This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Minderman, H. Articles by Baer, M. R. Search for Related Content PubMed PubMed Citation Articles by Minderman, H. Articles by Baer, M. R.

Departments of ¹ Medicine and ² Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Hans Minderman, Department of Medicine, Roswell Park Cancer Institute, Science Building 616, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: hans.minderman{at}roswellpark.org

Objective: To study irinotecan (CPT-11)–induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cells in vitro and in vivo. Methods: HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. Results: cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle–associated genes, consistent with loss of S-phase cells and temporary delay of G₁-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G₂-M and G₁ were delayed in G₁ and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed following in vitro SN-38 exposure were also seen following in vivo administration of 10 or 15 mg/m² CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. Conclusion: CPT-11-induced changes in gene expression profiles in vitro and in vivo are consistent with temporary delay in G₁-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ http://microarrays.roswellpark.org/supplemental/Minderman.

Received 2/20/05; revised 4/ 6/05; accepted 4/13/05.