The Experts below are selected from a list of 19551 Experts worldwide ranked by ideXlab platform
William Plunkett - One of the best experts on this subject based on the ideXlab platform.
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hdac inhibition induces microrna 182 which targets rad51 protein and impairs homologous recombination repair to sensitize cells to the double strand break inducing Nucleoside Analog sapacitabine in aml
Blood, 2015Co-Authors: Alma Zecevic, Brett Ewald, Liu Chaomei, Lara Rizzotto, Melanie Sulda, Dimitrios Papaioannou, Ramiro Garzon, William Plunkett, Deepa SampathAbstract:Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Effective clinical treatment of AML has largely depended on a class of antimetabolites - the Nucleoside Analogs. Of these, sapacitabine is a Nucleoside Analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Rad51 is a protein plays a critical role in HR, and high levels of Rad51 are linked to resistance to DNA damaging therapies. Histone deacetylases (HDACs) are chromatin modulating agents that decrease levels of acetylation of histones, repress gene expression. HDAC inhibitors (HDACis) function by modifying chromatin to epigenetically reverse gene silencing of coding and non-coding genes such as the microRNAs (miRs). miRs are endogenous noncoding RNAs 19-25 nucleotides in length that bind to complimentary sequences in target RNA to either destabilize it or prevent its transcription. In this study, we determined that determined primary AML blasts and cell lines express low levels of microRNA-182. Recruitment of HDAC1 and its co-repressors were linked to the epigenetic silencing of miR-182 in AML. Conversely, HDAC inhibition led to accumulation of activating chromatin modifications followed by the upregulation of miR-182 in AML blasts and cell lines. The HDACi-induced increases in miR-182 were linked to decreases in the levels of Rad51, an inhibition in the ability of cells to conduct homologous recombination repair as measured by the Homologous recombination directed repair (HDR) assay, persistent levels of DNA damage as measured by the levels of Ɣ-H2AX and sensitization to sapacitabine. We then mechanistically defined the relation between miR-182 and Rad51. Ectopic expression of miR-182 in AML cell lines identified that Rad51 was a target of miR-182. An assay with luciferase constructs bearing full length or mutated Rad51 39UTR indentified that Rad51 was a direct target of miR-182. We also determined that ectopic expression of miR-182 attenuated the ability of AML cells to conduct homologus repair as measured by the Homologous recombination directed repair (HDR) assay which resulted in sensitizing AML cells to the cytotoxic action of CNDAC as measured by colony forming assays. In conclusion, our data show that HDAC inhibitors target Rad51 via miR-182 to compromise HR repair to result in higher levels of residual DNA damage and sensitize AML cells to double strand damaging agents such as CNDAC. Disclosures No relevant conflicts of interest to declare.
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hdac inhibition induces microrna 182 which targets rad51 protein and impairs homologous recombination repair to sensitize cells to the double strand break inducing Nucleoside Analog sapacitabine in aml
Blood, 2015Co-Authors: Alma Zecevic, Brett Ewald, Liu Chaomei, Lara Rizzotto, Melanie Sulda, Dimitrios Papaioannou, Ramiro Garzon, William Plunkett, Deepa SampathAbstract:Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Effective clinical treatment of AML has largely depended on a class of antimetabolites - the Nucleoside Analogs. Of these, sapacitabine is a Nucleoside Analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Rad51 is a protein plays a critical role in HR, and high levels of Rad51 are linked to resistance to DNA damaging therapies. Histone deacetylases (HDACs) are chromatin modulating agents that decrease levels of acetylation of histones, repress gene expression. HDAC inhibitors (HDACis) function by modifying chromatin to epigenetically reverse gene silencing of coding and non-coding genes such as the microRNAs (miRs). miRs are endogenous noncoding RNAs 19-25 nucleotides in length that bind to complimentary sequences in target RNA to either destabilize it or prevent its transcription. In this study, we determined that determined primary AML blasts and cell lines express low levels of microRNA-182. Recruitment of HDAC1 and its co-repressors were linked to the epigenetic silencing of miR-182 in AML. Conversely, HDAC inhibition led to accumulation of activating chromatin modifications followed by the upregulation of miR-182 in AML blasts and cell lines. The HDACi-induced increases in miR-182 were linked to decreases in the levels of Rad51, an inhibition in the ability of cells to conduct homologous recombination repair as measured by the Homologous recombination directed repair (HDR) assay, persistent levels of DNA damage as measured by the levels of Ɣ-H2AX and sensitization to sapacitabine. We then mechanistically defined the relation between miR-182 and Rad51. Ectopic expression of miR-182 in AML cell lines identified that Rad51 was a target of miR-182. An assay with luciferase constructs bearing full length or mutated Rad51 39UTR indentified that Rad51 was a direct target of miR-182. We also determined that ectopic expression of miR-182 attenuated the ability of AML cells to conduct homologus repair as measured by the Homologous recombination directed repair (HDR) assay which resulted in sensitizing AML cells to the cytotoxic action of CNDAC as measured by colony forming assays. In conclusion, our data show that HDAC inhibitors target Rad51 via miR-182 to compromise HR repair to result in higher levels of residual DNA damage and sensitize AML cells to double strand damaging agents such as CNDAC. Disclosures No relevant conflicts of interest to declare.
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abstract 2551 brca1 deficient ovarian cancer cells are sensitized to the dna strand breaking Nucleoside Analog sapacitabine that synergizes with parp inhibition
Cancer Research, 2015Co-Authors: Xiaojun Liu, Billie Nowak, Yingjun Jiang, Dariya Tikhomirova, William PlunkettAbstract:Sapacitabine is an orally bioavailable prodrug of the deoxycytidine Analog, CNDAC. Sapacitabine is currently in a Phase III registration trial for elderly AML patients (NCT01303796). CNDAC (as DFP-10917) is in a Phase I/II trial for AML and ALL (NCT01702155). Sapacitabine/CNDAC-induced DNA damage, double-strand breaks converted from initial single-strand breaks, is repaired mainly by the homologous recombination (HR) pathway. Deficiency in HR components, including ATM, Rad51, Xrcc3, Brca2 and Brca1, confer sensitivity to CNDAC. Brca1 and Brca2 function is frequently compromised in ovarian cancer. To determine the role of Brca1 in DNA damage repair after sapacitabine, we used a Brca1-null ovarian carcinoma cell line, UWB1.289 and its complemented line, UWB1.289+Brca1 in this study. First, the clonogenic sensitivities of the two lines to therapeutic agents were compared. The deficient cells were 3-4 fold more sensitive to CNDAC than the repleted cells. In contrast, Brca1 repletion did not confer resistance to cytarabine, fludarabine or gemcitabine. These results confirm the unique action mechanism of CNDAC among Nucleoside Analogs. Second, a cytogenetic approach was taken to compare CNDAC-induced chromosome damage in both lines (N = 50 metaphases scored for each sample). We found Brca1-null cells bearing more chromosomal structural abnormalities (∼50% metaphases) than Brca1-complemented cells (∼30%), apparently due to genetic instability when lacking Brca1. UWB1.289 cells exposed to 15 nM CNDAC for 27 hr (1 cell cycle) and 54 hr (2 cell cycles) manifested massive chromosomal aberrations (>60% and >90% metaphases, respectively), nearly 40% and 70% of which could not be scored. In contrast, UWB1.289+Brca1 cells showed significantly fewer chromosome aberrations (42% and 48% metaphases, respectively), the majority of which were scorable, upon extended incubation with CNDAC under the same conditions. These results provided cytogenetic evidence for Brca1 involvement in DNA damage repair after CNDAC. Third, interaction between sapacitabine and other classes of therapeutic agents was explored using clonogenic assays. For example, CO-338, a camsylate salt of the PARP inhibitor, rucaparib, greatly sensitized Brca1-deficient cells. Despite the distinctive sensitivities of the two lines, the CO-338 - CNDAC combination showed synergistic cell killing by median-effect analysis (combination index Citation Format: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Dariya Tikhomirova, William Plunkett. Brca1-deficient ovarian cancer cells are sensitized to the DNA-strand-breaking Nucleoside Analog sapacitabine that synergizes with PARP inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2015-2551
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sapacitabine the prodrug of cndac is a Nucleoside Analog with a unique action mechanism of inducing dna strand breaks
Chinese Journal of Cancer, 2012Co-Authors: Xiaojun Liu, Billie Nowak, Ya Qing Wang, William PlunkettAbstract:Sapacitabine is an orally bioavailable prodrug of the Nucleoside Analog 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC). Both the prodrug and active metabolite are in clinical trials for hematologic malignancies and/or solid tumors. CNDAC has a unique mechanism of action: after incorporation into DNA, it induces single-strand breaks (SSBs) that are converted into double-strand breaks (DSBs) when cells go through a second S phase. In our previous studies, we demonstrated that CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway, whereas lethal DSBs are mainly repaired through homologous recombination. In the current work, we used clonogenic assays to compare the DNA damage repair mechanism of CNDAC with two other deoxycytidine Analogs: cytarabine, which is used in hematologic malignacies, and gemcitabine, which shows activity in solid tumors. Deficiency in two Rad51 paralogs, Rad51D and XRCC3, greatly sensitized cells to CNDAC, but not to cytarabine or gemcitabine, indicating that homologous recombination is not a major mechanism for repairing damage caused by the latter two Analogs. This study further suggests clinical activity and application of sapacitabine that is distinct from that of cytarabine or gemcitabine.
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the role of clofarabine in hematologic and solid malignancies development of a next generation Nucleoside Analog
Cancer, 2005Co-Authors: Stefan Faderl, William Plunkett, Varsha Gandhi, Michael J Keating, Sima Jeha, Hagop M KantarjianAbstract:Clofarabine is a new-generation Nucleoside Analog that has been synthesized to combine the most favorable pharmacokinetic properties of its congeners fludarabine and cladribine. In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in Nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials. Although it was synthesized early in the 1980s, the development of clofarabine was stalled until 1993, when, through efforts at The University of Texas M. D. Anderson Cancer Center, animal toxicology studies were conducted, and the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemias. By way of its unique metabolic properties, clofarabine also has lent itself to biochemical modulation strategies with other Nucleoside Analogs, such as cytarabine. Combinations of clofarabine with cytarabine have been studied in acute leukemia and currently are being evaluated in untreated elderly patients with acute myeloid leukemia. Novel schedules are being explored in lymphoproliferative disorders and solid tumors. Clofarabine is a new Nucleoside Analog with considerable activity and an acceptable safety profile in acute leukemias.
Deepa Sampath - One of the best experts on this subject based on the ideXlab platform.
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hdac inhibition induces microrna 182 which targets rad51 protein and impairs homologous recombination repair to sensitize cells to the double strand break inducing Nucleoside Analog sapacitabine in aml
Blood, 2015Co-Authors: Alma Zecevic, Brett Ewald, Liu Chaomei, Lara Rizzotto, Melanie Sulda, Dimitrios Papaioannou, Ramiro Garzon, William Plunkett, Deepa SampathAbstract:Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Effective clinical treatment of AML has largely depended on a class of antimetabolites - the Nucleoside Analogs. Of these, sapacitabine is a Nucleoside Analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Rad51 is a protein plays a critical role in HR, and high levels of Rad51 are linked to resistance to DNA damaging therapies. Histone deacetylases (HDACs) are chromatin modulating agents that decrease levels of acetylation of histones, repress gene expression. HDAC inhibitors (HDACis) function by modifying chromatin to epigenetically reverse gene silencing of coding and non-coding genes such as the microRNAs (miRs). miRs are endogenous noncoding RNAs 19-25 nucleotides in length that bind to complimentary sequences in target RNA to either destabilize it or prevent its transcription. In this study, we determined that determined primary AML blasts and cell lines express low levels of microRNA-182. Recruitment of HDAC1 and its co-repressors were linked to the epigenetic silencing of miR-182 in AML. Conversely, HDAC inhibition led to accumulation of activating chromatin modifications followed by the upregulation of miR-182 in AML blasts and cell lines. The HDACi-induced increases in miR-182 were linked to decreases in the levels of Rad51, an inhibition in the ability of cells to conduct homologous recombination repair as measured by the Homologous recombination directed repair (HDR) assay, persistent levels of DNA damage as measured by the levels of Ɣ-H2AX and sensitization to sapacitabine. We then mechanistically defined the relation between miR-182 and Rad51. Ectopic expression of miR-182 in AML cell lines identified that Rad51 was a target of miR-182. An assay with luciferase constructs bearing full length or mutated Rad51 39UTR indentified that Rad51 was a direct target of miR-182. We also determined that ectopic expression of miR-182 attenuated the ability of AML cells to conduct homologus repair as measured by the Homologous recombination directed repair (HDR) assay which resulted in sensitizing AML cells to the cytotoxic action of CNDAC as measured by colony forming assays. In conclusion, our data show that HDAC inhibitors target Rad51 via miR-182 to compromise HR repair to result in higher levels of residual DNA damage and sensitize AML cells to double strand damaging agents such as CNDAC. Disclosures No relevant conflicts of interest to declare.
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hdac inhibition induces microrna 182 which targets rad51 protein and impairs homologous recombination repair to sensitize cells to the double strand break inducing Nucleoside Analog sapacitabine in aml
Blood, 2015Co-Authors: Alma Zecevic, Brett Ewald, Liu Chaomei, Lara Rizzotto, Melanie Sulda, Dimitrios Papaioannou, Ramiro Garzon, William Plunkett, Deepa SampathAbstract:Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Effective clinical treatment of AML has largely depended on a class of antimetabolites - the Nucleoside Analogs. Of these, sapacitabine is a Nucleoside Analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Rad51 is a protein plays a critical role in HR, and high levels of Rad51 are linked to resistance to DNA damaging therapies. Histone deacetylases (HDACs) are chromatin modulating agents that decrease levels of acetylation of histones, repress gene expression. HDAC inhibitors (HDACis) function by modifying chromatin to epigenetically reverse gene silencing of coding and non-coding genes such as the microRNAs (miRs). miRs are endogenous noncoding RNAs 19-25 nucleotides in length that bind to complimentary sequences in target RNA to either destabilize it or prevent its transcription. In this study, we determined that determined primary AML blasts and cell lines express low levels of microRNA-182. Recruitment of HDAC1 and its co-repressors were linked to the epigenetic silencing of miR-182 in AML. Conversely, HDAC inhibition led to accumulation of activating chromatin modifications followed by the upregulation of miR-182 in AML blasts and cell lines. The HDACi-induced increases in miR-182 were linked to decreases in the levels of Rad51, an inhibition in the ability of cells to conduct homologous recombination repair as measured by the Homologous recombination directed repair (HDR) assay, persistent levels of DNA damage as measured by the levels of Ɣ-H2AX and sensitization to sapacitabine. We then mechanistically defined the relation between miR-182 and Rad51. Ectopic expression of miR-182 in AML cell lines identified that Rad51 was a target of miR-182. An assay with luciferase constructs bearing full length or mutated Rad51 39UTR indentified that Rad51 was a direct target of miR-182. We also determined that ectopic expression of miR-182 attenuated the ability of AML cells to conduct homologus repair as measured by the Homologous recombination directed repair (HDR) assay which resulted in sensitizing AML cells to the cytotoxic action of CNDAC as measured by colony forming assays. In conclusion, our data show that HDAC inhibitors target Rad51 via miR-182 to compromise HR repair to result in higher levels of residual DNA damage and sensitize AML cells to double strand damaging agents such as CNDAC. Disclosures No relevant conflicts of interest to declare.
Ling Peng - One of the best experts on this subject based on the ideXlab platform.
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targeting heat shock factor 1 with a triazole Nucleoside Analog to elicit potent anticancer activity on drug resistant pancreatic cancer
Cancer Letters, 2012Co-Authors: Yi Xia, Yang Liu, Palma Rocchi, Menghua Wang, Yuting Fan, Juan L Iovanna, Ling PengAbstract:Issued from a lead optimization process, we have identified a novel triazole Nucleoside Analog which elicits potent anticancer activity on drug-resistant pancreatic cancer. Most importantly, this compound targets heat shock response pathways by down-regulation of heat shock transcription factor 1 and consequential down-regulation of multiple heat shock proteins HSP27, HSP70 and HSP90. Down-regulation of these proteins caused the shut-down of several oncogenic pathways and caspase-dependent apoptosis resulting in a potent anticancer effect in vitro and in vivo. These results demonstrate the potential rewards gained in searching for anticancer candidates with multimodal actions on heat shock response pathways via HSF1 down-regulation.
Menghua Wang - One of the best experts on this subject based on the ideXlab platform.
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targeting heat shock factor 1 with a triazole Nucleoside Analog to elicit potent anticancer activity on drug resistant pancreatic cancer
Cancer Letters, 2012Co-Authors: Yi Xia, Yang Liu, Palma Rocchi, Menghua Wang, Yuting Fan, Juan L Iovanna, Ling PengAbstract:Issued from a lead optimization process, we have identified a novel triazole Nucleoside Analog which elicits potent anticancer activity on drug-resistant pancreatic cancer. Most importantly, this compound targets heat shock response pathways by down-regulation of heat shock transcription factor 1 and consequential down-regulation of multiple heat shock proteins HSP27, HSP70 and HSP90. Down-regulation of these proteins caused the shut-down of several oncogenic pathways and caspase-dependent apoptosis resulting in a potent anticancer effect in vitro and in vivo. These results demonstrate the potential rewards gained in searching for anticancer candidates with multimodal actions on heat shock response pathways via HSF1 down-regulation.
Xiaojun Liu - One of the best experts on this subject based on the ideXlab platform.
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abstract 2551 brca1 deficient ovarian cancer cells are sensitized to the dna strand breaking Nucleoside Analog sapacitabine that synergizes with parp inhibition
Cancer Research, 2015Co-Authors: Xiaojun Liu, Billie Nowak, Yingjun Jiang, Dariya Tikhomirova, William PlunkettAbstract:Sapacitabine is an orally bioavailable prodrug of the deoxycytidine Analog, CNDAC. Sapacitabine is currently in a Phase III registration trial for elderly AML patients (NCT01303796). CNDAC (as DFP-10917) is in a Phase I/II trial for AML and ALL (NCT01702155). Sapacitabine/CNDAC-induced DNA damage, double-strand breaks converted from initial single-strand breaks, is repaired mainly by the homologous recombination (HR) pathway. Deficiency in HR components, including ATM, Rad51, Xrcc3, Brca2 and Brca1, confer sensitivity to CNDAC. Brca1 and Brca2 function is frequently compromised in ovarian cancer. To determine the role of Brca1 in DNA damage repair after sapacitabine, we used a Brca1-null ovarian carcinoma cell line, UWB1.289 and its complemented line, UWB1.289+Brca1 in this study. First, the clonogenic sensitivities of the two lines to therapeutic agents were compared. The deficient cells were 3-4 fold more sensitive to CNDAC than the repleted cells. In contrast, Brca1 repletion did not confer resistance to cytarabine, fludarabine or gemcitabine. These results confirm the unique action mechanism of CNDAC among Nucleoside Analogs. Second, a cytogenetic approach was taken to compare CNDAC-induced chromosome damage in both lines (N = 50 metaphases scored for each sample). We found Brca1-null cells bearing more chromosomal structural abnormalities (∼50% metaphases) than Brca1-complemented cells (∼30%), apparently due to genetic instability when lacking Brca1. UWB1.289 cells exposed to 15 nM CNDAC for 27 hr (1 cell cycle) and 54 hr (2 cell cycles) manifested massive chromosomal aberrations (>60% and >90% metaphases, respectively), nearly 40% and 70% of which could not be scored. In contrast, UWB1.289+Brca1 cells showed significantly fewer chromosome aberrations (42% and 48% metaphases, respectively), the majority of which were scorable, upon extended incubation with CNDAC under the same conditions. These results provided cytogenetic evidence for Brca1 involvement in DNA damage repair after CNDAC. Third, interaction between sapacitabine and other classes of therapeutic agents was explored using clonogenic assays. For example, CO-338, a camsylate salt of the PARP inhibitor, rucaparib, greatly sensitized Brca1-deficient cells. Despite the distinctive sensitivities of the two lines, the CO-338 - CNDAC combination showed synergistic cell killing by median-effect analysis (combination index Citation Format: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Dariya Tikhomirova, William Plunkett. Brca1-deficient ovarian cancer cells are sensitized to the DNA-strand-breaking Nucleoside Analog sapacitabine that synergizes with PARP inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2015-2551
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sapacitabine the prodrug of cndac is a Nucleoside Analog with a unique action mechanism of inducing dna strand breaks
Chinese Journal of Cancer, 2012Co-Authors: Xiaojun Liu, Billie Nowak, Ya Qing Wang, William PlunkettAbstract:Sapacitabine is an orally bioavailable prodrug of the Nucleoside Analog 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC). Both the prodrug and active metabolite are in clinical trials for hematologic malignancies and/or solid tumors. CNDAC has a unique mechanism of action: after incorporation into DNA, it induces single-strand breaks (SSBs) that are converted into double-strand breaks (DSBs) when cells go through a second S phase. In our previous studies, we demonstrated that CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway, whereas lethal DSBs are mainly repaired through homologous recombination. In the current work, we used clonogenic assays to compare the DNA damage repair mechanism of CNDAC with two other deoxycytidine Analogs: cytarabine, which is used in hematologic malignacies, and gemcitabine, which shows activity in solid tumors. Deficiency in two Rad51 paralogs, Rad51D and XRCC3, greatly sensitized cells to CNDAC, but not to cytarabine or gemcitabine, indicating that homologous recombination is not a major mechanism for repairing damage caused by the latter two Analogs. This study further suggests clinical activity and application of sapacitabine that is distinct from that of cytarabine or gemcitabine.
