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 KML001and investigated its effects on telomerase and telomeres. Experimental Design: We compared telomere length to KML001cytotoxic activity 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 arsenite action 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 (r 2 = 0.9) between telomere length and cytotoxicity. KML001exhibited 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 g-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.

t(5;10)(q33;q21). 7 A common structural feature of TPM3 and H4/D10S170 proteins is the coiled-coil domain, which contributes with its dimerization/activation moiety to building tyrosine kinase fusion proteins.Given these findings, a double color double fusion FISH assay with clone CTD-2601I11 encompassing the PDGFRB breakpoint, and clone RP11-205M9 for TPM3 (Figure 2) is a valid diagnostic test for discriminating between t(1;5)(q21;q33)/ TPM3/PDGFRB, as described in the present letter, and t(1;5) involving other genes at 1q21-q23 such as PDE4DIP-PDGFRB, which has been reported in a pediatric case of chronic myeloproliferative disorder.

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<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> We compared telomere length to KML001 cytotoxic activity 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 arsenite action such as reactive oxygen species–related DNA damage induction. Binding of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry.</p><p><b>Results:</b> We established a significant inverse correlation (<i>r</i>² = 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 <i>in situ</i> 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.</p><p><b>Conclusions:</b> Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with short telomeres.</p></div>