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[PMID]:27455673
[Au] Autor:Song S; Hao Y; Yang X; Patra P; Chen J
[Ti] Título:Using Gold Nanoparticles as Delivery Vehicles for Targeted Delivery of Chemotherapy Drug Fludarabine Phosphate to Treat Hematological Cancers.
[So] Source:J Nanosci Nanotechnol;16(3):2582-6, 2016 Mar.
[Is] ISSN:1533-4880
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nanotechnology is an emerging paradigm for creating functional nanoscale materials for various biomedical applications. In this study, a new nanotechnology-based drug delivery method was developed using gold nanoparticles (GNPs) as a delivery vehicle to reduce adverse drug side effects. Fludarabine Phosphate is a commercial chemotherapy drug used in cancer treatment, and has ability to kill various cancer cells. KG-1 cell, a type of acute cancer leukemia cell, was selected as a proof-of-concept target in this study. Due to the small size of GNPs, they can help Fludarabine Phosphate enter cancer cells more efficiently and better interfere with DNA synthesis in the cancer cells. To enhance targeting ability, folic acid molecules were also covalently linked to GNPs, resulting in GNP-Fludarabine-folic acid (GNP-F/f). Compared to treatments with GNP-F or drugs on its own (Fludarabine Phosphate), the GNP-F/f achieves much improved cell-killing effects. The UV-Vis spectra results also revealed that the drugs had successfully bonded covalently to the GNPs. The higher cell-killing efficiency of GNP-F/f compared with GNP-Fludarabine (GNP-F) or drugs on their own further validates the effectiveness of both the vectors (GNPs) and folic acid in enhancing the drug delivery to the cancer cells. The MTT viability tests showed that the GNPs had no cytotoxicity.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Ouro/química
Neoplasias Hematológicas/tratamento farmacológico
Nanopartículas Metálicas
Fosfato de Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Microscopia Eletrônica de Transmissão
Espectrofotometria Ultravioleta
Fosfato de Vidarabina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); 7440-57-5 (Gold)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160727
[St] Status:MEDLINE


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[PMID]:26655063
[Au] Autor:Lehouritis P; Stanton M; McCarthy FO; Jeavons M; Tangney M
[Ad] Endereço:Cork Cancer Research Centre, University College Cork, Cork, Ireland.
[Ti] Título:Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.
[So] Source:J Control Release;222:9-17, 2016 Jan 28.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Proteínas de Bactérias/metabolismo
Neoplasias/tratamento farmacológico
Probióticos
Pró-Fármacos/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antraquinonas/administração & dosagem
Antraquinonas/uso terapêutico
Antineoplásicos/uso terapêutico
Aziridinas/administração & dosagem
Aziridinas/uso terapêutico
Bifidobacterium/enzimologia
Linhagem Celular Tumoral
Sistemas de Liberação de Medicamentos
Enzimas
Escherichia coli/enzimologia
Feminino
Lactobacillus/enzimologia
Lactococcus/enzimologia
Camundongos Endogâmicos BALB C
Neoplasias/patologia
Pró-Fármacos/uso terapêutico
Carga Tumoral/efeitos dos fármacos
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/análogos & derivados
Fosfato de Vidarabina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthraquinones); 0 (Antineoplastic Agents); 0 (Aziridines); 0 (Bacterial Proteins); 0 (Enzymes); 0 (Prodrugs); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); 658876KMFP (AQ4N); 7865D5D01M (tretazicar)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE


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[PMID]:25374408
[Au] Autor:McCune JS; Vicini P; Salinger DH; O'Donnell PV; Sandmaier BM; Anasetti C; Mager DE
[Ad] Endereço:Department of Pharmacy, School of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195, USA, jmccune@u.washington.edu.
[Ti] Título:Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration.
[So] Source:Cancer Chemother Pharmacol;75(1):67-75, 2015 Jan.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Quantitative relationships between 9-ß-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m², Protocol 1519) or with fludarabine (total dose 250 mg/m²) with rabbit antithymocyte globulin (rATG, Protocol 2041). METHODS: Individual pharmacokinetic parameters were fixed to post hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the 3 weeks prior to graft infusion. A semi-physiological cell-kill model with three lymphocyte transit compartments was applied and aptly characterized the time course of suppression of circulating ALC by fludarabine administration. Drug- and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check. RESULTS: The final model successfully characterized the time course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9-211 %). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC. CONCLUSIONS: This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/farmacocinética
Imunossupressão/efeitos adversos
Imunossupressores/farmacocinética
Linfopoese/efeitos dos fármacos
Modelos Biológicos
Condicionamento Pré-Transplante/efeitos adversos
Fosfato de Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Antimetabólitos Antineoplásicos/efeitos adversos
Antimetabólitos Antineoplásicos/sangue
Antimetabólitos Antineoplásicos/uso terapêutico
Criança
Estudos de Coortes
Meia-Vida
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Seres Humanos
Imunossupressores/efeitos adversos
Imunossupressores/sangue
Imunossupressores/uso terapêutico
Leucemia Mieloide/sangue
Leucemia Mieloide/imunologia
Leucemia Mieloide/metabolismo
Leucemia Mieloide/terapia
Contagem de Linfócitos
Meia-Idade
Transtornos Mieloproliferativos/sangue
Transtornos Mieloproliferativos/imunologia
Transtornos Mieloproliferativos/metabolismo
Transtornos Mieloproliferativos/terapia
Reprodutibilidade dos Testes
Estudos Retrospectivos
Fosfato de Vidarabina/efeitos adversos
Fosfato de Vidarabina/sangue
Fosfato de Vidarabina/farmacocinética
Fosfato de Vidarabina/uso terapêutico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Immunosuppressive Agents); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141107
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-014-2618-2


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[PMID]:25122069
[Au] Autor:Pessetto ZY; Ma Y; Hirst JJ; von Mehren M; Weir SJ; Godwin AK
[Ad] Endereço:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
[Ti] Título:Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor.
[So] Source:Mol Cancer Ther;13(10):2276-87, 2014 Oct.
[Is] ISSN:1538-8514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate-resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate-resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate-refractory tumors.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Benzamidas/farmacologia
Tumores do Estroma Gastrointestinal/tratamento farmacológico
Piperazinas/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Benzamidas/administração & dosagem
Proliferação Celular/efeitos dos fármacos
Reposicionamento de Medicamentos
Sinergismo Farmacológico
Feminino
Ensaios de Triagem em Larga Escala
Seres Humanos
Mesilato de Imatinib
Camundongos
Camundongos Nus
Piperazinas/administração & dosagem
Pirimidinas/administração & dosagem
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/análogos & derivados
Fosfato de Vidarabina/farmacologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzamides); 0 (Piperazines); 0 (Pyrimidines); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); 8A1O1M485B (Imatinib Mesylate)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140815
[St] Status:MEDLINE
[do] DOI:10.1158/1535-7163.MCT-14-0043


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[PMID]:23907443
[Au] Autor:Bemer MJ; Sorror M; Sandmaier BM; O'Donnell PV; McCune JS
[Ad] Endereço:Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
[Ti] Título:A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients.
[So] Source:Cancer Chemother Pharmacol;72(3):607-18, 2013 Sep.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Eleven patients diagnosed with various hematologic malignancies receiving an HLA-haploidentical hematopoietic cell transplant (HCT) participated in an ancillary biomarker trial. The goal of the trial was to evaluate potential pharmacologic biomarkers pertinent to the conditioning regimen [fludarabine monophosphate (fludarabine) and cyclophosphamide (CY)] or postgrafting immunosuppression [CY and mycophenolate mofetil (MMF)] in these patients. METHODS: We characterized the interpatient variability of nine pharmacologic biomarkers. The biomarkers evaluated were relevant to fludarabine (i.e., area under the curve (AUC) of 2-fluoro-ara-A or F-ara-A), CY (i.e., AUCs of CY and four of its metabolites), and MMF (i.e., total mycophenolic acid (MPA) AUC, unbound MPA AUC, and inosine monophosphate dehydrogenase (IMPDH) activity). RESULTS: Interpatient variability in the pharmacologic biomarkers was high. Among those related to HCT conditioning, the interpatient variability ranged from 1.5-fold (CY AUC) to 4.0-fold (AUC of carboxyethylphosphoramide mustard, a metabolite of CY). Among biomarkers evaluated as part of postgrafting immunosuppression, the interpatient variability ranged from 1.7-fold (CY AUC) to 4.9-fold (IMPDH area under the effect curve). There was a moderate correlation (R (2) = 0.441) of within-patient 4-hydroxycyclophosphamide formation clearance. CONCLUSIONS: Considerable interpatient variability exists in the pharmacokinetic and drug-specific biomarkers potentially relevant to clinical outcomes in HLA-haploidentical HCT recipients. Pharmacodynamic studies are warranted to optimize the conditioning regimen and postgrafting immunosuppression administered to HLA-haploidentical HCT recipients.
[Mh] Termos MeSH primário: Antígenos HLA/imunologia
Neoplasias Hematológicas/terapia
Transplante de Células-Tronco Hematopoéticas/métodos
Imunossupressores/farmacologia
Condicionamento Pré-Transplante/métodos
[Mh] Termos MeSH secundário: Adulto
Idoso
Área Sob a Curva
Biomarcadores Farmacológicos/metabolismo
Ciclofosfamida/administração & dosagem
Ciclofosfamida/farmacocinética
Ciclofosfamida/farmacologia
Feminino
Neoplasias Hematológicas/patologia
Seres Humanos
Imunossupressores/administração & dosagem
Imunossupressores/farmacocinética
Masculino
Meia-Idade
Ácido Micofenólico/administração & dosagem
Ácido Micofenólico/análogos & derivados
Ácido Micofenólico/farmacocinética
Ácido Micofenólico/farmacologia
Projetos Piloto
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/análogos & derivados
Fosfato de Vidarabina/farmacocinética
Fosfato de Vidarabina/farmacologia
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Pharmacological); 0 (HLA Antigens); 0 (Immunosuppressive Agents); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); 8N3DW7272P (Cyclophosphamide); HU9DX48N0T (Mycophenolic Acid)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130803
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-013-2232-8


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[PMID]:22760227
[Au] Autor:Sorscher EJ; Hong JS; Allan PW; Waud WR; Parker WB
[Ad] Endereço:Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sorscher@uab.edu
[Ti] Título:In vivo antitumor activity of intratumoral fludarabine phosphate in refractory tumors expressing E. coli purine nucleoside phosphorylase.
[So] Source:Cancer Chemother Pharmacol;70(2):321-9, 2012 Aug.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Systemically administered fludarabine phosphate (F-araAMP) slows growth of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (PNP). However, this treatment has been limited by the amount of F-araAMP that can be administered in vivo. The current study was designed to (1) determine whether efficacy of this overall strategy could be improved by intratumoral administration of F-araAMP, (2) test enhancement of the approach with external beam radiation, and (3) optimize recombinant adenovirus as a means to augment PNP delivery and bystander killing in vivo. METHODS: The effects of systemic or intratumoral F-araAMP in mice were investigated with human tumor xenografts (300 mg), in which 10 % of the cells expressed E. coli PNP from a lentiviral promoter. Tumors injected with an adenoviral vector expressing E. coli PNP (Ad/PNP; 2 × 10(11) viral particles, 2 times per day × 3 days) and the impact of radiotherapy on tumors treated by this approach were also studied. Radiolabeled F-araAMP was used to monitor prodrug activation in vivo. RESULTS: Intratumoral administration of F-araAMP in human tumor xenografts expressing E. coli PNP resulted in complete regressions and/or prolonged tumor inhibition. External beam radiation significantly augmented this effect. Injection of large human tumor xenografts (human glioma, nonsmall cell lung cancer, or malignant prostate tumors) with Ad/PNP followed by intratumoral F-araAMP resulted in excellent antitumor activity superior to that observed following systemic administration of prodrug. CONCLUSION: Activation of F-araAMP by E. coli PNP results in destruction of large tumor xenografts in vivo, augments radiotherapy, and promotes robust bystander killing. Our results indicate that intratumoral injection of F-araAMP leads to ablation of tumors in vivo with minimal toxicity.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/uso terapêutico
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Terapia Genética
Pró-Fármacos/uso terapêutico
Purina-Núcleosídeo Fosforilase/genética
Fosfato de Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Adenoviridae/genética
Animais
Antimetabólitos Antineoplásicos/administração & dosagem
Antimetabólitos Antineoplásicos/farmacocinética
Efeito Espectador/efeitos dos fármacos
Efeito Espectador/genética
Efeito Espectador/efeitos da radiação
Linhagem Celular Tumoral
Terapia Combinada
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/genética
Resistência a Medicamentos Antineoplásicos/efeitos da radiação
Escherichia coli/genética
Vetores Genéticos
Glioma/tratamento farmacológico
Glioma/genética
Glioma/radioterapia
Seres Humanos
Injeções Intralesionais
Camundongos
Camundongos Nus
Pró-Fármacos/administração & dosagem
Pró-Fármacos/farmacocinética
Purina-Núcleosídeo Fosforilase/metabolismo
Transfecção
Transplante Heterólogo
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/farmacocinética
Fosfato de Vidarabina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Prodrugs); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); EC 2.4.2.1 (Purine-Nucleoside Phosphorylase)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120705
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-012-1908-9


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[PMID]:21909959
[Au] Autor:McCune JS; Woodahl EL; Furlong T; Storer B; Wang J; Heimfeld S; Deeg HJ; O'Donnell PV
[Ad] Endereço:School of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195-7630, USA. jmccune@u.washington.edu
[Ti] Título:A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients.
[So] Source:Cancer Chemother Pharmacol;69(1):263-72, 2012 Jan.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients. METHODS: We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4(+) and CD8(+) T-lymphocyte populations. RESULTS: Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3 year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8(+) cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance. CONCLUSIONS: The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/(T)busulfan/rATG conditioning regimen.
[Mh] Termos MeSH primário: Soro Antilinfocitário/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Neoplasias Hematológicas/terapia
Transplante de Células-Tronco Hematopoéticas/métodos
[Mh] Termos MeSH secundário: Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética
Área Sob a Curva
Biomarcadores Farmacológicos/metabolismo
Bussulfano/administração & dosagem
Linfócitos T CD4-Positivos
Linfócitos T CD8-Positivos/metabolismo
Terapia Combinada
Feminino
Seguimentos
Doença Enxerto-Hospedeiro/epidemiologia
Neoplasias Hematológicas/patologia
Seres Humanos
Masculino
Meia-Idade
Projetos Piloto
Modelos de Riscos Proporcionais
Recidiva
Taxa de Sobrevida
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/análogos & derivados
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antilymphocyte Serum); 0 (Biomarkers, Pharmacological); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); D7RD81HE4W (thymoglobulin); G1LN9045DK (Busulfan)
[Em] Mês de entrada:1202
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110913
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-011-1736-3


  8 / 404 MEDLINE  
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[PMID]:22009763
[Au] Autor:Xie X; Guo J; Kong Y; Xie GX; Li L; Lv N; Xiao X; Tang J; Wang X; Liu P; Yang M; Xie Z; Wei W; Spencer DM; Xie X
[Ad] Endereço:State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
[Ti] Título:Targeted expression of Escherichia coli purine nucleoside phosphorylase and Fludara® for prostate cancer therapy.
[So] Source:J Gene Med;13(12):680-91, 2011 Dec.
[Is] ISSN:1521-2254
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Previous studies have shown that Herpes Simplex Virus thymidine kinase (HSV-tk)/ganciclovir (GCV) comprised the most commonly used suicide gene therapy for prostate cancer, with modest results being obtained. However, novel suicide genes, such as Escherichia coli purine nucleoside phosphorylase (PNP), have been utilized to demonstrate more potent tumor killing and an enhanced bystander effect on local, non-expressing cells compared to HSV-tk. METHODS: PNP/fludarabine (Fludara®; fludarabine phosphate; Berlex Labs, Richmond, CA, USA) was deliveried by prostate-specific, rat probasin-based promoter, ARR2PB. After infection of various cell lines with ADV.ARR(2) PB-PNP and administration of androgen analog, R1881, expression of PNP mRNA was detected; in vivo, the antitumor effect of the ARR(2) PB-PNP/Fludara system was monitored and analyzed, as well as animal survival. RESULTS: After in vitro infection with ADV.ARR(2) PB-PNP (multiplicity of infection = 10), LNCaP cells were more sensitive to a lower concentration Fludara (LD(50) , approximately 0.1 µg/ml) in the presence of R1881. Furthermore, robust bystander effects after R1881/Fludara treatment were observed in LNCaP cells after infection with bicistronic vector ADV.ARR2PB/PNP-IRES-EGFP in contrast to a much weaker effect in cells treated with ADV.CMV-HSV-tk/GCV. In vivo, tumor size in the ADV.ARR2PB-PNP/Fludara treatment group was dramatically smaller than in the control groups, and the mice treated with our system had a significantly prolonged survival, with three of eight mice surviving up to the 160-day termination point, as well as no systemic toxicity. CONCLUSIONS: The ARR(2) PB-PNP/Fludara system induced massive tumor cell death and a prolonged life span without systemic cytotoxicity; therefore, it might be a more attractive strategy for suicide gene therapy of prostate cancer.
[Mh] Termos MeSH primário: Genes Transgênicos Suicidas
Terapia Genética
Neoplasias da Próstata
Purina-Núcleosídeo Fosforilase/genética
Fosfato de Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Arrestinas/genética
Morte Celular/efeitos dos fármacos
Morte Celular/genética
Linhagem Celular Tumoral
Escherichia coli
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/genética
Genes Transgênicos Suicidas/genética
Vetores Genéticos
Proteínas de Fluorescência Verde/metabolismo
Seres Humanos
Masculino
Metribolona/administração & dosagem
Camundongos
Regiões Promotoras Genéticas
Neoplasias da Próstata/genética
Neoplasias da Próstata/patologia
Neoplasias da Próstata/terapia
Purina-Núcleosídeo Fosforilase/uso terapêutico
Ratos
Fosfato de Vidarabina/uso terapêutico
beta-Arrestinas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arrestins); 0 (beta-Arrestins); 0 (enhanced green fluorescent protein); 106XV160TZ (Vidarabine Phosphate); 147336-22-9 (Green Fluorescent Proteins); 1X9VK9O1SC (fludarabine phosphate); 2C323EGI97 (Metribolone); EC 2.4.2.1 (Purine-Nucleoside Phosphorylase)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111020
[St] Status:MEDLINE
[do] DOI:10.1002/jgm.1620


  9 / 404 MEDLINE  
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[PMID]:21745173
[Au] Autor:Marti GE; Stetler-Stevenson M; Grant ND; White T; Figg WD; Tohnya T; Jaffe ES; Dunleavy K; Janik JE; Steinberg SM; Wilson WH
[Ad] Endereço:Laboratory of Stem Cell Biology, Cellular and Tissue Therapy Branch, Division of Cell and Gene Therapies,Office of Cellular, Tissues and Gene Therapies, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. gemarti@helix.nih.gov
[Ti] Título:Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia.
[So] Source:Leuk Lymphoma;52(12):2284-92, 2011 Dec.
[Is] ISSN:1029-2403
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
Estaurosporina/análogos & derivados
Fosfato de Vidarabina/análogos & derivados
[Mh] Termos MeSH secundário: Adulto
Idoso
Antineoplásicos/administração & dosagem
Antineoplásicos/efeitos adversos
Feminino
Seres Humanos
Linfocitose/tratamento farmacológico
Masculino
Meia-Idade
Estaurosporina/administração & dosagem
Estaurosporina/efeitos adversos
Estaurosporina/uso terapêutico
Resultado do Tratamento
Fosfato de Vidarabina/administração & dosagem
Fosfato de Vidarabina/efeitos adversos
Fosfato de Vidarabina/uso terapêutico
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 106XV160TZ (Vidarabine Phosphate); 1X9VK9O1SC (fludarabine phosphate); 7BU5H4V94A (7-hydroxystaurosporine); H88EPA0A3N (Staurosporine)
[Em] Mês de entrada:1207
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110713
[St] Status:MEDLINE
[do] DOI:10.3109/10428194.2011.589547


  10 / 404 MEDLINE  
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[PMID]:21394111
[Au] Autor:Parker WB; Allan PW; Waud WR; Hong JS; Sorscher EJ
[Ad] Endereço:Southern Research Institute, Birmingham, AL 35205, USA. parker@sri.org
[Ti] Título:Effect of expression of adenine phosphoribosyltransferase on the in vivo anti-tumor activity of prodrugs activated by E. coli purine nucleoside phosphorylase.
[So] Source:Cancer Gene Ther;18(6):390-8, 2011 Jun.
[Is] ISSN:1476-5500
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The use of E. coli purine nucleoside phosphorylase (PNP) to activate prodrugs has demonstrated excellent activity in the treatment of various human tumor xenografts in mice. E. coli PNP cleaves purine nucleoside analogs to generate toxic adenine analogs, which are activated by adenine phosphoribosyl transferase (APRT) to metabolites that inhibit RNA and protein synthesis. We created tumor cell lines that encode both E. coli PNP and excess levels of human APRT, and have used these new cell models to test the hypothesis that treatment of otherwise refractory human tumors could be enhanced by overexpression of APRT. In vivo studies with 6-methylpurine-2'-deoxyriboside (MeP-dR), 2-F-2'-deoxyadenosine (F-dAdo) or 9-ß-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate (F-araAMP) indicated that increased APRT in human tumor cells coexpressing E. coli PNP did not enhance either the activation or the anti-tumor activity of any of the three prodrugs. Interestingly, expression of excess APRT in bystander cells improved the activity of MeP-dR, but diminished the activity of F-araAMP. In vitro studies indicated that increasing the expression of APRT in the cells did not significantly increase the activation of MeP. These results provide insight into the mechanism of bystander killing of the E. coli PNP strategy, and suggest ways to enhance the approach that are independent of APRT.
[Mh] Termos MeSH primário: Adenina Fosforribosiltransferase/metabolismo
Escherichia coli/enzimologia
Pró-Fármacos/farmacologia
Purina-Núcleosídeo Fosforilase/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Escherichia coli/metabolismo
Terapia Genética
Vetores Genéticos/genética
Seres Humanos
Camundongos
Pró-Fármacos/uso terapêutico
Nucleosídeos de Purina/metabolismo
Transplante Heterólogo
Fosfato de Vidarabina/análogos & derivados
Fosfato de Vidarabina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Prodrugs); 0 (Purine Nucleosides); 106XV160TZ (Vidarabine Phosphate); 16006-64-7 (6-methylpurine 2'-deoxyriboside); 1X9VK9O1SC (fludarabine phosphate); EC 2.4.2.1 (Purine-Nucleoside Phosphorylase); EC 2.4.2.7 (Adenine Phosphoribosyltransferase)
[Em] Mês de entrada:1111
[Cu] Atualização por classe:161122
[Lr] Data última revisão:
161122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110312
[St] Status:MEDLINE
[do] DOI:10.1038/cgt.2011.4



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