Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer
<p>Abstract</p> <p>Background</p> <p>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 interve...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2008-05-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/8/128 |
| _version_ | 1819180205801996288 |
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| author | Momparler Richard L Bernstein Mark L Hurtubise Annie Momparler Louise F Chabot Guy G Raynal Noël JM Lemaire Maryse |
| author_facet | Momparler Richard L Bernstein Mark L Hurtubise Annie Momparler Louise F Chabot Guy G Raynal Noël JM Lemaire Maryse |
| author_sort | Momparler Richard L |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>Clonogenic assays were performed on leukemic and tumor cell lines to evaluate the <it>in vitro </it>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 <it>in vivo </it>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 <it>in vitro </it>clonogenic assay.</p> <p>Results</p> <p>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 (<it>p57KIP2 </it>in HL-60 leukemic cells and <it>p16CDKN2A </it>in Calu-6 lung carcinoma cells) and the inhibition of global DNA methylation in HL-60 leukemic cells increased with DAC concentration. In mice with L1210 leukemia and in mice bearing EMT6 tumors, the antineoplastic action of DAC also increased with the dose. The plasma level of DAC that produced a very potent antineoplastic effect in mice with leukemia or solid tumors was > 200 ng/ml (> 1 μM).</p> <p>Conclusion</p> <p>We have shown that intensification of the DAC dose markedly increased its antineoplastic activity in mouse models of cancer. Our data also show that there is a good correlation between the concentrations of DAC that reduce <it>in vitro </it>clonogenicity, reactivate TSGs and inhibit DNA methylation. These results suggest that the antineoplastic action of DAC is related to its epigenetic action. Our observations provide a strong rationale to perform clinical trials using dose intensification of DAC to maximize the chemotherapeutic potential of this epigenetic agent in patients with cancer.</p> |
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| format | Article |
| id | doaj.art-7ee13706d9cc4efaa0f5c367b240979e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-22T22:10:39Z |
| publishDate | 2008-05-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-7ee13706d9cc4efaa0f5c367b240979e2022-12-21T18:10:53ZengBMCBMC Cancer1471-24072008-05-018112810.1186/1471-2407-8-128Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancerMomparler Richard LBernstein Mark LHurtubise AnnieMomparler Louise FChabot Guy GRaynal Noël JMLemaire Maryse<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>Clonogenic assays were performed on leukemic and tumor cell lines to evaluate the <it>in vitro </it>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 <it>in vivo </it>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 <it>in vitro </it>clonogenic assay.</p> <p>Results</p> <p>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 (<it>p57KIP2 </it>in HL-60 leukemic cells and <it>p16CDKN2A </it>in Calu-6 lung carcinoma cells) and the inhibition of global DNA methylation in HL-60 leukemic cells increased with DAC concentration. In mice with L1210 leukemia and in mice bearing EMT6 tumors, the antineoplastic action of DAC also increased with the dose. The plasma level of DAC that produced a very potent antineoplastic effect in mice with leukemia or solid tumors was > 200 ng/ml (> 1 μM).</p> <p>Conclusion</p> <p>We have shown that intensification of the DAC dose markedly increased its antineoplastic activity in mouse models of cancer. Our data also show that there is a good correlation between the concentrations of DAC that reduce <it>in vitro </it>clonogenicity, reactivate TSGs and inhibit DNA methylation. These results suggest that the antineoplastic action of DAC is related to its epigenetic action. Our observations provide a strong rationale to perform clinical trials using dose intensification of DAC to maximize the chemotherapeutic potential of this epigenetic agent in patients with cancer.</p>http://www.biomedcentral.com/1471-2407/8/128 |
| spellingShingle | Momparler Richard L Bernstein Mark L Hurtubise Annie Momparler Louise F Chabot Guy G Raynal Noël JM Lemaire Maryse Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer BMC Cancer |
| title | Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer |
| title_full | Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer |
| title_fullStr | Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer |
| title_full_unstemmed | Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer |
| title_short | Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer |
| title_sort | importance of dose schedule of 5 aza 2 deoxycytidine for epigenetic therapy of cancer |
| url | http://www.biomedcentral.com/1471-2407/8/128 |
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