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Lorraine J Gudas - One of the best experts on this subject based on the ideXlab platform.

  • a DNA Methyltransferase Inhibitor and all trans retinoic acid reduce oral cavity carcinogenesis induced by the carcinogen 4 nitroquinoline 1 oxide
    Cancer Prevention Research, 2009
    Co-Authors: Xiaohan Tang, Martin L Albert, Theresa Scognamiglio, Lorraine J Gudas
    Abstract:

    The transcriptional silencing of some cell cycle Inhibitors and tumor suppressors, such as p16 and retinoic acid receptor β2, by DNA hypermethylation at CpG islands is commonly found in human oral squamous carcinoma cells. We examined the effects of the DNA Methyltransferase Inhibitor 5-Aza-2′-deoxycytidine (5-Aza; 0.25 mg/kg body weight), all-trans retinoic acid (RA; given at 100 μg/kg body weight and 1 mg/kg body weight), and the combination of 5-Aza and the low-dose RA on murine oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model. All the drug treatments were done for 15 weeks after a 10-week 4-NQO treatment. Mice in all drug treatment groups showed decreases in the average numbers of neoplastic tongue lesions. The combination of 5-Aza and RA effectively attenuated tongue lesion severity. Although all drug treatments limited the increase in the percentage of proliferating cell nuclear antigen–positive cells and the decrease in the percentage of p16-positive cells caused by the 4-NQO treatment in mouse tongue epithelial regions without visible lesions and in the neoplastic tongue lesions, the combination of 5-Aza and RA was the most effective. Collectively, our results show that the combination of a DNA demethylating drug and RA has potential as a strategy to reduce oral cavity cancer in this 4-NQO model.

  • a DNA Methyltransferase Inhibitor and all trans retinoic acid reduce oral cavity carcinogenesis induced by the carcinogen 4 nitroquinoline 1 oxide
    Cancer Prevention Research, 2009
    Co-Authors: Xiaohan Tang, Martin L Albert, Theresa Scognamiglio, Lorraine J Gudas
    Abstract:

    The transcriptional silencing of some cell cycle Inhibitors and tumor suppressors, such as p16 and retinoic acid receptor beta(2), by DNA hypermethylation at CpG islands is commonly found in human oral squamous carcinoma cells. We examined the effects of the DNA Methyltransferase Inhibitor 5-Aza-2'-deoxycytidine (5-Aza; 0.25 mg/kg body weight), all-trans retinoic acid (RA; given at 100 microg/kg body weight and 1 mg/kg body weight), and the combination of 5-Aza and the low-dose RA on murine oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model. All the drug treatments were done for 15 weeks after a 10-week 4-NQO treatment. Mice in all drug treatment groups showed decreases in the average numbers of neoplastic tongue lesions. The combination of 5-Aza and RA effectively attenuated tongue lesion severity. Although all drug treatments limited the increase in the percentage of proliferating cell nuclear antigen-positive cells and the decrease in the percentage of p16-positive cells caused by the 4-NQO treatment in mouse tongue epithelial regions without visible lesions and in the neoplastic tongue lesions, the combination of 5-Aza and RA was the most effective. Collectively, our results show that the combination of a DNA demethylating drug and RA has potential as a strategy to reduce oral cavity cancer in this 4-NQO model.

Xiaohan Tang - One of the best experts on this subject based on the ideXlab platform.

  • a DNA Methyltransferase Inhibitor and all trans retinoic acid reduce oral cavity carcinogenesis induced by the carcinogen 4 nitroquinoline 1 oxide
    Cancer Prevention Research, 2009
    Co-Authors: Xiaohan Tang, Martin L Albert, Theresa Scognamiglio, Lorraine J Gudas
    Abstract:

    The transcriptional silencing of some cell cycle Inhibitors and tumor suppressors, such as p16 and retinoic acid receptor β2, by DNA hypermethylation at CpG islands is commonly found in human oral squamous carcinoma cells. We examined the effects of the DNA Methyltransferase Inhibitor 5-Aza-2′-deoxycytidine (5-Aza; 0.25 mg/kg body weight), all-trans retinoic acid (RA; given at 100 μg/kg body weight and 1 mg/kg body weight), and the combination of 5-Aza and the low-dose RA on murine oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model. All the drug treatments were done for 15 weeks after a 10-week 4-NQO treatment. Mice in all drug treatment groups showed decreases in the average numbers of neoplastic tongue lesions. The combination of 5-Aza and RA effectively attenuated tongue lesion severity. Although all drug treatments limited the increase in the percentage of proliferating cell nuclear antigen–positive cells and the decrease in the percentage of p16-positive cells caused by the 4-NQO treatment in mouse tongue epithelial regions without visible lesions and in the neoplastic tongue lesions, the combination of 5-Aza and RA was the most effective. Collectively, our results show that the combination of a DNA demethylating drug and RA has potential as a strategy to reduce oral cavity cancer in this 4-NQO model.

  • a DNA Methyltransferase Inhibitor and all trans retinoic acid reduce oral cavity carcinogenesis induced by the carcinogen 4 nitroquinoline 1 oxide
    Cancer Prevention Research, 2009
    Co-Authors: Xiaohan Tang, Martin L Albert, Theresa Scognamiglio, Lorraine J Gudas
    Abstract:

    The transcriptional silencing of some cell cycle Inhibitors and tumor suppressors, such as p16 and retinoic acid receptor beta(2), by DNA hypermethylation at CpG islands is commonly found in human oral squamous carcinoma cells. We examined the effects of the DNA Methyltransferase Inhibitor 5-Aza-2'-deoxycytidine (5-Aza; 0.25 mg/kg body weight), all-trans retinoic acid (RA; given at 100 microg/kg body weight and 1 mg/kg body weight), and the combination of 5-Aza and the low-dose RA on murine oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model. All the drug treatments were done for 15 weeks after a 10-week 4-NQO treatment. Mice in all drug treatment groups showed decreases in the average numbers of neoplastic tongue lesions. The combination of 5-Aza and RA effectively attenuated tongue lesion severity. Although all drug treatments limited the increase in the percentage of proliferating cell nuclear antigen-positive cells and the decrease in the percentage of p16-positive cells caused by the 4-NQO treatment in mouse tongue epithelial regions without visible lesions and in the neoplastic tongue lesions, the combination of 5-Aza and RA was the most effective. Collectively, our results show that the combination of a DNA demethylating drug and RA has potential as a strategy to reduce oral cavity cancer in this 4-NQO model.

Kosei Hirakawa - One of the best experts on this subject based on the ideXlab platform.

  • DNA Methyltransferase Inhibitor 5 aza cdr enhances the radiosensitivity of gastric cancer cells
    Cancer Science, 2009
    Co-Authors: Hong Qiu, Masakazu Yashiro, Osamu Shinto, Taro Matsuzaki, Kosei Hirakawa
    Abstract:

    The National Comprehensive Cancer Network guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because radiation is harmful to the surrounding organs, a radiation sensitizer might therefore be useful to decrease the side effects of patients with advanced gastric carcinoma. The aim of the current study was to clarify the effect of a DNA Methyltransferase Inhibitor, 5-aza-2′-deoxycytidine (CdR), on radiation sensitivity in gastric cancer cells. Five gastric cancer cell lines, OCUM-2M, OCUM-12, KATO-III, MKN-45, and MKN-74, were used. The effects of 5-aza-CdR with irradiation on the growth activity, cell-cycle distribution, apoptosis, and apoptosis-associated gene expression were examined. 5-aza-CdR sensitized three of five gastric cancer cell lines to radiation. A combination of irradiation and 5-aza-CdR significantly (P < 0.05) decreased the growth activity compared with irradiation alone in OCUM-2M, OCUM-12, and MKN-45 cells, but not in KATO-III and MKN-74 cells. The percentage of cells in G2–M phase and the apoptotic rate with irradiation in combination with 5-aza-CdR were increased in OCUM-2M, OCUM-12, and MKN-45 cells compared with irradiation alone, but not in KATO-III and MKN-74 cells. 5-aza-CdR increased the expression of p53, RASSF1, and death-associated protein kinases (DAPK) genes compared with the control or irradiation alone. These findings suggest that 5-aza-CdR might therefore be useful as a radiation sensitizer to treat some types of gastric carcinoma. The arrest at G2–M phase and increased apoptotic rate might be partly mediated by enhanced expression of the p53, RASSF1, or DAPK gene families by 5-aza-CdR. (Cancer Sci 2009; 100: 181–188)

  • DNA Methyltransferase Inhibitor 5 aza cdr enhances the radiosensitivity of gastric cancer cells
    Cancer Science, 2009
    Co-Authors: Hong Qiu, Masakazu Yashiro, Osamu Shinto, Taro Matsuzaki, Kosei Hirakawa
    Abstract:

    The National Comprehensive Cancer Network guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because radiation is harmful to the surrounding organs, a radiation sensitizer might therefore be useful to decrease the side effects of patients with advanced gastric carcinoma. The aim of the current study was to clarify the effect of a DNA Methyltransferase Inhibitor, 5-aza-2'-deoxycytidine (CdR), on radiation sensitivity in gastric cancer cells. Five gastric cancer cell lines, OCUM-2M, OCUM-12, KATO-III, MKN-45, and MKN-74, were used. The effects of 5-aza-CdR with irradiation on the growth activity, cell-cycle distribution, apoptosis, and apoptosis-associated gene expression were examined. 5-aza-CdR sensitized three of five gastric cancer cell lines to radiation. A combination of irradiation and 5-aza-CdR significantly (P<0.05) decreased the growth activity compared with irradiation alone in OCUM-2M, OCUM-12, and MKN-45 cells, but not in KATO-III and MKN-74 cells. The percentage of cells in G2-M phase and the apoptotic rate with irradiation in combination with 5-aza-CdR were increased in OCUM-2M, OCUM-12, and MKN-45 cells compared with irradiation alone, but not in KATO-III and MKN-74 cells. 5-aza-CdR increased the expression of p53, RASSF1, and death-associated protein kinases (DAPK) genes compared with the control or irradiation alone. These findings suggest that 5-aza-CdR might therefore be useful as a radiation sensitizer to treat some types of gastric carcinoma. The arrest at G2-M phase and increased apoptotic rate might be partly mediated by enhanced expression of the p53, RASSF1, or DAPK gene families by 5-aza-CdR.

  • synergic antiproliferative effect of DNA Methyltransferase Inhibitor in combination with anticancer drugs in gastric carcinoma
    Cancer Science, 2006
    Co-Authors: Xiaotian Zhang, Masakazu Yashiro, Masaichi Ohira, Jun Ren, Kosei Hirakawa
    Abstract:

    Epigenetic alterations of DNA methylation play an important role in the regulation of gene expression associated with chemosensitivity of gastric carcinomas. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of DNA Methyltransferase Inhibitor, 5-aza-CdR, on the chemosensitivity of five anticancer drugs was investigated. Human gastric cancer cell lines, OCUM-2M and MKN-74, and five anticancer drugs, 5-FU, PTX, OXA, SN38, and GEM, were used. In both gastric cancer cell lines, a synergistic antiproliferative effect by a combination of 5-aza-CdR at 5 microM was found in SN38 and GEM. 5-Aza-CdR at 5 microM increased apoptosis induced by SN38 and GEM in both cell lines. 5-Aza-CdR increases the expression of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes in both OCUM-2M and MKN-74 cells, but not that of hMLH1, p16, MGMT, E-cadherin, and p53 genes. These findings suggest that 5-aza-CdR is a promising chemotherapeutical agent for gastric carcinomas, in combination with the anticancer drugs SN38 and GEM, in apoptosis signaling. The upregulation of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes by 5-aza-CdR might be associated with the synergistic effect.

Edward M. Newman - One of the best experts on this subject based on the ideXlab platform.

  • a phase i pharmacokinetic and pharmacodynamic evaluation of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine administered with tetrahydrouridine
    Cancer Chemotherapy and Pharmacology, 2015
    Co-Authors: Edward M. Newman, Jan H. Beumer, Anthony B Elkhoueiry, Shivaani Kummar, Robert Morgan, Suzette M Blanchard, Christopher Ruel, Mary I Carroll, Jessie Hou, H J Lenz
    Abstract:

    Purpose Inhibitors of DNA (cytosine-5)-Methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2′-deoxycytidine (FdCyd), a DNMT Inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU).

  • abstract 1283 phase i and pharmacokinetic evaluation of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine a california cancer consortium study
    Cancer Research, 2011
    Co-Authors: Edward M. Newman, Jan H. Beumer, Timothy W. Synold, Anthony B Elkhoueiry, Robert J Morgan, Suzette Blanchard, Shivaani Kummar, Mary Carroll, H J Lenz, James H. Doroshow
    Abstract:

    Background: The California Cancer Consortium conducted the first-in-human clinical trial of the investigational new drug 5-fluoro-2′-deoxycytidine (FdC), a DNA Methyltransferase Inhibitor stable in aqueous solution, as a 3-hour infusion concurrent with 350 mg/m 2 of the cytidine deaminase Inhibitor tetrahydrouridine (THU), included to prolong the half-life of FdC in vivo. Methods: A 3+3 design was used; initial FdC dose doubling ended when two moderate toxicities or one severe toxicity were observed. Pharmacokinetics of FdC and THU were obtained. Results: On the initial schedule, daily (QD) × 5 every 21 days (d), FdC was escalated from 2.5 to 80 mg/m 2 /d without treatment-related grade 3 toxicity other than anemia and lymphopenia. At FdC doses ≥20 mg/m 2 /d, peak plasma FdC concentrations were above those that inhibit DNA methylation in vitro (Beumer, et al., Cancer Chemother Pharmacol 62:363-8, 2008). The schedule was amended to QD × 5 for 2 consecutive weeks every 28 d, and patients (pts) were enrolled at 40, 67, 100, 134, and 180 mg/m 2 /d. Overall, 51 pts were treated [28 M; 23 F; median (range): age 63 (30-85), KPS 80 (60-100)]; 44 pts were evaluable for toxicity (1 cycle). 1/6 pts at 134 mg/m 2 /d had dose-limiting toxicity (DLT) (grade 3 colitis) and 2/2 pts at 180 mg/m 2 /d had DLT (1-grade 3 fatigue + LFT; 1-grade 4 mucositis + ANC + platelets). Of the 31 pts on 28-d cycles, 8 had clinical progression prior to the first scheduled evaluation at 8 weeks and 5 did not complete 2 cycles for other reasons; 7 pts had progressive disease at 8 weeks; and 10 pts had stable disease for ≥8 weeks. In addition, 1 heavily-pretreated pt with breast cancer, treated at 67 mg/m 2 /d, had a partial response lasting 1 year. Conclusions: The Maximum Tolerated Dose was 134 mg/m 2 /d FdC + 350 mg/m 2 /d THU QD × 5 for 2 consecutive weeks every 28 d. An expansion cohort is being accrued to determine the pharmacokinetics of oral FdC and THU. Based on the nature of the toxicities and the observed response at 67 mg/m 2 /d, a multi-histology Phase II trial has been initiated at 100 mg/m 2 /d QD × 5 for 2 consecutive weeks every 28 d. Supported by U01 CA62505, P30 CA33572, N01-CM-52202, and P30CA47904. The authors acknowledge the invaluable contribution of Dr. M. J. Egorin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1283. doi:10.1158/1538-7445.AM2011-1283

  • concentrations of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine fdcyd and its cytotoxic metabolites in plasma of patients treated with fdcyd and tetrahydrouridine thu
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Jan H. Beumer, Robert A. Parise, Edward M. Newman, James H. Doroshow, Timothy W. Synold, Heinz-josef Lenz, Merrill J. Egorin
    Abstract:

    Although the DNA Methyltransferase Inhibitor 5-fluoro-2′-deoxycytidine (FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase Inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-fluoro-2′-deoxyuridine (FdUrd), 5-fluorouracil (FU), and 5-fluorouridine (FUrd). We assessed plasma concentrations of FdCyd and metabolites in patients receiving FdCyd and THU. We validated an LC-MS/MS assay, developed for a preclinical study, to quantitate FdCyd and metabolites in human plasma. Patients were treated with five daily, 3-h infusions of FdCyd at doses of 5–80 mg/m2 with 350 mg/m2 THU. Plasma was obtained during, and before the end of infusions on days 1 and 5. The lower limits of quantitation for FU, FdUrd, FUrd, FC and FdCyd were 1, 1.5, 10, 3, and 10 ng/ml, respectively. Plasma FdCyd increased with dose, from 19–96 ng/ml at 5 mg/m2 to 1,600–1,728 ng/ml at 80 mg/m2. FdUrd was undetectable in patients treated with FdCyd doses <20 mg/m2, and increased from 2.3 ng/ml at 20 mg/m2 to 3.5–5.7 ng/ml at 80 mg/m2. FU increased from 1.2–5.5 ng/ml at 5 mg/m2 to 6.0–12 ng/ml at 80 mg/m2. By co-administering FdCyd with THU, FdCyd plasma concentrations were achieved that are known to inhibit DNA methylation in vitro. The accompanying plasma FU and FdUrd concentrations are <10% those observed after therapeutic infusions of FU or FdUrd, while FdCyd levels are well above those required to inhibit methylation in vitro. Therefore, inhibition of DNA methylation with FdCyd and THU appears feasible.

  • concentrations of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycyticine fdcyd its metabolites 5 fluoro 2 deoxyuridine fdurd 5 fluorouracil fu 5 fluorouridine furd 5 fluorocytosine fc in plasma of patients treated with fdcyd
    Journal of Clinical Oncology, 2006
    Co-Authors: Jan H. Beumer, Robert A. Parise, Edward M. Newman, James H. Doroshow, Timothy W. Synold, Heinz-josef Lenz, Merrill J. Egorin
    Abstract:

    2023 Background: The DNA Methyltransferase Inhibitor, FdCyd, is in phase I clinical trials. It is combined with tetrahydrouridine (THU), a cytidine deaminase Inhibitor, to prevent rapid metabolism of FdCyd to the pharmacologically active metabolites FdUrd, FU, FUrd, & FC. We assessed the plasma levels of these active, yet undesired, metabolites in patients receiving FdCyd+THU. Methods: We developed a hydrophilic interaction chromatography LC-MS/MS assay capable of simultaneously quantitating FdCyd & metabolites. Patients were treated with 5 daily, 3-h infusions of FdCyd at doses of 5–80 mg/m2. Plasma was obtained before & at the end of infusions (EOI) on days 1 & 5. Results: The lower limits of quantitation for FU, FdUrd, FUrd, FC & FdCyd were 1, 1.5, 10, 3, & 10 ng/ml, respectively, & the assay for each analyte was linear over a 300–1000 fold range of concentrations. Plasma FdCyd increased with dose from 19–96 ng/ml at 5 mg/m2 to 1600–1728 ng/ml at 80 mg/m2, as previously described. FdUrd was not detecta...

Jan H. Beumer - One of the best experts on this subject based on the ideXlab platform.

  • a phase i pharmacokinetic and pharmacodynamic evaluation of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine administered with tetrahydrouridine
    Cancer Chemotherapy and Pharmacology, 2015
    Co-Authors: Edward M. Newman, Jan H. Beumer, Anthony B Elkhoueiry, Shivaani Kummar, Robert Morgan, Suzette M Blanchard, Christopher Ruel, Mary I Carroll, Jessie Hou, H J Lenz
    Abstract:

    Purpose Inhibitors of DNA (cytosine-5)-Methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2′-deoxycytidine (FdCyd), a DNMT Inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU).

  • abstract 1283 phase i and pharmacokinetic evaluation of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine a california cancer consortium study
    Cancer Research, 2011
    Co-Authors: Edward M. Newman, Jan H. Beumer, Timothy W. Synold, Anthony B Elkhoueiry, Robert J Morgan, Suzette Blanchard, Shivaani Kummar, Mary Carroll, H J Lenz, James H. Doroshow
    Abstract:

    Background: The California Cancer Consortium conducted the first-in-human clinical trial of the investigational new drug 5-fluoro-2′-deoxycytidine (FdC), a DNA Methyltransferase Inhibitor stable in aqueous solution, as a 3-hour infusion concurrent with 350 mg/m 2 of the cytidine deaminase Inhibitor tetrahydrouridine (THU), included to prolong the half-life of FdC in vivo. Methods: A 3+3 design was used; initial FdC dose doubling ended when two moderate toxicities or one severe toxicity were observed. Pharmacokinetics of FdC and THU were obtained. Results: On the initial schedule, daily (QD) × 5 every 21 days (d), FdC was escalated from 2.5 to 80 mg/m 2 /d without treatment-related grade 3 toxicity other than anemia and lymphopenia. At FdC doses ≥20 mg/m 2 /d, peak plasma FdC concentrations were above those that inhibit DNA methylation in vitro (Beumer, et al., Cancer Chemother Pharmacol 62:363-8, 2008). The schedule was amended to QD × 5 for 2 consecutive weeks every 28 d, and patients (pts) were enrolled at 40, 67, 100, 134, and 180 mg/m 2 /d. Overall, 51 pts were treated [28 M; 23 F; median (range): age 63 (30-85), KPS 80 (60-100)]; 44 pts were evaluable for toxicity (1 cycle). 1/6 pts at 134 mg/m 2 /d had dose-limiting toxicity (DLT) (grade 3 colitis) and 2/2 pts at 180 mg/m 2 /d had DLT (1-grade 3 fatigue + LFT; 1-grade 4 mucositis + ANC + platelets). Of the 31 pts on 28-d cycles, 8 had clinical progression prior to the first scheduled evaluation at 8 weeks and 5 did not complete 2 cycles for other reasons; 7 pts had progressive disease at 8 weeks; and 10 pts had stable disease for ≥8 weeks. In addition, 1 heavily-pretreated pt with breast cancer, treated at 67 mg/m 2 /d, had a partial response lasting 1 year. Conclusions: The Maximum Tolerated Dose was 134 mg/m 2 /d FdC + 350 mg/m 2 /d THU QD × 5 for 2 consecutive weeks every 28 d. An expansion cohort is being accrued to determine the pharmacokinetics of oral FdC and THU. Based on the nature of the toxicities and the observed response at 67 mg/m 2 /d, a multi-histology Phase II trial has been initiated at 100 mg/m 2 /d QD × 5 for 2 consecutive weeks every 28 d. Supported by U01 CA62505, P30 CA33572, N01-CM-52202, and P30CA47904. The authors acknowledge the invaluable contribution of Dr. M. J. Egorin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1283. doi:10.1158/1538-7445.AM2011-1283

  • concentrations of the DNA Methyltransferase Inhibitor 5 fluoro 2 deoxycytidine fdcyd and its cytotoxic metabolites in plasma of patients treated with fdcyd and tetrahydrouridine thu
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Jan H. Beumer, Robert A. Parise, Edward M. Newman, James H. Doroshow, Timothy W. Synold, Heinz-josef Lenz, Merrill J. Egorin
    Abstract:

    Although the DNA Methyltransferase Inhibitor 5-fluoro-2′-deoxycytidine (FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase Inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-fluoro-2′-deoxyuridine (FdUrd), 5-fluorouracil (FU), and 5-fluorouridine (FUrd). We assessed plasma concentrations of FdCyd and metabolites in patients receiving FdCyd and THU. We validated an LC-MS/MS assay, developed for a preclinical study, to quantitate FdCyd and metabolites in human plasma. Patients were treated with five daily, 3-h infusions of FdCyd at doses of 5–80 mg/m2 with 350 mg/m2 THU. Plasma was obtained during, and before the end of infusions on days 1 and 5. The lower limits of quantitation for FU, FdUrd, FUrd, FC and FdCyd were 1, 1.5, 10, 3, and 10 ng/ml, respectively. Plasma FdCyd increased with dose, from 19–96 ng/ml at 5 mg/m2 to 1,600–1,728 ng/ml at 80 mg/m2. FdUrd was undetectable in patients treated with FdCyd doses <20 mg/m2, and increased from 2.3 ng/ml at 20 mg/m2 to 3.5–5.7 ng/ml at 80 mg/m2. FU increased from 1.2–5.5 ng/ml at 5 mg/m2 to 6.0–12 ng/ml at 80 mg/m2. By co-administering FdCyd with THU, FdCyd plasma concentrations were achieved that are known to inhibit DNA methylation in vitro. The accompanying plasma FU and FdUrd concentrations are <10% those observed after therapeutic infusions of FU or FdUrd, while FdCyd levels are well above those required to inhibit methylation in vitro. Therefore, inhibition of DNA methylation with FdCyd and THU appears feasible.

  • Pharmacokinetics, metabolism, and oral bioavailability of the DNA Methyltransferase Inhibitor 5-fluoro-2'-deoxycytidine in mice.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006
    Co-Authors: Jan H. Beumer, Erin Joseph, Joseph M. Covey, Julie L. Eiseman, Julianne L. Holleran, Robert A. Parise, Merrill J. Egorin
    Abstract:

    Purpose: In vivo , 5-fluoro-2′-deoxycytidine (FdCyd) is rapidly and sequentially converted to 5-fluoro-2′-deoxyuridine, 5-fluorouracil, and 5-fluorouridine. The i.v. combination of FdCyd and 3,4,5,6-tetrahydrouridine (THU), a cytidine deaminase (CD) Inhibitor that blocks the first metabolic step in FdCyd catabolism, is being investigated clinically for its ability to inhibit DNA Methyltransferase. However, the full effects of THU on FdCyd metabolism and pharmacokinetics are unknown. We aimed to characterize the pharmacokinetics, metabolism, and bioavailability of FdCyd with and without THU in mice. Experimental Design: We developed a sensitive high-performance liquid chromatography tandem mass spectrometry assay to quantitate FdCyd and metabolites in mouse plasma. Mice were dosed i.v. or p.o. with 25 mg/kg FdCyd with or without coadministration of 100 mg/kg THU p.o. or i.v. Results: The oral bioavailability of FdCyd alone was ∼4%. Coadministration with THU increased exposure to FdCyd and decreased exposure to its metabolites; i.v. and p.o. coadministration of THU increased exposure to p.o. FdCyd by 87- and 58-fold, respectively. FdCyd exposure after p.o. FdCyd with p.o. THU was as much as 54% that of i.v. FdCyd with i.v. THU. Conclusions: FdCyd is well absorbed but undergoes substantial first-pass catabolism by CD to potentially toxic metabolites that do not inhibit DNA Methyltransferase. THU is sufficiently bioavailable to reduce the first-pass effect of CD on FdCyd. Oral coadministration of THU and FdCyd is a promising approach that warrants clinical testing because it may allow maintaining effective FdCyd concentrations on a chronic basis, which would be an advantage over other DNA Methyltransferase Inhibitors that are currently approved or in development.

  • A mass balance and disposition study of the DNA Methyltransferase Inhibitor zebularine (NSC 309132) and three of its metabolites in mice.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006
    Co-Authors: Jan H. Beumer, Erin Joseph, Merrill J. Egorin, Joseph M. Covey, Robert S. Parker, David Z. D'argenio, Julie L. Eiseman
    Abstract:

    Purpose: To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA Methyltransferase Inhibitor proposed for clinical evaluation in the treatment of cancer. Experimental Design: Male, CD2F1 mice were dosed i.v. with 100 mg/kg 2-[14C]zebularine. At specified times between 5 and 1,440 minutes, mice were euthanized. Plasma, organs, carcass, urine, and feces were collected and assayed for total radioactivity. Plasma and urine were also analyzed for zebularine and its metabolites with a previously validated high-pressure liquid chromatography assay. A similar experiment was done with 2-[14C]uridine, the proposed primary metabolite of zebularine. Results: Maximum plasma concentrations were 462, 306, 33.6, 21.7, and 11.5 μmol/L for total radioactivity, zebularine, uridine, uracil (each at 5 minutes), and dihydrouracil (at 15 minutes), respectively. Total radioactivity, zebularine, uridine, uracil, and dihydrouracil were rapidly eliminated from plasma, and after 45 minutes, none of the individual compounds could be quantitated by high-pressure liquid chromatography. Plasma data were consistent with sequential conversion of zebularine to uridine, uracil, and dihydrouracil. 2-Pyrimidinone was not observed. Prolonged retention of radioactivity, at concentrations higher than in plasma, was observed in tissues. Recovery of given radioactivity in urine (30.3% of dose), feces (0.4% of dose), cage wash (7.9% of dose), and tissues and carcass (6.1% of dose) after 24 hours implied that up to 55% of radioactivity was expired as 14CO2. Comparison of zebularine and uridine pharmacokinetic data indicated that ∼40% of the zebularine dose was converted to uridine. Conclusions: Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.