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2.
J Contin Educ Nurs ; 46(11): 481-3, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26509397

RESUMO

Few articles contemplate the need for good guidance in question item-writing in the continuing education (CE) space. Although many of the core principles of sound item design translate to the CE health education team, the need exists for specific examples for nurse educators that clearly describe how to measure changes in competence and knowledge using multiple choice items. In this article, some keys points and specific examples for nursing CE providers are shared.


Assuntos
Competência Clínica , Educação Continuada em Enfermagem/métodos , Avaliação Educacional/métodos , Rememoração Mental , Inquéritos e Questionários/normas , Redação/normas , Humanos
3.
Cancer ; 116(4 Suppl): 1059-66, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20127951

RESUMO

BACKGROUND: Human epidermal growth factor receptor-2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with (213)Bi or (212)Pb. (213)Bi-humanized CC49 monoclonal antibody (HuCC49DeltaCH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously. METHODS: Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HuCC49DeltaCH2 labeled with (213)Bi administered through an intraperitoneal route. The sequence of administration also was examined. RESULTS: Before combining the 2 monoclonal antibodies, the effective doses of (213)Bi-CC49DeltaCH2 and (213)Bi-trastuzumab for the treatment of peritoneal disease were determined to be 500 muCi for each labeled antibody. Treatment with (213)Bi-HuCC49DeltaCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with (213)Bi-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when (213)Bi-HuCC49DeltaCH2 and (213)Bi-trastuzumab were coinjected, and a median survival of 147 days was obtained. CONCLUSIONS: Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with alpha-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated.


Assuntos
Partículas alfa/uso terapêutico , Antígenos de Neoplasias/imunologia , Neoplasias do Colo/terapia , Glicoproteínas/imunologia , Radioimunoterapia/métodos , Receptor ErbB-2/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/efeitos da radiação , Linhagem Celular Tumoral , Feminino , Glicoproteínas/efeitos da radiação , Humanos , Camundongos , Camundongos Nus , Receptor ErbB-2/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Cancer Res ; 14(16): 5108-15, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18698028

RESUMO

PURPOSE: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of alpha-particle-targeted radiation therapy. EXPERIMENTAL DESIGN: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 microg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [212Pb]trastuzumab. RESULTS: Paclitaxel (300 or 600 microg) followed 24 h later with [213Bi]trastuzumab (500 microCi) provided no therapeutic enhancement. Paclitaxel (300 microg) administered concurrently with [213Bi]trastuzumab or [213Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 microg paclitaxel. Mice receiving just [213Bi]trastuzumab or [213Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 microg) given 24 h after [213Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 microg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 microCi). The 300 microg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 microg extended the median survival from 44 to 171 days. CONCLUSIONS: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.


Assuntos
Neoplasias Experimentais/terapia , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/terapia , Radiossensibilizantes/administração & dosagem , Radioimunoterapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Terapia Combinada , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Camundongos , Camundongos Nus , Neoplasias Experimentais/patologia , Neoplasias Peritoneais/secundário , Radioimunoterapia/métodos , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Bioconjug Chem ; 19(7): 1439-47, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18564868

RESUMO

The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T 1 relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with (177)Lu, (90)Y, (203)Pb, (205/6)Bi, and (153)Gd; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for 11 days with the exception being the (203)Pb complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled (177)Lu, (90)Y, or (153)Gd complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. (205/6)Bi- C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while (205/6)Bi- C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.


Assuntos
Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/metabolismo , Glicina/análogos & derivados , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/metabolismo , Imageamento por Ressonância Magnética/métodos , Radioimunoterapia/métodos , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados , Reagentes de Ligações Cruzadas/farmacocinética , Glicina/síntese química , Glicina/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Humanos , Isotiocianatos/química , Ligantes , Camundongos , Distribuição Tecidual , Trastuzumab
6.
J Med Chem ; 51(1): 118-25, 2008 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-18062661

RESUMO

An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of (212)Bi, (213)Bi, and (177)Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. (177)Lu -C-NETA and (205/6)Bi -C-NETA possess an excellent or acceptable in vivo biodistribution profile.


Assuntos
Bismuto , Quelantes/síntese química , Glicina/análogos & derivados , Compostos Heterocíclicos com 1 Anel/síntese química , Lutécio , Compostos Radiofarmacêuticos/síntese química , Animais , Anticorpos , Quelantes/química , Desenho de Fármacos , Estabilidade de Medicamentos , Feminino , Glicina/síntese química , Glicina/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Marcação por Isótopo , Cinética , Ligantes , Camundongos , Camundongos Nus , Radioimunoterapia , Radioisótopos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Soro , Espectrofotometria Ultravioleta , Distribuição Tecidual
7.
Clin Cancer Res ; 13(6): 1926-35, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17363549

RESUMO

PURPOSE: Recent studies from this laboratory with (212)Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb as an in vivo generator of (212)Bi. The objective of the studies presented here was improvement of the efficacy of alpha-particle radioimmunotherapy using a chemotherapeutic agent. EXPERIMENTAL DESIGN: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by (212)Pb radioimmunotherapy. RESULTS: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 muCi (212)Pb-trastuzumab. Improvement in median survival was observed at 5 microCi (212)Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 microCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single (212)Pb radioimmunotherapy (10 microCi) administration was then evaluated. Mice received three doses of gemcitabine: one before (212)Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to (212)Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 microCi (212)Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 microCi (212)Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before (212)Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before (212)Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because (212)Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine). CONCLUSIONS: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma/radioterapia , Desoxicitidina/análogos & derivados , Neoplasias Peritoneais/radioterapia , Radiossensibilizantes/uso terapêutico , Radioimunoterapia/métodos , Receptor ErbB-2/imunologia , Animais , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Carcinoma/mortalidade , Carcinoma/secundário , Desoxicitidina/uso terapêutico , Feminino , Humanos , Radioisótopos de Chumbo/uso terapêutico , Transferência Linear de Energia/efeitos dos fármacos , Camundongos , Camundongos Nus , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Análise de Sobrevida , Trastuzumab , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
8.
Nucl Med Biol ; 33(4): 459-67, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16720237

RESUMO

Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadec-3-yl]-acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-carboxymethyl-amino)-methyl]-azepan-1-yl}-acetic acid (AZEP-DTPA), [2-(4,7-bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and [{4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of 177Lu, 90Y, 212Pb and 213Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with 177Lu, 86/88/90Y, 203Pb and 205/6Bi, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of 90Y-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold 177Lu in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but 177Lu in vivo. NETA and NPTA radiolabeled with 86Y or 177Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with 203Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both 203Pb-PIP-DOTA and 205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for 205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind 203Pb and 205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for 177Lu and 90Y. Serum stability and in vivo biodistribution results suggest PIP-DTPA as a potential chelating agent with broad applicability for use in 177Lu, 90Y, 212Pb and 213Bi RIT.


Assuntos
Acetatos/farmacocinética , Azepinas/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Glicina/análogos & derivados , Piperidinas/farmacocinética , Radioimunoterapia/métodos , Acetatos/química , Acetatos/uso terapêutico , Animais , Azepinas/química , Azepinas/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Quelantes/síntese química , Quelantes/farmacocinética , Quelantes/uso terapêutico , Desenho de Fármacos , Feminino , Glicina/química , Glicina/farmacocinética , Glicina/uso terapêutico , Marcação por Isótopo/métodos , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Especificidade de Órgãos , Piperidinas/química , Piperidinas/uso terapêutico , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Distribuição Tecidual
9.
J Med Chem ; 49(6): 2055-62, 2006 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-16539394

RESUMO

Novel chelates PIP-DTPA, AZEP-DTPA, NETA, NPTA, and PIP-DOTA were synthesized and evaluated as potential magnetic resonance imaging (MRI) contrast enhancement agents. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the clinically used contrast agents Gd(DTPA) and Gd(DOTA). The serum stability of the 153Gd-labeled complexes, Gd(PIP-DTPA), Gd(AZEP-DTPA), Gd(PIP-DOTA), Gd(NETA), and Gd(NPTA), was assessed by measuring the release of 153Gd from the complexes. 153Gd(NETA), 153Gd(PIP-DTPA), and 153Gd(PIP-DOTA) were found to be stable in human serum for up to 14 days without any measurable loss of radioactivity. Significant release of 153Gd was observed with the 153Gd(III) radiolabled NPTA. In vivo biodistribution of the153Gd-labeled complexes was performed to evaluate their in vivo stability. While Gd(AZEP-DTPA) and Gd(NPTA) were found to be unstable in vivo, Gd(NETA), Gd(PIP-DTPA), and Gd(PIP-DOTA) were excreted without dissociation. These results suggest that the Gd(III) complexes of the novel chelates NETA, PIP-DTPA, and PIP-DOTA possess potential as MRI contrast enhancement agents. In particular, the piperidine backboned chelates Gd(PIP-DTPA) and Gd(PIP-DOTA) displayed reduced kidney retention as compared to the nonspecific MRI contrast agent Gd(DOTA) at all time points, although the observed effects were relatively small at 0.5 h postinjection. Incorporation of the lipophilic piperidine ring appears to confer a moderate effect on the liver uptake of these two chelates.


Assuntos
Quelantes/síntese química , Meios de Contraste/síntese química , Gadolínio , Compostos Macrocíclicos/síntese química , Compostos Organometálicos/síntese química , Animais , Quelantes/química , Meios de Contraste/química , Meios de Contraste/farmacocinética , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Ligantes , Fígado/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Radioisótopos , Soro , Distribuição Tecidual
10.
Cancer Biother Radiopharm ; 20(5): 557-68, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16248771

RESUMO

These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb-labeled Herceptin as an in vivo generator of (212)Bi. In vitro studies compare the potential of the bismuth radioisotopes, (213)Bi and (212)Bi, to that of (212)Pb. Overall, (212)Pb results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (microCi) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenografts determined a maximum tolerated dose (MTD) of 20-40 microCi with i.p. administration. A specific dose response was observed and 10 microCi was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 microCi increased from 19 to 56 days (p = 0.008). The efficacy of (212)Pb-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to 213Bi-Herceptin (p = 0.002). Multiple dosing of (212)Pb-Herceptin was evaluated in both animal models. The median survival of mice bearing 3 d LS-174T i.p. xenografts increased to 110 days, with up to 3 doses of (212)Pb-Herceptin given at approximately monthly intervals; however, there was no evidence of a correlation with the second and third doses (p = 0.98). No improvement in median survival was noted with a similar regimen in the Shaw xenograft model.


Assuntos
Doenças Peritoneais/terapia , Radioimunoterapia/métodos , Receptor ErbB-2/metabolismo , Partículas alfa , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Citometria de Fluxo , Genes erbB-2 , Humanos , Imunoconjugados/química , Radioisótopos de Chumbo , Dose Máxima Tolerável , Camundongos , Transplante de Neoplasias , Radioimunoensaio , Receptor ErbB-2/imunologia , Fatores de Tempo , Trastuzumab
11.
Nucl Med Biol ; 32(3): 301-5, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15820766

RESUMO

A simple and rapid procedure was developed for the purification of cyclotron-produced 203Pb via the 203Tl(d,2n) 203Pb reaction. A Pb(II) selective ion-exchange resin, with commercial name Pb Resin from Eichrom Technologies, Inc., was used to purify 203Pb from the cyclotron-irradiated Tl target with excellent recovery of the enriched Tl target material. The purified 203Pb was used to radiolabel the monoclonal antibody Herceptin. The in vitro and in vivo properties of the 203Pb radioimmunoconjugate were evaluated.


Assuntos
Anticorpos Monoclonais/farmacocinética , Carcinoma/metabolismo , Neoplasias do Colo/metabolismo , Radioisótopos de Chumbo/farmacocinética , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Ciclotrons , Feminino , Humanos , Marcação por Isótopo/métodos , Radioisótopos de Chumbo/isolamento & purificação , Radioisótopos de Chumbo/uso terapêutico , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Especificidade de Órgãos , Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/isolamento & purificação , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Distribuição Tecidual , Trastuzumab
12.
Clin Cancer Res ; 10(23): 7834-41, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15585615

RESUMO

The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of (213)Bi-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 muCi, respectively. The therapeutic effectiveness of (213)Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P = 0.001).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias do Colo/radioterapia , Radioisótopos de Índio/uso terapêutico , Ácido Pentético/análogos & derivados , Doenças Peritoneais/radioterapia , Radioimunoterapia , Receptor ErbB-2/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Neoplasias do Colo/metabolismo , Neoplasias do Colo/secundário , Feminino , Humanos , Radioisótopos de Índio/farmacocinética , Isotiocianatos/química , Isotiocianatos/metabolismo , Camundongos , Camundongos Nus , Ácido Pentético/química , Ácido Pentético/metabolismo , Doenças Peritoneais/metabolismo , Projetos Piloto , Receptor ErbB-2/metabolismo , Estereoisomerismo , Taxa de Sobrevida , Distribuição Tecidual , Transplante Heterólogo , Trastuzumab
13.
Nucl Med Biol ; 31(6): 795-802, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15246371

RESUMO

A simple, non-radioactive method for the determination of ligand-to-protein ratio (L/P) for novel ligand-antibody conjugates has been developed based on an exchange equilibrium with the purple Cu(II) complex of arsenazo III. The method requires a UV/Vis spectrometer and has been verified for monoclonal antibody Herceptin conjugates of a variety of ligand modalities, including common macrocyclic compounds NOTA and TETA, and with a new bifunctional tachpyridine (1H-Pyrrole-1-butanamide,N-[4-[[(1alpha,3alpha,5alpha)-3,5-bis[(2-pyridinylmethyl)amino]cyclohexyl](2-pyridinylmethyl)amino]butyl]-2,5-dihydro-2,5-dioxo-(9CI)). The spectroscopically derived values for L/P were verified by titration of the ligand-antibody conjugate with 64Cu. In each case, the value obtained by UV/Vis spectroscopy matches that found by radiolabeling. The method is rapid, taking less than 30 minutes with each ligand in this study.


Assuntos
Cobre/química , Cicloexilaminas/química , Maleimidas/química , Proteínas/química , Compostos Radiofarmacêuticos/química , Anticorpos Monoclonais/química , Anticorpos Monoclonais Humanizados , Cromatografia em Camada Fina , Radioisótopos de Cobre , Indicadores e Reagentes , Ligantes , Espectrofotometria Ultravioleta , Trastuzumab
15.
Inorg Chem ; 43(1): 116-31, 2004 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-14704059

RESUMO

Pu L(3) X-ray near edge absorption spectra for Pu(0-VII) are reported for more than 60 chalcogenides, chlorides, hydrates, hydroxides, nitrates, carbonates, oxy-hydroxides, and other compounds both as solids and in solution, and substituted in zirconolite, perovskite, and borosilicate glass. This large database extends the known correlations between the energy and shape of these spectra from the usual association of the XANES with valence and site symmetry to higher order chemical effects. Because of the large number of compounds of these different types, a number of novel and unexpected behaviors are observed, such as effects resulting from the medium and disorder that can be as large as those from valence.

16.
Discov Med ; 4(22): 213-9, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20704989

RESUMO

Extract: Hybridoma/monoclonal antibody (mAb) technology as described in Kohler and Milstein's work resurrected Ehrlich's century old concept of "magic bullets." This seminal publication described fusion of a plasmacytoma (tumor of activated B lymphocytes) with spleen cells and subsequent isolation of hybrids that secreted mAb with pre-defined specificity. Generation of mouse mAbs against tumor-associated antigens became a focus in the 1980's. Pre-clinical studies provided proof-of-concept for the potential of mAbs for therapy although inherent limitations of these models demonstrated discordance in predictability of actual efficacy. Clinical investigations also illustrated deficiencies; foremost, an inevitable immune response, i.e., the production of human anti-murine immunoglobulin antibodies (HAMA). Other limitations included (1) inadequate tumor dose delivery; (2) insufficient activation of effector function(s); (3) slow blood clearance; (4) low affinity and avidity; (5) normal organ targeting; (6) tumor antigen heterogeneity; and (7) insufficient tumor penetration. Most of these were handled with genetic engineering or chemical modification, but some obstacles remained. HAMA production has been addressed by chimerization (combining portions of mouse and human antibodies) or complete humanization (grafting only the key antigen-binding portions of mouse antibody to a human antibody framework) of the mAb.

17.
Inorg Chem ; 42(21): 6682-90, 2003 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-14552620

RESUMO

The compound Sm[N(SiMe(3))(2)](3) has been investigated experimentally by X-ray crystallography and computationally by DFT methods. The structure is analogous to that of other tris[bis(trimethylsilyl)amido]lanthanides, featuring positional disorder of the metal atom above and below the plane defined by the three N donor atoms, resulting in a trigonal pyramidal configuration. One of the methyl groups of each amido ligand is placed above the apex of the pyramid at close distance to the metal center suggesting the presence of agostic interactions. The DFT calculations have been carried out on the real molecule and on a Si[N(SiH(3))(SiH(2)Me)](3) model where the unique Me group was placed above the apex of the pyramid to probe the agostic interaction. In both cases, the optimized geometry reproduces very well the experimental structure and indicates the presence of beta-Si-C agostic interactions. A comparison of the optimized geometries obtained in the presence/absence of the Sm d and the Si d orbitals serves to illustrate the relevance of these orbitals for (i). the establishment of the pyramidal configuration at Sm, (ii). the Sm-N bond length, and (iii). the Sm-(beta-Si-C) bond length. The bonding analysis, which was carried out by both Mulliken and NBO methods, not only confirms the importance of the metal d orbitals for the Sm-N and Sm-(beta-Si-C) chemical bonding but also illustrates the relevance of electrostatic terms in the agostic interaction. Sm-N and N-Si pi bonding is present according to the bonding analysis but is not important for enforcing the planar configuration at N, nor the pyramidal configuration at Sm.

18.
J Am Chem Soc ; 124(32): 9556-66, 2002 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-12167050

RESUMO

The rotational orientation of cyclopentadienyl rings usually has no effect on d-orbital energy levels and splitting in transition metal complexes. With related but less symmetrical carbocyclic ligands, however, the magnetic properties of the associated complexes can be altered by the alignment of the ligands. Examples of this effect are found in substituted organochromium(II) bis(indenyl) complexes. The monosubstituted compounds (1-RC(9)H(6))(2)Cr (R = t-Bu, SiMe(3)) are prepared from the substituted lithium indenides and CrCl(2) in THF; they are high-spin species with four unpaired electrons. Their spin state likely reflects that in the unknown monomeric (C(9)H(7))(2)Cr, which is calculated to have a high-spin (S = 2) ground state in the staggered configuration (180 degrees rotation angle). However, the analogous bis(indenyl) complexes containing t-Bu or SiMe(3) groups in both the 1 and 3 positions on the indenyl ligands ((1,3-R(2)C(9)H(5))(2)Cr) are low-spin compounds with two unpaired electrons. X-ray diffraction results indicate that [1-(t-Bu)C(9)H(6)](2)Cr exists in a staggered conformation, with Cr-C (av) = 2.32(4) A. In contrast, the average Cr-C distances in [1,3-(t-Bu or SiMe(3))(2)C(9)H(5)](2)Cr are 2.22(2) and 2.20(2) A, respectively, and the rings are in a gauche configuration, with rotation angles of 87 degrees. The indenyl conformations are sterically imposed by the bulk of the t-Bu and SiMe(3) substituents. The change from a staggered to a gauche indenyl orientation lowers the symmetry of a (C(9)H(7))(2)M complex and allows greater mixing of metal and ligand orbitals. Calculations indicate that previously nonbonding pi orbitals of the indenyl anion are able to interact with the chromium d orbitals, producing bonding and antibonding combinations. The latter remain unpopulated, and the resulting increase in the HOMO-LUMO gap forces the complexes to adopt a low-spin configuration. The possibility of using sterically imposed ligand rotation as a means of spin-state manipulation makes indenyl compounds a potentially rich source of magnetically adjustable molecules.

19.
J Am Chem Soc ; 124(24): 7007-15, 2002 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-12059224

RESUMO

Treatment of nitrobenzene and other various nitroarenes with 6 equiv of samarium(II) under strictly anhydrous conditions allows for the isolation of aniline or the corresponding arylamine. Reducing the number of samarium(II) equivalents allows for the isolation of intermediate species, e.g., azoarenes or hydrazines. Use of Sm[N(SiMe(3))(2)](2), in place of the typically used SmI(2), has allowed for the detailed examination of the aqueous and nonaqueous species formed in this reduction and has been instrumental in delineation of the stepwise reaction mechanism. This is the first time that the reaction intermediates of an organic reaction mediated by samarium(II) have been isolated and analyzed by (1)H NMR and X-ray crystallography.

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