Abstract 3713: Comparison of endpoints and data analysis methods for exposure of human tumor cells to dasatinib (NSC732517) and 6-MP (NSC755) in culture

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.3713-3713
• Main Authors: Kaur, Gurmeet, Kondapaka, Sudhir B., Teicher, Beverly A.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3713

Previous research using the NCI60 cell line combination screen suggested that dasatinib (NSC732517) and 6-mercaptopurine (6-MP; NSC755) may have greater than additive cytotoxicity in selected cell lines. We have conducted a detailed combination study using 6-MP and dasatinib in p53 wild type (MCF-7, H460, A498) and p53 mutant (MDA-MB-468, H23, 786-O) breast, lung and renal cell lines. These studies were performed measuring ATP as the endpoint using Cell Titer Glo after 72h exposure to 6-MP and dasatinib alone or in combination and measuring survival using colony formation after 72hr exposure to the compounds alone or in combination. As a single agent, the lung and renal mutant cell lines (H23, 786-O) were 2-10 fold more sensitive to 6-MP than wild type (H460, A498) with the exception of MDA-MD-468 (mutant), which was more resistant to 6-MP than MCF-7 (wild type). On the other hand all cell lines were sensitive to dasatinib with the IC50 ranging from 0.2-2 μM. For the combination studies, additivity/synergy was calculated using CompuSyn Software (Chou and Martin) or MacSynergy (Prichard and Shipman). Combination index (CI) analysis of the single agent and combination data for 6-MP and dasatinib was additive or antagonist in most of the cell lines. In A498, 786-0, MCF-7 and H460 cell lines a synergistic effect was observed at >10 fold the clinical plasma levels of 6-MP (0.59 μM) or dasatinib (0.19 μM). NCI-H23 cell line demonstrated an additive effect at 0.3 μM of 6-MP and 0.2 μM of dasatinib (CI = 0.94). MDA-MB-468 cell lines demonstrated a strong synergy (CI = 0.2-0.4) for 6-MP (0.03-1 μM) and dasatinib (0.05 μM) at concentrations less than the clinical plasma levels. In a single agent colony formation assay, the H460 cells were sensitive to 6-MP (IC50= 0.21 μM) and resistant to dasatinib (IC50= >10 μM). In a combination study, a synergistic effect (CI = 0.59-0.8) was observed in H460 cell line at concentrations below the clinical plasma level of 6-MP (0.2 μM-0.6 μM) and dasatinib (0.1 μM). These drug effects will be further evaluated in all cell lines by the determination of survival using colony formation assay. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3713. doi:1538-7445.AM2012-3713