Epigenetic Therapy of Non-Small Cell Lung Cancer Using Decitabine (5-Aza-2′-Deoxycytidine)

Richard L Momparler

doi:10.3389/fonc.2013.00188

Abstract

Epigenetic analysis shows that many genes that suppress malignancy are silenced by aberrant DNA methylation in lung cancer. Many of these genes are interesting targets for reactivation by the inhibitor of DNA methylation, decitabine (5-aza-2′-deoxycytidine, DAC). A pilot study on intense dose DAC showed promising results in patients with metastatic non-small cell lung cancer (NSCLC). However, subsequent clinical studies using low dose DAC were not very effective against NSCLC and interest in this therapy diminished. Recently, interesting responses were observed in a patient with NSCLC following treatment with a combination of the related inhibitor of DNA methylation, 5-azacytidine, and an inhibitor of histone deacetylation. This finding has generated a renewed interest in the epigenetic therapy of lung cancer. Preclinical studies indicate that DAC has remarkable chemotherapeutic potential for tumor therapy. This epigenetic agent has a delayed and prolonged epigenetic action on tumor cells. This delayed action should be taken into consideration in the design and evaluation of clinical studies on DAC. Future research should be directed at finding the optimal dose-schedule of de DAC for the treatment of NSCLC.

Highlights

The life expectancy of most patients with metastatic non-small cell lung cancer (NSCLC) following standard chemotherapy is very limited [1,2,3]
One of the major epigenetic changes that take place in lung cancer is aberrant DNA methylation in the promoter region of genes that suppress malignancy. The silencing of these genes can promote tumorigenesis by several mechanisms including increasing cell proliferation, inactivation of genes that suppress metastasis and angiogenesis, suppressing apoptosis, and DNA repair. These genes are interesting targets for intervention using a potent inhibitor of DNA methylation, such a decitabine (5-aza-2 -deoxycytidine, DAC)
DESIGN OF CLINICAL TRIALS ON DAC IN PATIENTS WITH NSCLC It is not justified to conclude that DAC is weak antitumor drug based on the results of clinical trial that used very poor doseschedule? In order to determine the full chemotherapeutic potential of DAC for the treatment of lung cancer, it is important to find its optimal dose-schedule

Summary

INTRODUCTION

The life expectancy of most patients with metastatic non-small cell lung cancer (NSCLC) following standard chemotherapy is very limited [1,2,3]. One of the major epigenetic changes that take place in lung cancer is aberrant DNA methylation in the promoter region of genes that suppress malignancy The silencing of these genes can promote tumorigenesis by several mechanisms including increasing cell proliferation, inactivation of genes that suppress metastasis and angiogenesis, suppressing apoptosis, and DNA repair. The patient who survived >5 years received an 8-h infusion of DAC at a dose of 660 mg/m2, which produced a plasma level was 2.7 μM This interesting correlation shows that in the clinical trial with intense dose DAC, concentrations of this analog were present in the plasma of the patients that had the potential to significantly reduce the clonogenic potential of the tumor cells.

MGMT DNA repair

Findings

CONCLUSION