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Mol Cancer Ther. 2005 Jun;4(6):885-900.

In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.

Author information

  • 1Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. hans.minderman@roswellpark.org

Abstract

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 G(1)-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G(2)-M and G(1) were delayed in G(1) 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/m(2) 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 G(1)-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.

PMID:
15956246
[PubMed - indexed for MEDLINE]
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