute, 44 Binney Street M557, Boston, MA 02115. Fax: (617) 363-5592. E-mail: Nikhil_Munshi{at}DFCI.Harvard.edu

Objective: The aim of this study was to test the efficacy of telomerase inhibitor (TMPyP4 [tetra(N-methyl-4-pyridyl)-porphyrin chloride]; a G-quadruplex-intercalating porphyrin) as a potential therapeutic agent for multiple myeloma. Materials and Methods: We studied telomere length, telomerase activity, and effect of telomerase inhibition in multiple myeloma cells. Several myeloma cell lines were analyzed for telomerase activity, telomere length, and gene expression. Three myeloma cell lines (U266, ARH77, and ARD) were treated with TMPyP4 for 3–4 weeks. Viable cell number was assessed by trypan blue exclusion, and nature of cell death was determined by annexin labeling and/or DNA fragmentation. In situ oligo ligation technique was used to identify specific DNase I-type DNA cleavage. Results: We report high telomerase activity and shortened telomeres in myeloma cells compared to normal B cells. We have also observed inhibition of telomerase activity, reduction in telomere length, and decline of myeloma cell growth, as measured by trypan blue dye exclusion, following exposure to TMPyP4. Exposure to porphyrin reduced telomerase activity of U266, ARH77, and ARD myeloma cells by 98%, 92%, and 99%, respectively. Exposure to porphyrin had no effect on viability for the first 14 days, followed by death of 75–90% of cells over the next 2 weeks. The nature of cell death was apoptotic, as determined by annexin and DNA nick labeling. Majority of cells showed DNA fragmentation specific to caspase-3-activated DNase I. Conclusions: These results demonstrate anti-proliferative activity of G-quadruplex-intercalating agents, and suggest telomerase as an important therapeutic target for myeloma therapy.

Key Words: Telomerase • Telomere • Multiple myeloma • Porphyrin • Cancer

The costs of publication for this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support: Multiple Myeloma Research Foundation (2001 Fellow's Award) to M.A.S.; the Department of Veterans Affairs (Merit Review Award) to N.C.M; and the Department of Veterans Affairs (Merit Review and REAP) to R.J.S.R.

Note: N.C.M. is a Leukemia Society Scholar in Translational Research.

¹ M. A. Shammas, R. J. Schmookler Reis, C. Li, H. Koley, K. C. Anderson, and N. C. Munshi. Gene expression profile of multiple myeloma cells following treatment with telomerase inhibitors, submitted for publication.

Received 11/15/02; revised 2/ 3/03; accepted 6/20/03.

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