20thEORTC-NCI-AACR Geneva,Switzerland
P. Phatak M. Edelman H. Hendriks A. Burger
KML001 (sodiummetaarsenite) is an orally bioavailable, trivalent arsenic compound that iscurrently undergoing phase Ⅱ clinical studies in Europe. We have previouslyfound that KML001 binds to telomeric sequences at a ratio of one per three TTAGGG repeats.This results in telomere-associated DNA damage and telomere attrition.Similarly, cisplatin is known tobind to the guanine-rich telomeric sequences at a ratio of one molecule per telomeric repeat and toactivate p53.
Tumor cells with short telomeres are particularly responsive totelomere targeting agents such as KML001 and cisplatin. In the studywe investigated telomere length and the functional status of the DNA damageresponse regulator p53 in a panel of 12 non-small cell lung cancer cell lines(A549, H460, H23, H183, H59, H177, H182, H292, H358, H522, Calu-1, andpatient-derived primary cells) and compared them to KML001 antiproliferative activity. Wefurther assessed whether a combination of the two telomere binding agentsKML001 and cisplatin would besynergistic. Inhibitory concentrations 50% (IC50) for KML001 and cisplatin in lung cancercells were determined by using the methltetrazolium proliferationassay. Combination studies were performed at a fixed IC50 ratio according tothe method developed by Chou and Talalay and combination indices (CI) werecalculated. Telomere length was determined by Southern blotting and employingthe telo TAGGG-telomerelength assay. To assess p53 utational status PCR-based exon specificmutation analyses were performed. KML001 IC50s ranged between 2 and 20 μM, concentrationsthat have been eached in plasma of patients in phase Ⅰ studies. Mean telomerelengths varied from very short (2.1 kb in Calu-1) to very long (13 kb in H183).While there was no overall correlation between mean telomere length of a cell lineand its IC50 for KML001, we found that lung cancer cell lines withdysfunctional or impaired p53 (H23 transcriptionally defective, H522mt, and Calu-1null) and short telomeres were sensitive to KML001.