The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Barry Gold - One of the best experts on this subject based on the ideXlab platform.
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DNA damage and cytotoxicity induced by minor groove binding methyl Sulfonate Esters.
Biochemistry, 2003Co-Authors: Sridhar Varadarajan, Dharini Shah, Prasad Dande, Gilberto Fronza, Fa Xian Chen, Samuel Settles, Barry GoldAbstract:Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl Sulfonate Ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mu...
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evidence in escherichia coli that n3 methyladenine lesions and cytotoxicity induced by a minor groove binding methyl Sulfonate Ester can be modulated in vivo by netropsin
Biochemistry, 2003Co-Authors: Dharini Shah, Barry GoldAbstract:The use of DNA equilibrium binding molecules to transfer alkyl groups to specific positions on DNA is an approach to generating cytotoxic DNA damage while avoiding the formation of promutagenic lesions that increase the risk for the development of secondary cancer. We have previously reported that in vitro a neutral DNA equilibrium binding agent based on an N-methylpyrrolecarboxamide dipeptide (lex) and modified with an O-methyl Sulfonate Ester functionality (Me-lex) selectively affords N3-methyladenine lesions in >90% yield relative to the formation of other adducts. While in vitro interactions between the lex dipeptide and DNA have been thoroughly studied, in vivo interactions are more difficult to elucidate. We report herein the relationship between the in vivo formation of N3-methyladenine and toxicity in wild-type and base excision repair defective mutant Escherichia coli. In addition, it is demonstrated that both N3-methyladenine adduction and cytotoxicity can be inhibited in vivo with netropsin, a potent competitive inhibitor of binding of lex to DNA. The results show a clear relationship between the levels of N3-methyladenine and toxicity in an alkA/tag glycosylase mutant that cannot remove the adduct from its genome. For methyl methaneSulfonate, which does not sequence selectively methylate DNA, a relationship between the formation of N3-methyladenine and toxicity is also observed. However, netropsin affects neither the level of N3-methyladenine nor the toxicity of methyl methaneSulfonate in E. coli.
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apoptotic and genotoxic effects of a methyl Sulfonate Ester that selectively generates n3 methyladenine and poly adp ribose polymerase inhibitors in normal peripheral blood lymphocytes
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Barry Gold, Grazia GrazianiAbstract:Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO2(CH2)2-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 µM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 µM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.
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poly adp ribose polymerase inhibitor increases apoptosis and reduces necrosis induced by a dna minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Barry Gold, Enzo Bonmassar, Grazia GrazianiAbstract:Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
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cytotoxic and clastogenic effects of a dna minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Lucio Tentori - One of the best experts on this subject based on the ideXlab platform.
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apoptotic and genotoxic effects of a methyl Sulfonate Ester that selectively generates n3 methyladenine and poly adp ribose polymerase inhibitors in normal peripheral blood lymphocytes
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Barry Gold, Grazia GrazianiAbstract:Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO2(CH2)2-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 µM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 µM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.
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poly adp ribose polymerase inhibitor increases apoptosis and reduces necrosis induced by a dna minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Barry Gold, Enzo Bonmassar, Grazia GrazianiAbstract:Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
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cytotoxic and clastogenic effects of a dna minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
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Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Mismatch repair deficiency contributes to tumor cell resistance to O^6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO_2(CH_2)_2- lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N^3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N^3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross- complementing 1 transcript (a component of base excision repair). These results indicate that N^3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.
P Vernole - One of the best experts on this subject based on the ideXlab platform.
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apoptotic and genotoxic effects of a methyl Sulfonate Ester that selectively generates n3 methyladenine and poly adp ribose polymerase inhibitors in normal peripheral blood lymphocytes
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Barry Gold, Grazia GrazianiAbstract:Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO2(CH2)2-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 µM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 µM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.
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poly adp ribose polymerase inhibitor increases apoptosis and reduces necrosis induced by a dna minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Barry Gold, Enzo Bonmassar, Grazia GrazianiAbstract:Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
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Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: L Tentori, P Vernole, Enzo Bonmassar, A Balduzzi, I Portarena, L Levati, B Gold, Grazia GrazianiAbstract:The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO_2(CH_2)_2-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c- myc , increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se , or by the methylated base in the presence of PARP inhibitor. Cell Death and Differentiation (2001) 8, 817–828
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cytotoxic and clastogenic effects of a dna minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
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Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Mismatch repair deficiency contributes to tumor cell resistance to O^6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO_2(CH_2)_2- lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N^3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N^3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross- complementing 1 transcript (a component of base excision repair). These results indicate that N^3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.
Grazia Graziani - One of the best experts on this subject based on the ideXlab platform.
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apoptotic and genotoxic effects of a methyl Sulfonate Ester that selectively generates n3 methyladenine and poly adp ribose polymerase inhibitors in normal peripheral blood lymphocytes
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Barry Gold, Grazia GrazianiAbstract:Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO2(CH2)2-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 µM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 µM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.
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poly adp ribose polymerase inhibitor increases apoptosis and reduces necrosis induced by a dna minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Barry Gold, Enzo Bonmassar, Grazia GrazianiAbstract:Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
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Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: L Tentori, P Vernole, Enzo Bonmassar, A Balduzzi, I Portarena, L Levati, B Gold, Grazia GrazianiAbstract:The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO_2(CH_2)_2-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c- myc , increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se , or by the methylated base in the presence of PARP inhibitor. Cell Death and Differentiation (2001) 8, 817–828
Ilaria Portarena - One of the best experts on this subject based on the ideXlab platform.
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apoptotic and genotoxic effects of a methyl Sulfonate Ester that selectively generates n3 methyladenine and poly adp ribose polymerase inhibitors in normal peripheral blood lymphocytes
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Barry Gold, Grazia GrazianiAbstract:Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO2(CH2)2-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Purpose: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). Methods: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. Results: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 µM NU and 4 mM AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 µM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Conclusions: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.
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poly adp ribose polymerase inhibitor increases apoptosis and reduces necrosis induced by a dna minor groove binding methyl Sulfonate Ester
Cell Death & Differentiation, 2001Co-Authors: Lucio Tentori, P Vernole, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Barry Gold, Enzo Bonmassar, Grazia GrazianiAbstract:Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl Sulfonate Ester
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cytotoxic and clastogenic effects of a dna minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
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Cytotoxic and clastogenic effects of a DNA minor groove binding methyl Sulfonate Ester in mismatch repair deficient leukemic cells
Leukemia, 2000Co-Authors: Lucio Tentori, P Vernole, Pedro Miguel Lacal, R Madaio, Ilaria Portarena, Lauretta Levati, Alessandra Balduzzi, Mario Turriziani, P Dande, Barry GoldAbstract:Mismatch repair deficiency contributes to tumor cell resistance to O^6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO_2(CH_2)_2- lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N^3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N^3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross- complementing 1 transcript (a component of base excision repair). These results indicate that N^3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.
