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1.
PLoS One ; 8(2): e56181, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23457523

RESUMO

Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1 to 2 years of age to a slower progressive course that causes significant morbidity and early mortality in children and adults. The aim of this study is to better understand the biochemical consequences of glycogen accumulation in the Pompe mouse. We evaluated glycogen metabolism in heart, triceps, quadriceps, and liver from wild type and several strains of GAA(-/-) mice. Unexpectedly, we observed that lysosomal glycogen storage correlated with a robust increase in factors that normally promote glycogen biosynthesis. The GAA(-/-) mouse strains were found to have elevated glycogen synthase (GS), glycogenin, hexokinase, and glucose-6-phosphate (G-6-P, the allosteric activator of GS). Treating GAA(-/-) mice with recombinant human GAA (rhGAA) led to a dramatic reduction in the levels of glycogen, GS, glycogenin, and G-6-P. Lysosomal glycogen storage also correlated with a dysregulation of phosphorylase, which normally breaks down cytoplasmic glycogen. Analysis of phosphorylase activity confirmed a previous report that, although phosphorylase protein levels are identical in muscle lysates from wild type and GAA(-/-) mice, phosphorylase activity is suppressed in the GAA(-/-) mice in the absence of AMP. This reduction in phosphorylase activity likely exacerbates lysosomal glycogen accumulation. If the dysregulation in glycogen metabolism observed in the mouse model of Pompe disease also occurs in Pompe patients, it may contribute to the observed broad spectrum of disease severity.


Assuntos
Doença de Depósito de Glicogênio Tipo II/metabolismo , Glicogênio/análise , Glicogênio/metabolismo , alfa-Glucosidases/genética , Animais , Modelos Animais de Doenças , Deleção de Genes , Glucosiltransferases/metabolismo , Glicogênio Fosforilase/metabolismo , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Glicogênio Sintase/metabolismo , Glicoproteínas/metabolismo , Hexoquinase/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , alfa-Glucosidases/uso terapêutico
2.
Mol Ther ; 18(11): 1983-94, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20736932

RESUMO

Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was ~1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.


Assuntos
Dependovirus/genética , Terapia Genética , Hepatócitos/imunologia , Doenças por Armazenamento dos Lisossomos/terapia , Transgenes/fisiologia , alfa-Galactosidase/sangue , Animais , Anticorpos Neutralizantes/imunologia , Western Blotting , Vetores Genéticos/administração & dosagem , Células HeLa , Hepatócitos/metabolismo , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/imunologia , Macaca fascicularis , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Plasmaferese , Biossíntese de Proteínas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , alfa-Galactosidase/genética
3.
Mol Ther ; 18(12): 2146-54, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20664526

RESUMO

The efficacy of recombinant enzyme therapy for genetic diseases is limited in some patients by the generation of a humoral immune response to the therapeutic protein. Inducing immune tolerance to the protein prior to treatment has the potential to increase therapeutic efficacy. Using an AAV8 vector encoding human acid α-glucosidase (hGAA), we have evaluated direct intrathymic injection for inducing tolerance. We have also compared the final tolerogenic states achieved by intrathymic and intravenous injection. Intrathymic vector delivery induced tolerance equivalent to that generated by intravenous delivery, but at a 25-fold lower dose, the thymic hGAA expression level was 10,000-fold lower than the liver expression necessary for systemic tolerance induction. Splenic regulatory T cells (Tregs) were apparent after delivery by both routes, but with different phenotypes. Intrathymic delivery resulted in Tregs with higher FoxP3, TGFß, and IL-10 mRNA levels. These differences may account for the differences noted in splenic T cells, where only intravenous delivery appeared to inhibit their activation. Our results imply that different mechanisms may be operating to generate immune tolerance by intrathymic and intravenous delivery of an AAV vector, and suggest that the intrathymic route may hold promise for decreasing the humoral immune response to therapeutic proteins in genetic disease indications.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Tolerância Imunológica/genética , Linfócitos T Reguladores/imunologia , Timo , alfa-Glucosidases/genética , Adenoviridae/genética , Humanos , Injeções Intravenosas , Ativação Linfocitária , Linfócitos T Reguladores/citologia , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/farmacologia
4.
Mol Genet Metab ; 100(4): 309-15, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20554235

RESUMO

Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1-2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle.


Assuntos
Doença de Depósito de Glicogênio Tipo II/terapia , Glicogênio/biossíntese , Fatores de Transcrição/antagonistas & inibidores , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Relação Dose-Resposta a Droga , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Glicogênio Sintase/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Proteínas , Proteínas Recombinantes/uso terapêutico , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Fatores de Transcrição/metabolismo , alfa-Glucosidases/metabolismo , alfa-Glucosidases/uso terapêutico
5.
Blood ; 112(13): 5161-70, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18820131

RESUMO

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.


Assuntos
Antineoplásicos/farmacologia , Carbanilidas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Proteínas Mutantes/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Estaurosporina/análogos & derivados
6.
Gerontol Geriatr Educ ; 28(3): 59-72, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18215988

RESUMO

Virginia Commonwealth University developed an enhanced medical student geriatric curriculum that includes required home visits and nursing home visits for second year students (180 per year), an annual Forum on Aging for all first and second year students, and small group exercises. We added 30 hours of basic science material to pre-clinical courses and increased clinical exposure to geriatricians in third and fourth years. Student satisfaction with individual experiences was high. Persistent effects of "high valence" required activities, where emotion played a role, was shown by post-pre survey techniques and focus groups. Fourth year AAMC exit questionnaire items in areas addressed by this curriculum improved markedly between 2002 and 2006, while an internal control changed much less.


Assuntos
Geriatria/educação , Idoso , Competência Clínica , Comportamento do Consumidor , Educação Médica/organização & administração , Instituição de Longa Permanência para Idosos/organização & administração , Visita Domiciliar , Humanos , Casas de Saúde/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Avaliação de Programas e Projetos de Saúde
7.
Blood ; 111(7): 3723-34, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18184863

RESUMO

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhibitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL-, and induce apoptosis of BCR-ABL-expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL- and mutant FLT3-expressing cells both in vitro and in vivo.


Assuntos
Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/biossíntese , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Inibidores Enzimáticos/agonistas , Inibidores Enzimáticos/uso terapêutico , Proteínas de Fusão bcr-abl , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Masculino , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/biossíntese , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR , Tirosina Quinase 3 Semelhante a fms/genética
8.
Mol Cancer Ther ; 6(7): 1951-61, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17620426

RESUMO

Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Proteínas de Transporte , Leucemia/tratamento farmacológico , Proteínas Mitocondriais , Proteínas Mutantes/metabolismo , Oligopeptídeos/farmacologia , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Proteínas Mutantes/genética , Oligopeptídeos/química , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Células Estromais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/genética
9.
Blood ; 109(5): 2112-20, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17068153

RESUMO

Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Benzamidas , Linhagem Celular , Quimioterapia Combinada , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia/genética , Leucemia/patologia , Masculino , Camundongos , Modelos Biológicos , Fosfotirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Gastroenterology ; 131(6): 1734-42, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17087936

RESUMO

BACKGROUND & AIMS: Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib. METHODS: The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo. RESULTS: PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA. CONCLUSIONS: Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Piperazinas/farmacologia , Mutação Puntual/genética , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estaurosporina/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib , Masculino , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Estaurosporina/farmacologia , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Cell ; 7(2): 129-41, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15710326

RESUMO

The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Benzamidas , Células da Medula Óssea/citologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Hematopoéticas/citologia , Mesilato de Imatinib , Concentração Inibidora 50 , Camundongos , Modelos Biológicos , Modelos Químicos , Mutação , Mycoplasma/metabolismo , Fosforilação , Piperazinas/farmacologia , Retroviridae/genética , Fatores de Tempo
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