Abstract
Although chemotherapy is considered the mainstay of cancer therapy, unfortunate side effects of chemotherapy create a continuous demand for developing other novel and specific targets for cancer therapy. Re-expression of epigenetically silenced tumor suppressor genes is a rational strategy for the treatment of human neoplasms. Epigenetic modifiers like DNA methyltransferase (DNMT) inhibitors and histone deacteylase (HDAC) inhibitors induce the re-expression of epigenetically silenced genes in vitro and in vivo. Moreover, they demonstrate safety and efficacy against neoplastic diseases in clinical trials. DNMT inhibitors like 5-azacytidine and 5-aza-2-deoxycytidine are currently FDA approved for the treatment of myelodysplastic syndrome. Nonetheless, the mechanism of action behind their clinical efficacy remains unclear. Ongoing clinical trials are attempting to identify tumor suppressor genes that upon re-expression can induce remission and cure in patients. On the other hand, the pleiotropic biological effects of DNMT inhibitors and recent reports demonstrating lack of association between clinical response and methylation reversal of candidate tumor suppressor genes, suggest a complex mechanism behind their clinical efficacy that may involve a cytotoxic effect.
Keywords: 5-azacytidine, decitabine, zebularine, RG108, DNA methylation, DNA methyltransferases
Current Medicinal Chemistry
Title: Development of DNA Methyltransferase Inhibitors for the Treatment of Neoplastic Diseases
Volume: 16 Issue: 17
Author(s): Tamer E. Fandy
Affiliation:
Keywords: 5-azacytidine, decitabine, zebularine, RG108, DNA methylation, DNA methyltransferases
Abstract: Although chemotherapy is considered the mainstay of cancer therapy, unfortunate side effects of chemotherapy create a continuous demand for developing other novel and specific targets for cancer therapy. Re-expression of epigenetically silenced tumor suppressor genes is a rational strategy for the treatment of human neoplasms. Epigenetic modifiers like DNA methyltransferase (DNMT) inhibitors and histone deacteylase (HDAC) inhibitors induce the re-expression of epigenetically silenced genes in vitro and in vivo. Moreover, they demonstrate safety and efficacy against neoplastic diseases in clinical trials. DNMT inhibitors like 5-azacytidine and 5-aza-2-deoxycytidine are currently FDA approved for the treatment of myelodysplastic syndrome. Nonetheless, the mechanism of action behind their clinical efficacy remains unclear. Ongoing clinical trials are attempting to identify tumor suppressor genes that upon re-expression can induce remission and cure in patients. On the other hand, the pleiotropic biological effects of DNMT inhibitors and recent reports demonstrating lack of association between clinical response and methylation reversal of candidate tumor suppressor genes, suggest a complex mechanism behind their clinical efficacy that may involve a cytotoxic effect.
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Cite this article as:
Fandy E. Tamer, Development of DNA Methyltransferase Inhibitors for the Treatment of Neoplastic Diseases, Current Medicinal Chemistry 2009; 16 (17) . https://dx.doi.org/10.2174/092986709788612738
DOI https://dx.doi.org/10.2174/092986709788612738 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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