The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
Aru Narendran - One of the best experts on this subject based on the ideXlab platform.
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systematic in vitro evaluation of the nci nih developmental therapeutics program approved oncology drug set for the identification of a candidate drug repertoire for mll rearranged leukemia
OncoTargets and Therapy, 2011Co-Authors: Kimberley A Hoeksema, Aarthi Jayanthan, Todd Cooper, Lia Gore, Tanya M Trippett, Jessica Boklan, Robert J Arceci, Aru NarendranAbstract:Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program) were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have measurable cytotoxicity against leukemia cells, and among these, 12 were effective against all five MLL-rearranged cell lines (IC50 [half maximal inhibitory concentration] < 1 μM). These 12 agents include cladribine, dactinomycin, daunorubicin, docetaxel, etoposide, gemcitabine, mitomycin C, mitoxantrone, teniposide, topotecan, Triethylenemelamine, and vinblastine. We show that the Approved Oncology Drug Set II contains a number of agents with potent antileukemic activity in the tested cell lines. As approved drugs, these agents have been used in clinical settings for many years for other malignancies, thus their toxicity profile, pharmacokinetics, and other properties are readily available. Further evaluation of their use in future clinical trials for pediatric leukemia with MLL abnormalities should be considered.
H V Malling - One of the best experts on this subject based on the ideXlab platform.
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comparison of the mutagenicity and mutagen specificity of ethylenimine with Triethylenemelamine in the ad 3 region of heterokaryon 12 of neurospora crassa
Mutation Research, 1995Co-Authors: F. J. De Serres, H V Malling, Tongman OngAbstract:Abstract Studies have been performed to compare the mutagenicity and mutagenic specificity of the trifunctional alkylating agent, Triethylenemelamine (TEM), and a closely related monofunctional agent, ethylenimine (EI), in the adenine-3 ( ad-3 ) region of a 2-component heterokaryon (H-12) of Neurospora crassa . The primary objective of our studies was to characterize the genetic damage produced by each agent with regard to (1) mutagenic potency, and (2) the spectrum of specific-locus mutations induced in a lower eukaryotic organism. As in higher eukaryotes, specific-locus mutations in the ad-3 region of H-12 result from gene/point mutations, multilocus deletion mutations, and multiple-locus mutations. Specific-locus mutations resulting from gene/point mutation and multilocus deletion mutation can be detected in higher eukaryotes, but multiple-locus mutations can be detected only with difficultly or not at all. Our experiments with the ad-3 forward-mutation assay have demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10 6 survivors) and EI is a moderate mutagen (maximum forward-mutation frequency between 10 and 100 ad-3 mutations per 10 6 survivors) for the induction of specific-locus mutations in the ad-3 region. Classical genetic tests were used to identify the different genotypic classes and subclasses among the EI- and TEM-induced ad-3 mutations from each experiment. The overall data base demonstrates that both EI- and TEM-induced ad-3 mutations result predominantly from gene/point mutations at the ad-3A and ad-3B loci (97.3% and 95.5%, respectively), and infrequently from multilocus deletion mutations (2.7% and 4.5%, respectively). Heterokaryon tests for allelic complementation on TEM- and EI-induced ad-3B mutations, however, have revealed a difference between the percentages showing allelic complementation (63.1% and 40.9%, respectively). Based on the specific revertibility of complementing and noncomplementing ad-3B mutations induced by other agents, this difference in the percentages of ad-3B mutations showing allelic complementation results from a difference between the spectrum of genetic alterations at the molecular level. In addition, comparison of the ratio of TEM-induced ad-3A and ad-3B mutations with those induced by EI has revealed a difference between the ad-3B ad-3A ratios. Additional comparisons are made of the mutagenic effects of TEM and EI with those of other chemical mutagens and carcinogens in the ad-3 specific-locus assay in Neurospora.
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Triethylenemelamine: induction of specific-locus mutations in the ad-3 region of heterokaryon 12 of Neurospora crassa.
Mutation research, 1995Co-Authors: F. J. De Serres, H V MallingAbstract:The mutagenicity of the trifunctional alkylating (or cross-linking) agent TEM (Triethylenemelamine or 2,4,6-tris(1-aziridinyl)-1,3,5-triazine) in the adenine-3 (ad-3) region was studied with a two-component heterokaryon (H-12) of Neurospora crassa. The objective was to characterize the genetic damage produced by this chemical to determine the spectrum of specific-locus mutations induced in a lower eukaryotic organism and to compare this spectrum with that induced in the mouse. Specific-locus mutations in the ad-3 region of strain H-12 result from gene/point mutations, multiple-locus mutations, and multilocus deletion mutations at the closely linked ad-3A and ad-3B loci. These loci control two sequential biochemical reactions in the purine biosynthetic pathway. A 0.1 M solution of TEM was used to treat conidial suspensions of H-12 for 20, 40, 80, 120, or 170 min to obtain dose-response curves for (1) inactivation of conidia, and (2) the induction of specific-locus mutations in the ad-3 region. These experiments demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10(6) survivors) for the induction of specific-locus mutations in the ad-3 region. Both biochemical and classical genetic tests were used to characterize the TEM-induced ad-3 mutations from each of the five treatment groups to distinguish between the different genotypic classes and subclasses. The overall data base from these genetic studies demonstrates that TEM-induced ad-3 mutations result predominantly (95.5% [769/805]) from gene/point mutations at the ad-3A and ad-3B loci, and from a low percentage (4.5% [36/805) of multilocus deletion mutations. In addition, TEM induces an unusually high frequency of multiple-locus mutations with sites of recessive lethal damage closely linked with the ad-3 region. Comparison of the dose-response curves for the major classes and subclasses of TEM-induced ad-3 mutations demonstrates (1) that gene/point mutations and multilocus deletion mutations increase as the 1.4 power of TEM treatment time, and (2) that the two classes of TEM-induced multiple-locus ad-3 mutations consisting of gene/point mutations with separate sites of recessive lethal damage increase at about the 1.96 power of TEM treatment time. When the data from the present specific-locus studies are compared with those in the mouse, we find, insofar as such comparisons are possible, that a similar spectrum of specific-locus mutations has been induced by TEM in each assay system.
Kimberley A Hoeksema - One of the best experts on this subject based on the ideXlab platform.
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systematic in vitro evaluation of the nci nih developmental therapeutics program approved oncology drug set for the identification of a candidate drug repertoire for mll rearranged leukemia
OncoTargets and Therapy, 2011Co-Authors: Kimberley A Hoeksema, Aarthi Jayanthan, Todd Cooper, Lia Gore, Tanya M Trippett, Jessica Boklan, Robert J Arceci, Aru NarendranAbstract:Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program) were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have measurable cytotoxicity against leukemia cells, and among these, 12 were effective against all five MLL-rearranged cell lines (IC50 [half maximal inhibitory concentration] < 1 μM). These 12 agents include cladribine, dactinomycin, daunorubicin, docetaxel, etoposide, gemcitabine, mitomycin C, mitoxantrone, teniposide, topotecan, Triethylenemelamine, and vinblastine. We show that the Approved Oncology Drug Set II contains a number of agents with potent antileukemic activity in the tested cell lines. As approved drugs, these agents have been used in clinical settings for many years for other malignancies, thus their toxicity profile, pharmacokinetics, and other properties are readily available. Further evaluation of their use in future clinical trials for pediatric leukemia with MLL abnormalities should be considered.
F. J. De Serres - One of the best experts on this subject based on the ideXlab platform.
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comparison of the mutagenicity and mutagen specificity of ethylenimine with Triethylenemelamine in the ad 3 region of heterokaryon 12 of neurospora crassa
Mutation Research, 1995Co-Authors: F. J. De Serres, H V Malling, Tongman OngAbstract:Abstract Studies have been performed to compare the mutagenicity and mutagenic specificity of the trifunctional alkylating agent, Triethylenemelamine (TEM), and a closely related monofunctional agent, ethylenimine (EI), in the adenine-3 ( ad-3 ) region of a 2-component heterokaryon (H-12) of Neurospora crassa . The primary objective of our studies was to characterize the genetic damage produced by each agent with regard to (1) mutagenic potency, and (2) the spectrum of specific-locus mutations induced in a lower eukaryotic organism. As in higher eukaryotes, specific-locus mutations in the ad-3 region of H-12 result from gene/point mutations, multilocus deletion mutations, and multiple-locus mutations. Specific-locus mutations resulting from gene/point mutation and multilocus deletion mutation can be detected in higher eukaryotes, but multiple-locus mutations can be detected only with difficultly or not at all. Our experiments with the ad-3 forward-mutation assay have demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10 6 survivors) and EI is a moderate mutagen (maximum forward-mutation frequency between 10 and 100 ad-3 mutations per 10 6 survivors) for the induction of specific-locus mutations in the ad-3 region. Classical genetic tests were used to identify the different genotypic classes and subclasses among the EI- and TEM-induced ad-3 mutations from each experiment. The overall data base demonstrates that both EI- and TEM-induced ad-3 mutations result predominantly from gene/point mutations at the ad-3A and ad-3B loci (97.3% and 95.5%, respectively), and infrequently from multilocus deletion mutations (2.7% and 4.5%, respectively). Heterokaryon tests for allelic complementation on TEM- and EI-induced ad-3B mutations, however, have revealed a difference between the percentages showing allelic complementation (63.1% and 40.9%, respectively). Based on the specific revertibility of complementing and noncomplementing ad-3B mutations induced by other agents, this difference in the percentages of ad-3B mutations showing allelic complementation results from a difference between the spectrum of genetic alterations at the molecular level. In addition, comparison of the ratio of TEM-induced ad-3A and ad-3B mutations with those induced by EI has revealed a difference between the ad-3B ad-3A ratios. Additional comparisons are made of the mutagenic effects of TEM and EI with those of other chemical mutagens and carcinogens in the ad-3 specific-locus assay in Neurospora.
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Triethylenemelamine: induction of specific-locus mutations in the ad-3 region of heterokaryon 12 of Neurospora crassa.
Mutation research, 1995Co-Authors: F. J. De Serres, H V MallingAbstract:The mutagenicity of the trifunctional alkylating (or cross-linking) agent TEM (Triethylenemelamine or 2,4,6-tris(1-aziridinyl)-1,3,5-triazine) in the adenine-3 (ad-3) region was studied with a two-component heterokaryon (H-12) of Neurospora crassa. The objective was to characterize the genetic damage produced by this chemical to determine the spectrum of specific-locus mutations induced in a lower eukaryotic organism and to compare this spectrum with that induced in the mouse. Specific-locus mutations in the ad-3 region of strain H-12 result from gene/point mutations, multiple-locus mutations, and multilocus deletion mutations at the closely linked ad-3A and ad-3B loci. These loci control two sequential biochemical reactions in the purine biosynthetic pathway. A 0.1 M solution of TEM was used to treat conidial suspensions of H-12 for 20, 40, 80, 120, or 170 min to obtain dose-response curves for (1) inactivation of conidia, and (2) the induction of specific-locus mutations in the ad-3 region. These experiments demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10(6) survivors) for the induction of specific-locus mutations in the ad-3 region. Both biochemical and classical genetic tests were used to characterize the TEM-induced ad-3 mutations from each of the five treatment groups to distinguish between the different genotypic classes and subclasses. The overall data base from these genetic studies demonstrates that TEM-induced ad-3 mutations result predominantly (95.5% [769/805]) from gene/point mutations at the ad-3A and ad-3B loci, and from a low percentage (4.5% [36/805) of multilocus deletion mutations. In addition, TEM induces an unusually high frequency of multiple-locus mutations with sites of recessive lethal damage closely linked with the ad-3 region. Comparison of the dose-response curves for the major classes and subclasses of TEM-induced ad-3 mutations demonstrates (1) that gene/point mutations and multilocus deletion mutations increase as the 1.4 power of TEM treatment time, and (2) that the two classes of TEM-induced multiple-locus ad-3 mutations consisting of gene/point mutations with separate sites of recessive lethal damage increase at about the 1.96 power of TEM treatment time. When the data from the present specific-locus studies are compared with those in the mouse, we find, insofar as such comparisons are possible, that a similar spectrum of specific-locus mutations has been induced by TEM in each assay system.
Tongman Ong - One of the best experts on this subject based on the ideXlab platform.
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comparison of the mutagenicity and mutagen specificity of ethylenimine with Triethylenemelamine in the ad 3 region of heterokaryon 12 of neurospora crassa
Mutation Research, 1995Co-Authors: F. J. De Serres, H V Malling, Tongman OngAbstract:Abstract Studies have been performed to compare the mutagenicity and mutagenic specificity of the trifunctional alkylating agent, Triethylenemelamine (TEM), and a closely related monofunctional agent, ethylenimine (EI), in the adenine-3 ( ad-3 ) region of a 2-component heterokaryon (H-12) of Neurospora crassa . The primary objective of our studies was to characterize the genetic damage produced by each agent with regard to (1) mutagenic potency, and (2) the spectrum of specific-locus mutations induced in a lower eukaryotic organism. As in higher eukaryotes, specific-locus mutations in the ad-3 region of H-12 result from gene/point mutations, multilocus deletion mutations, and multiple-locus mutations. Specific-locus mutations resulting from gene/point mutation and multilocus deletion mutation can be detected in higher eukaryotes, but multiple-locus mutations can be detected only with difficultly or not at all. Our experiments with the ad-3 forward-mutation assay have demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10 6 survivors) and EI is a moderate mutagen (maximum forward-mutation frequency between 10 and 100 ad-3 mutations per 10 6 survivors) for the induction of specific-locus mutations in the ad-3 region. Classical genetic tests were used to identify the different genotypic classes and subclasses among the EI- and TEM-induced ad-3 mutations from each experiment. The overall data base demonstrates that both EI- and TEM-induced ad-3 mutations result predominantly from gene/point mutations at the ad-3A and ad-3B loci (97.3% and 95.5%, respectively), and infrequently from multilocus deletion mutations (2.7% and 4.5%, respectively). Heterokaryon tests for allelic complementation on TEM- and EI-induced ad-3B mutations, however, have revealed a difference between the percentages showing allelic complementation (63.1% and 40.9%, respectively). Based on the specific revertibility of complementing and noncomplementing ad-3B mutations induced by other agents, this difference in the percentages of ad-3B mutations showing allelic complementation results from a difference between the spectrum of genetic alterations at the molecular level. In addition, comparison of the ratio of TEM-induced ad-3A and ad-3B mutations with those induced by EI has revealed a difference between the ad-3B ad-3A ratios. Additional comparisons are made of the mutagenic effects of TEM and EI with those of other chemical mutagens and carcinogens in the ad-3 specific-locus assay in Neurospora.
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transplacental genotoxicity of Triethylenemelamine benzene and vinblastine in mice
Teratogenesis Carcinogenesis and Mutagenesis, 1992Co-Authors: S G Xing, X Shi, J K Chen, W Wallace, Wenzong Whong, Tongman OngAbstract:Transplacental cytogenetic effects of Triethylenemelamine (TEM), benzene, and vinblastine on maternal mice and their fetuses have been investigated using micronucleus and sister chromatid exchange (SCE) as genetic endpoints. CD-1 mice were treated on day 14 and 15 of gestation with TEM (0.125, 0.25, and 0.5 mg/kg), benzene (439,878, and 1,318 mg/kg), and vinblastine (0.5, 1, and 2 mg/kg) by intraperitoneal injection at 24 hr intervals, and sacrificed 40 hr after the first injection. Erythrocytic precursor cells in maternal bone marrow and fetal livers (2-4) from each pregnant mouse were used for the micronucleus and/or the SCE analyses. Significant dose-related increases in both micronuclei and SCE were found in maternal bone marrow and fetal liver following TEM treatment. Benzene at the highest dose (1,318 mg/kg) also caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells. The embryonic genotoxic effect of TEM was much higher than that of benzene for both genetic endpoints, and the frequency of micronuclei induced by benzene was higher in fetal liver than in maternal bone marrow cells. Vinblastine, a spindle poison, induced micronuclei but not SCE. Micronuclei induction by vinblastine was 7 fold greater in maternal bone marrow than in fetal liver cells. All three chemicals were cytotoxic in maternal bone marrow cells, but not in fetal liver cells except for TEM, which showed a weak cytotoxicity in fetal liver cells in the micronucleus assay. These results indicate that TEM, benzene, and vinblastine are transplacental genotoxicants in mice.
