LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models.

Autor: Barnard D; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Diaz HB; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Burke T; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Donoho G; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Beckmann R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Jones B; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Barda D; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., King C; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA., Marshall M; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA. mmarshall@lilly.com.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2016 Feb; Vol. 34 (1), pp. 49-60. Date of Electronic Publication: 2015 Nov 27.
DOI: 10.1007/s10637-015-0310-y
Abstrakt: Pharmacological inhibition of CHK1 in the absence of p53 functionality leads to abrogation of the S and G2/M DNA damage checkpoints. We report the preclinical therapeutic activity of LY2603618 (CHK1 inhibitor) at inhibiting CHK1 activation by gemcitabine and enhancing in vivo efficacy. The in vivo biochemical effects of CHK1 inhibition in the absence or presence of DNA damage were measured in human tumor xenograft models. Colon, lung and pancreatic xenografts models were treated with gemcitabine, LY2603618, or gemcitabine plus LY2603618. Gemcitabine treatment alone induced a significant increase in CHK1 autophosphorylation over untreated tumors. Co-administration of LY2603618 with gemcitabine showed a clear inhibition of CHK1 autophosphorylation for at least 24 h. Combining LY2603618 with gemcitabine resulted in an increase in H2AX serine 139 phosphorylation, indicating a corresponding increase in damaged DNA in the tumors. LY2603618 abrogated the S-phase DNA damage checkpoint in Calu-6 xenograft tumors treated with gemcitabine but did not significantly alter the G2/M checkpoint. Combining gemcitabine with LY2603618 resulted in a significant increase in tumor growth inhibition in Calu-6, HT-29 and PAXF 1869 xenografts over gemcitabine treatment alone. The best combination efficacy occurred when LY2603618 was given 24 h following dosing with gemcitabine. LY2603618 worked effectively to remove the S-phase DNA damage checkpoint and increase the DNA damage and the antitumor activity of gemcitabine treatment.
Databáze: MEDLINE
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