P38 MAPK inhibitor, LY2228820, causes significant chemopotentiation of temozolomide in U87MG human glioblastoma xenografts

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The p38 MAPK pathway plays an important role in the cellular response to environmental stress and exposure to cytokines. A recent report (Y. Hirose, et al., Mol. Cellular Biol., 23: 8306-8315, 2003) indicated that p38α-MAPK was activated in U87MG glioblastoma cells treated with temozolomide (TMZ). These investigators suggested that this effect was linked to DNA mismatch repair-dependent G2 arrest and resistance to chemotherapeutic DNA-methylating agents. Therefore, we sought to determine if treatment of U87MG glioblastoma xenografts with a combination of a potent p38α-MAPK inhibitor, LY2228820.2MsOH (LY), and carmustine (BCNU) or TMZ would result in increased efficacy in an in vivo tumor model. Exposure and in vivo target inhibition studies demonstrated that a 44 mg/kg dose of LY administered orally every 8 hours provided maximum inhibition of phospho-MAPKAPK2 in tumor tissue and ex vivo anisomycin-stimulated peripheral blood mononuclear cells. This dose regimen was subsequently used in combination experiments. Initial studies indicated that treatment of U87MG tumors with a single i.p. injection of 10 or 30 mg/kg BCNU given on the second day of a three day dosing schedule of LY resulted in significant potentiation of BCNU single agent activity. In a similar study, 10 mg/kg TMZ was given to mice bearing U87MG tumors on the second day of a six day dosing schedule of LY. This combination also resulted in significant enhancement of TMZ anti-tumor activity. In order to determine if a durable response to the combination treatment could be maintained, a second cycle of TMZ LY was given 16 days after completion of the first cycle of therapy. U87MG tumor growth was not significantly reduced by the second round of TMZ alone while significant tumor suppression was maintained in the second cycle of TMZ combination therapy. These results indicate that inhibition of the p38 MAPK pathway enhances the anti-tumor effects of DNA-alkylating agents in U87MG human glioblastoma xenografts and this combination therapy may represent a viable strategy for improved treatment of human tumors.