May 6, 2008

Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer

BMC Cancer
Maryse LemaireRichard L Momparler

Abstract

The inactivation of tumor suppressor genes (TSGs) by aberrant DNA methylation plays an important role in the development of malignancy. Since this epigenetic change is reversible, it is a potential target for chemotherapeutic intervention using an inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (DAC). Although clinical studies show that DAC has activity against hematological malignancies, the optimal dose-schedule of this epigenetic agent still needs to be established. Clonogenic assays were performed on leukemic and tumor cell lines to evaluate the in vitro antineoplastic activity of DAC. The reactivation of TSGs and inhibition of DNA methylation by DAC were investigated by reverse transcriptase-PCR and Line-1 assays. The in vivo antineoplastic activity of DAC administered as an i.v. infusion was evaluated in mice with murine L1210 leukemia by measurement of survival time, and in mice bearing murine EMT6 mammary tumor by excision of tumor after chemotherapy for an in vitro clonogenic assay. Increasing the DAC concentration and duration of exposure produced a greater loss of clonogenicity for both human leukemic and tumor cell lines. The reactivation of the TSGs (p57KIP2 in HL-60 leukemic cells and p16CDKN2A in Cal...Continue Reading

Mentioned in this Paper

Cyclin-Dependent Kinase Inhibitor Proteins
Tumor Cells, Uncertain Whether Benign or Malignant
Cytarabine
Structure of Calf of Leg
Hydrogen sulfite
DNA Methylation [PE]
Antineoplastic Agents
Tumor Suppressor Genes
Hematologic Neoplasms
Mice, Inbred BALB C

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