Epigenetic Therapy of Cancer With 5-Aza-2′-Deoxycytidine (decitabine)

doi:10.1053/j.seminoncol.2005.07.008

Seminars in Oncology

Volume 32, Issue 5, October 2005, Pages 443-451

https://doi.org/10.1053/j.seminoncol.2005.07.008 Get rights and content

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.

Section snippets

Metabolism and Molecular Mechanism of Action

5-AZA-CdR is a deoxycytidine analog in which the carbon at the 5 position of the pyrimidine ring is replaced by a nitrogen (Fig 1). This analog is a prodrug that is activated via phosphorylation by deoxycytidine kinase (Fig 2). Other kinases in the cell rapidly convert the monophosphate (5AZA-dCMP) to its triphosphate form (5AZA-dCTP), the active form of the drug in the cell. 5AZA-dCTP is a very good substrate for DNA polymerase and is rapidly incorporated into DNA.²² Deamination of 5-AZA-CdR

Phase I and II Studies

A summary of the major clinical trials that have been performed on 5-AZA-CdR as a single agent on patients with hematologic malignancies and solid tumors is shown in Table 4. Several different dose-schedules have been investigated, producing a wide range of plasma concentrations of this analog. In patients with acute leukemia, dose-schedule A employed an intermediate dose of 5-AZA-CdR (1,000 to 2,000 mg/m² administered as a 36- to 60-hour infusion) producing plasma levels of this analog in the

Patient Selection

Since aberrant DNA methylation of genes that suppress malignancy has been detected in all types of malignancy, 5-AZA-CdR has the potential for therapy of all types of cancer. In support of this hypothesis are the preclinical investigations that have shown that all human leukemic and tumor cell lines lose their clonogenic potential upon in vitro treatment with this analog.⁴⁷ As for all anticancer drugs, the ideal time for treatment with 5-AZA-CdR is when the leukemic or tumor cell load is

Discussion

To exploit the full chemotherapeutic potential of 5-AZA-CdR in cancer therapy, we have to find the optimal dose-schedule for this interesting inhibitor of DNA methylation. This requires knowledge of the pharmacology of this analog, its mechanism of action, its hematopoietic toxicity and the molecular targets in neoplastic cells. The novel mechanism of action of 5-AZA-CdR is very different from genotoxic anticancer drugs, suggesting that a different dose-schedule and different response analysis

Conclusions

The epigenetic silencing of many genes that suppress transformation to a malignant phenotype by aberrant DNA methylation provides interesting targets for chemotherapeutic intervention. Since this epigenetic change is reversible, the potent and specific inhibitor of DNA methylation, 5-AZA-CdR, merits clinical investigation for cancer therapy. This analog was shown to reactivate many types of tumor-suppressor genes in human tumor and leukemic cell lines. In animal models, 5-AZA-CdR was

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Epigenetic Therapy of Cancer With 5-Aza-2′-Deoxycytidine (decitabine)

Section snippets

Metabolism and Molecular Mechanism of Action

Phase I and II Studies

Patient Selection

Discussion

Conclusions

Leuk Res

Cell

Blood

Leuk Res

Blood

Eur J Clin Oncol

Ann Oncol

Leuk Res

Cell

Cancer epigenetics comes of age

Nature Genet

Cancer epigenetics

Oncogene

Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B1

Cancer Res

CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza-2′-deoxycytidine

Oncogene

E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas

Cancer Res

Demethylation by 5′-aza-2′-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor beta gene in human colon carcinoma cells

Anticancer Drugs

Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN

Nature Med

TMS1, a novel proapoptotic caspase domain protein, is a target of methylation-induced silencing in human breast cancer

Cancer Res

Methylation and silencing of the thrombospondin-1 promoter in human cancer

Oncogene

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Proc Natl Acad Sci U S A

Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression

Cancer Res

Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine

Cancer Res

Promoter methylation controls the expression of MAGE 2, 3 and 4 genes in human cutaneous melanoma

J Immunother

Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription

Nature Genet

DNA methylation and cancer

J Cell Physiol

Preclinical antitumor activity of 5-aza-2′-deoxcytidine against human head and neck cancer xenografts

Invest New Drugs

Clinical trial on 5-aza-2-deoxycytidine in patients with acute leukemia

Pharmac Ther

Decitabine

Curr Opin Oncol

Potential of 5-aza-2′-deoxycytidine (decitabine) a potent inhibitor of DNA methylation for therapy of advanced non-small cell lung cancer

Lung Cancer

Molecular, cellular and animal pharmacology of 5-aza-2-deoxycytidine

Pharmac Ther

Incorporation of 5-aza-2′-deoxycytidine 5′-triphosphate into DNAInteractions with mammalian DNA polymerase and DNA methylase

Mol Pharmacol