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Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan

Authors' Affiliations: Departments of ¹ Neuro-Oncology, ² Neurosurgery, and ³ Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁴ Cancer Research Institute, University of California at San Francisco, San Francisco, California; ⁵ Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama; and ⁶ Institut Catala d'Oncologia, Barcelona, Spain

Requests for reprints: Juan Fueyo, Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 1002, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6221; Fax: 713-834-6230; E-mail: jfueyo{at}mdanderson.org.

Purpose: In this study, we sought to determine whether Delta-24 could sensitize glioma cells to the topoisomerase I inhibitor irinotecan (CPT-11) and to identify the mechanisms underlying this enhanced anticancer effect.

Experimental Design: We used human glioblastoma cell lines for the in vitro studies. The expression of topoisomerase I was determined in Western blot analyses, and topoisomerase I activity was determined by measuring the relaxation of a supercoiled DNA. The cell cycle distribution of cells was determined by flow cytometry analysis of the cellular DNA content. Cell viability was quantified by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tissue culture infection dose assays were used to quantitate adenovirus replication. For the in vivo studies, athymic mice received intracranial/intratumoral injections of Delta-24 in combination with CPT-11, after which animal survival was monitored.

Results: Delta-24 infection caused human glioma cells to accumulate in the S phase and induced the expression and activity of topoisomerase I as shown by Western blot and in vitro enzymatic activity assays. Further, we showed that the sequential administration of Delta-24 and CPT-11 to human glioma cell cultures potentiated the CPT-11-mediated anticancer effect in vitro without modifying the replicative phenotype of the oncolytic adenovirus. In vivo experiments showed that the single intratumoral administration of Delta-24 to intracranially implanted human glioma xenografts followed by the systemic administration of CPT-11 resulted in significantly prolonged animal survival.

Conclusions: The combination of Delta-24 treatment with CPT-11 showed an enhanced anticancer effect, which suggests that the interaction between adenoviral and human proteins can be exploited in rational anticancer therapies comprising replication-competent adenoviruses and conventional chemotherapeutic agents.

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