Abstract
SCLC accounts for approximately 25% of lung cancers and chemoresistance is a considerable problem in this disease. Unfortunately, little in vitro work has been carried out due to the difficulties involved in working with the SCLC suspension cell lines. The six SCLC cell lines that were studied were classified into two groups. The first group showed decreased viability based on the MTT assay and a rapid activation of caspase 3 at low cisplatin concentrations. The second, more resistant, group showed relatively low loss of viability and delayed caspase 3 activation following incubation with the same drug concentrations. The two groups could also be distinguished on the basis of cell cycle profile following incubation with IC50 doses of cisplatin. The more sensitive cells showed a marked accumulation at the G2 phase of the cell cycle following 48 hours incubation whereas the more resistant cells arrested earlier, around the G1/S border. In an attempt to increase the efficacy of cisplatin in the resistant cells, the indolocarbazole Gö6976 was used which is known to abrogate G2 and S phase arrest. This abrogation is thought to arise from the inhibition of the cell cycle checkpoint kinase Chk1. When cells were treated with Gö6976 concurrently with cisplatin, the previously observed cell cycle arrests were diminished in the resistant cells and caspase 3 was activated at much lower cisplatin concentrations. For example, in the resistant H345 cell line, 6\#956;M cisplatin alone resulted in 25.66% (+/- 14.21) cell death and 6\#956;M cisplatin plus 1\#956;M Gö6976 results in 40.09% (+/- 14.17) cell death. These results suggest a possible role for Gö6976 in combination therapy with cisplatin for treatment of SCLC and further laboratory work will seek to clarify this further and study the cell cycle proteins involved.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4607.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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