각종 학술지 및 학회 논문 학계 소개

    국제 학술지 발표 (2008.07)-Clinical Cancer Research July 2008; 14(14) 4593 -4602
    학술지  Komipharm 2014.03.18 10:21

Pornima PhatakFangping Dai, Melody Butler, M.P. Nandakumar, Peter L. Gutierrez, Martin J. Edelman, Hans Hendriks and Angelika M. Burger


 Purpose: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials

   in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase

   and telomeres.

Experimental Design: We compared telomere length to KML001 cytotoxicactivity in a panel of human solid tumor cell lines.

   Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation 

   to established mechanisms of arseniteaction such as reactive oxygen species–related DNA damage induction. Binding 

   of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry.

Results: We established a significant inverse correlation (r2 = 0.9) between telomere length and cytotoxicity. KML001

   exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients. 

   We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences

   at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into 

   the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling

   as shown by γ-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by

   metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres.

   Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production.

Conclusions: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with

   short telomeres.