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Epigenetic therapy of cancer with 5-aza-2'-deoxycytidine (decitabine)
1Département de pharmacologie, Université de Montréal and Centre de recherche pédiatrique, Hõpital Ste-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada. Richard.l.momparler@umontreal.ca
Abstract:
Epigenetic events, such as aberrant DNA methylation, have been demonstrated to silence the expression of many genes that suppress malignancy. Since the event is reversible, it is an interesting target for intervention with specific inhibitors of DNA methylation, such as 5-aza-2'-deoxycytidine (5-AZA-CdR, decitabine). 5-AZA-CdR is a prodrug that requires activation via phosphorylation by deoxcytidine kinase. The nucleotide analog is incorporated into DNA, where it produces an irreversible inactivation of DNA methyltransferase. 5-AZA-CdR is an S-phase-specific agent. The demethylation of DNA by this analog in neoplastic cells can lead to the reactivation of silent tumor-suppressor genes, induction of differentiation or senescence, growth inhibition, and loss of clonogenicity. 5-AZA-CdR was demonstrated to be a potent antineoplastic agent against leukemia and tumors in animal models. Preliminary clinical trials of 5-AZA-CdR using different dose-schedules have shown interesting antineoplastic activity in patients with leukemia, myelodysplastic syndrome (MDS), and non-small cell lung cancer (NSCLC). Pharmacokinetic studies have shown that 5-AZA-CdR has a short in vivo half-life of 15 to 25 minutes. The major toxicity produced by this analog is granulocytopenia. To exploit the full chemotherapeutic potential of 5-AZA-CdR for the treatment of cancer, its optimal dose-schedule has to be found. This will require a good understanding of the pharmacology of this analog and its action on both normal and neoplastic cells.
Insights
Aberrant DNA methylation silences tumor-suppressor genes. The DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-AZA-CdR) shows promise in reversing this, offering a potential new cancer therapy.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Aberrant DNA methylation is a key mechanism for silencing tumor-suppressor genes in cancer.
- DNA methylation is a reversible epigenetic modification, making it a target for therapeutic intervention.
- 5-aza-2 -deoxycytidine (5-AZA-CdR, decitabine) is a DNA methyltransferase inhibitor that can reverse aberrant methylation.
Purpose of the Study:
- To investigate the potential of 5-AZA-CdR as an antineoplastic agent.
- To understand the mechanism of action and pharmacokinetic properties of 5-AZA-CdR.
- To explore the optimal dosing and scheduling for 5-AZA-CdR in cancer treatment.
Main Methods:
- 5-AZA-CdR is a prodrug activated by deoxcytidine kinase and incorporated into DNA.
- It irreversibly inactivates DNA methyltransferase, acting as an S-phase-specific agent.
- Studies involved animal models and preliminary clinical trials in leukemia, MDS, and NSCLC patients.
Main Results:
- 5-AZA-CdR demonstrated potent antineoplastic activity in preclinical models.
- Clinical trials showed promising antineoplastic activity in patients with leukemia, MDS, and NSCLC.
- 5-AZA-CdR has a short in vivo half-life (15-25 minutes) and its major toxicity is granulocytopenia.
Conclusions:
- 5-AZA-CdR can reactivate silent tumor-suppressor genes, induce differentiation, inhibit growth, and reduce clonogenicity in neoplastic cells.
- Further research is needed to determine the optimal dose-schedule for 5-AZA-CdR to maximize its therapeutic potential.
- Understanding the pharmacology and cellular effects of 5-AZA-CdR is crucial for its effective clinical application in cancer therapy.
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