RESUMO
BACKGROUND: Radiofrequency ablation (RFA) is rapidly evolving as an effective minimally invasive technique for the treatment of small and unresectable liver tumors. A potential cause of treatment failure is the inability to determine the optimum number of overlapping ablations needed to completely destroy tumors larger than the size of a single ablation. To clarify this relationship, we performed a mathematical evaluation that enables us to accurately estimate the number of ablations needed to completely ablate larger tumors. METHODS: This estimation is based on the assumptions that complete ablation of the surface of a target tumor, including its blood supply, would completely destroy the tumor and that the tumor and ablations produced are perfectly spherical. The smallest possible number of partially overlapping ablations that would completely cover the surface of the target tumor is the same as the number of faces on a regular polyhedron that has a circumscribing diameter equal to or greater than the diameter of the target sphere. RESULTS: This mathematical analysis shows that for a 5-cm ablation device, tumors with diameters ranging between 3.01 and 3.30 cm will require at least four ablations. Tumors between 3.31 and 4.12 cm require six overlapping ablations, and tumors between 4.13 and 6.23 cm require 12 overlapping ablations. The number of ablations needed for larger tumors and for 3-, 4-, 6-, and 7-cm ablation devices are also determined. CONCLUSION: The smallest number of ablations required to completely ablate a spherical target tumor larger than the size of the ablation sphere increases dramatically as tumor size increases. Because this model is geometrically optimized, even a small change in the position of the ablation spheres with respect to the target sphere can leave potentially unablated tumor and thus result in treatment failure.
Assuntos
Ablação por Cateter , Neoplasias Hepáticas/cirurgia , Modelos Teóricos , Planejamento de Assistência ao Paciente , Humanos , Neoplasias Hepáticas/patologia , Planejamento de Assistência ao Paciente/estatística & dados numéricosRESUMO
In comparative tests of the capabilities of various analogs of doxorubicin and daunorubicin to augment oxygen consumption in microsome preparations from P388 mouse leukemia cells and from rat liver cells, we found statistically significant positive correlations between the Km values for microsomes from the two sources for parent compounds and analogs containing morpholinyl, cyanomorpholinyl- or imino-substitutions. Km values ranged from 0.015 to 1.3 mM, or about 90-fold for all analogs tested. Thus, rat liver microsomes are predictive for this characteristic in P388 microsomes. Examinations of the relationships between Km values from either source and ED50 values for cytotoxicity of the compounds against the P-388 cells also showed statistically significant positive correlations. However, the ED50 values encompassed a range from 0.00020 to 0.22 microM, or about 1000-fold. Therefore, additional mechanism(s) of action besides toxic oxygen radical formation must explain the extremely high cytotoxicity of the cyanomorpholinyl anthracyclines compared with their parent drugs.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Leucemia P388/metabolismo , Leucemia Experimental/metabolismo , Microssomos Hepáticos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Animais , Radicais Livres , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Naftacenos/farmacologia , Oxirredução , RatosRESUMO
Treatment of doxorubicin with formaldehyde and NaCN afforded the N-(cyanomethyl) derivative as a stable alpha-cyanoamine with but moderate antitumor activity in mice, although it was prototypal to the intensely potent alpha-cyanomorpholine derivative. 2-Methoxyacetaldehyde and NaCN afforded the N-(2-methoxy-1-cyanoethyl) derivative as an open-chain analogue of the cyanomorpholine. This analogue underwent rapid hydrolysis to doxorubicin and appeared to act as a prodrug, giving increased antitumor efficacy although with decreased potency. N-(Carboxymethyl)daunorubicin was a highly water-soluble but inactive analogue, synthesized by N-alkylation with ethyl iodoacetate and saponification. The similar N-alkylation of N-(cyanomethyl) daunorubicin demonstrated the combining of N-alkyl chains having different functional substituents.
Assuntos
Antibióticos Antineoplásicos/síntese química , Naftacenos/síntese química , Animais , Antibióticos Antineoplásicos/farmacologia , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Leucemia Experimental/tratamento farmacológico , Camundongos , Naftacenos/farmacologia , Relação Estrutura-AtividadeRESUMO
The susceptibility of 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin to hydrolysis at pH 7, 4, and 2 has been compared with that of the typically stable morpholine analogue. At pH 7, 74% of the cyanomorpholine was unchanged after 24 h at room temperature, but at pH 2 only 10% remained. Products identified were aglycon (8%) and N-(2-hydroxyethyl)doxorubicin (7%). Most of the losses were to unidentified polar products not eluted from HPLC. Authentic hydroxyethyl was synthesized from doxorubicin by reductive alkylation with glycolaldehyde. Antitumor potency was comparable to that of doxorubicin rather than of cyanomorpholine.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/análogos & derivados , Animais , Antineoplásicos/síntese química , Linhagem Celular , Doxorrubicina/farmacologia , Resistência a Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Leucemia P388/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
3'-Deamino-3'-(4-morpholinyl)adriamycin (MRA) and 3'-deamino-3'(3-cyano-4-morpholinyl)adriamycin (MRA-CN) were compared with adriamycin (ADR) in ADR-sensitive (P388/S) and -resistant (P388/ADR) murine leukemia cell lines with respect to cytotoxicity and cellular accumulation. MRA is only two- to threefold more cytotoxic to P388/S in culture than ADR, whereas MRA-CN is 500-fold more cytotoxic than ADR to this cell line. Yet both MRA and MRA-CN retain their potency against P388/ADR in spite of a 150-fold decrease in potency for ADR. The observed noncross-resistance of both MRA and MRA-CN in P388/ADR correlates with their increased cellular uptake and retention relative to ADR and the inability of P388/ADR to exclude these analogs as readily as it does ADR. The decreased uptake of MRA and MRA-CN in P388/ADR relative to P388/S (1.5 to 2.0-fold), the increased efflux, and the ability of verapamil to enhance cellular uptake of these analogs in P388/ADR, as it does with ADR, all indicate that the mechanism of ADR-resistance effects ADR and the morpholino analogs in a similar manner but to far different extents. The potent cytotoxicity of MRA-CN appears to be related to strong cellular interactions of the drug with macromolecules that are characterized by its nonextraction from cells by chloroform: methanol or 10 M urea and may therefore represent covalent binding.
Assuntos
Antibióticos Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Leucemia P388/metabolismo , Leucemia Experimental/metabolismo , Animais , Linhagem Celular , Doxorrubicina/metabolismo , Resistência a Medicamentos , Camundongos , Naftacenos/metabolismo , Naftacenos/farmacologia , Relação Estrutura-Atividade , Verapamil/farmacologiaRESUMO
A series of quinone- and sugar-modified analogs of adriamycin have been tested for growth inhibition of adriamycin-sensitive (P388/S) and -resistant (P388/ADR) sublines of P388 murine leukemia cells in vitro. P388/ADR is less resistant to analogs of adriamycin containing either a 3'-deamino-3'-(4"-morpholinyl) group, MRA; or a -(3"-cyano-4"-morpholinyl) group, MRA-CN, than to adriamycin. However, MRA-CN was the most potent growth inhibitor of either subline. This potency is reduced by either modification of the quinone unit with a 5-imino substituent or restriction of the cyano-morpholinyl ring by an oxygen bridge to the daunosamine sugar. The calcium antagonist verapamil substantially increases the cytotoxicity of adriamycin to P388/ADR but has no appreciable effect on the cytotoxicity of either MRA or MRA-CN. The results suggest that increased uptake and retention by both MRA and MRA-CN may contribute to their increased cytotoxicity, but that the intense potency of the cyano-morpholinyl analogs must be due to other unique properties of these compounds.
Assuntos
Antineoplásicos , Doxorrubicina/análogos & derivados , Leucemia P388/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Doxorrubicina/uso terapêutico , Resistência a Medicamentos , Sinergismo Farmacológico , Camundongos , Fatores de Tempo , Verapamil/uso terapêuticoRESUMO
The principal excretion products derived from radiolabeled N,N-dimethylaminoisopropanol (Dip) and p-acetamidobenzoic acid (PAcBA) components of inosiplex (Isoprinosine) were identified and quantified in urine following single iv and oral administration of the drug in rhesus monkeys. The major metabolite derived from [3H] PAcBA was identified as PAcBA-O-acylglucuronide by 1) positive naphthorescorcinol reaction for glucuronic acid and 2) hydrolysis of the metabolite to PAcBA and glucuronic acid, using either dilute base (but not acid) or beta-glucuronidase. This metabolite accounted for 50% of the administered dose in orally dosed animals and 31% in iv dosed animals. A minor metabolite, which constituted approximately 5% of the excreted 3H from either iv or orally dosed animals, was identified as the hippuric acid conjugate of PAcBA by co-chromatography with a commercial standard. A single metabolite derived from [14C]Dip was identified as Dip-N-oxide by co-chromatography with synthetic material in several chromatographic systems; this metabolite accounted for 17 to 18% of the administered 14C in either the iv or orally dosed animals.
Assuntos
Ácido 4-Aminobenzoico/urina , Aminobenzoatos/urina , Inosina Pranobex/metabolismo , Inosina/análogos & derivados , Propanolaminas/urina , Administração Oral , Animais , Autorradiografia , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Hidrólise , Injeções Intravenosas , Inosina Pranobex/urina , Macaca mulatta , para-AminobenzoatosRESUMO
Muscle fiber pathways in the heart wall are described. Procedures are introduced which permit data to be standardized from cadaver and animal hearts fixed at different points of the cardiac cycle or obtained in vivo from patients with different ejection fractions and heart masses. Design criteria are also developed here to construct a hypothetical standard left ventricle to compare the data from different hearts. The equations allow the nested set of toroidal fiber-shells to be depicted with typical muscle fiberpaths. With this formulation the heart wall and typical elements in it can be shown computergraphically as they move from the contracted state to the distended. Man-made fiber structures that simulate the fail-safe shockload absorbing features of the heart can now be designed and tested computergraphically by use of the mathematical procedures described here.
Assuntos
Coração/anatomia & histologia , Miocárdio/citologia , Animais , Fenômenos Biomecânicos , Computadores , Ventrículos do Coração , Matemática , Modelos Cardiovasculares , Contração MiocárdicaRESUMO
2-beta-D-Ribofuranosylselenazole-4-carboxamide, a selenazole analog of the antitumor agent Tiazofurin, is severalfold more cytotoxic to murine tumor cells in culture than Tiazofurin. Like Tiazofurin, the cytotoxicity of the selenazole analog is reversed by exogenous guanosine, and both nucleosides specifically inhibit IMP dehydrogenase activity in cultured P388 cells. The dose-dependency for this inhibition correlates with the relative cytotoxicities of both drugs, indicating that a more potent inhibition of IMP dehydrogenase by the selenazole analog is primarily responsible for its increased cytotoxicity. The specific inhibition of the isolated enzyme by potential metabolites of the selenazole analog is discussed.
Assuntos
Antineoplásicos , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Compostos Organosselênicos , Ribavirina/uso terapêutico , Ribonucleosídeos/uso terapêutico , Selênio/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , IMP Desidrogenase/metabolismo , Leucemia L1210/enzimologia , Leucemia P388/enzimologia , Camundongos , Núcleosídeo-Difosfato Quinase/antagonistas & inibidores , Ribavirina/análogos & derivadosAssuntos
Carcinoma de Ehrlich/metabolismo , Nucleotídeos de Purina/biossíntese , Nucleotídeos de Adenina/biossíntese , Animais , Nucleotídeos de Guanina/biossíntese , IMP Desidrogenase/antagonistas & inibidores , Cinética , Camundongos , Núcleosídeo-Difosfato Quinase/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Cultures of Escherichia coli kept at 0 degree C in a phosphate buffer solution were exposed to a sinusoidal weak 60- or 600-Hz magnetic field of strength 2 X 10(-3) Tesla. A decrease of more than 40% in bacterial count was observed after a 60-h exposure to the magnetic field. Electron micrographs of exposed bacteria show ruptured cell walls, possibly due to the breaking away of flagella under the influence of the sinusoidally varying electromotive force.
Assuntos
Campos Eletromagnéticos , Fenômenos Eletromagnéticos , Escherichia coli/crescimento & desenvolvimento , Membrana Celular/ultraestrutura , Células Cultivadas , Temperatura Baixa , Escherichia coli/ultraestrutura , Fatores de TempoAssuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Guanosina/análogos & derivados , Animais , Antibacterianos/metabolismo , Biotransformação , Carcinoma de Ehrlich/metabolismo , Resistência Microbiana a Medicamentos , Escherichia coli/enzimologia , Guanina/metabolismo , Guanosina/metabolismo , Guanosina/farmacologia , Humanos , Hipoxantinas/metabolismo , Técnicas In Vitro , Fígado/metabolismo , Purinas/farmacologia , Pirimidinas/farmacologia , RatosRESUMO
Gallium-67 scanning was evaluated in 100 patients with proved carcinoma of the lung. It was valuable in separating primary from secondary lung tumors, determining the extent of contralateral hilar or mediastinal lymph node involvement, and detecting distant organ metastases. In addition to multiplane whole-body Ga-67 tomographic scanning, colloid liver scans, bone scans, and computerized axial tomography scans of the brain were obtained to determine the presence of distant metastasis. The gallium scan detected 11 of 12 occult metastases and identified 7 of 7 liver, 9 of 14 brain, 4 of 4 soft tissues, 1 of 4 contralateral lung, and 9 of 11 bone metastases. The whole-body gallium scan accurately detected or excluded extrathoracic metastatic disease in 11 of 12 patients examined postmortem within three months of a gallium scan. An approach is recommended using gallium scanning along with chest roentgenograms for clinical staging and preoperative evaluation of patients with carcinoma of the lung. Specific organ scans should be reserved for the occasional symptomatic patient with a negative gallium scan or for clarification of an indeterminate gallium scan.
Assuntos
Radioisótopos de Gálio , Neoplasias Pulmonares/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Erros de Diagnóstico , Estudos de Avaliação como Assunto , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/cirurgia , Metástase Linfática/diagnóstico por imagem , Cintilografia , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/secundário , Tomografia Computadorizada por Raios XAssuntos
Antivirais/síntese química , Guanina/análogos & derivados , Imidazóis/síntese química , Nucleotídeos de Purina/biossíntese , Adenilossuccinato Sintase/antagonistas & inibidores , Animais , Anti-Infecciosos/síntese química , Antivirais/uso terapêutico , Carcinoma de Ehrlich/metabolismo , Células Cultivadas , Efeito Citopatogênico Viral/efeitos dos fármacos , Guanina/síntese química , Guanina/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Imidazóis/farmacologia , Masculino , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Ribavirina/farmacologiaRESUMO
The synthesis, characterization, and biochemical evaluation of 1-beta-D-ribofuranosylnaphtho[2,3-d]imidazole-4,9-dione (3), 2-beta-D-ribofuranosylnaphtho[2,3-d]pyrazole-4,9-dione (6), and 2-beta-D-ribofuranosylnaphthol[2,3-d]triazole-4,9-dione (9) are reported. These quinone nucleosides and the corresponding quinone heterocycles were tested as inhibitors of purine nucleotide biosynthesis in Ehrlich ascites cells. The nucleosides 3 and 9 and naphtho[2,3-d]imidazole-4,9-dione were effective inhibitors of hypoxanthine phosphoribosyltransferase.
Assuntos
Naftoquinonas/síntese química , Ribonucleosídeos/síntese química , Animais , Carcinoma de Ehrlich/enzimologia , Carcinoma de Ehrlich/metabolismo , Depressão Química , Hipoxantina Fosforribosiltransferase/antagonistas & inibidores , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Naftoquinonas/farmacologia , Nucleotídeos de Purina/biossíntese , Ribonucleosídeos/farmacologiaAssuntos
Ribavirina/metabolismo , Ribonucleosídeos/metabolismo , Administração Oral , Animais , Cromatografia Gasosa , Meia-Vida , Injeções Intravenosas , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Espectrometria de Massas , Ratos , Ribavirina/administração & dosagem , Baço/metabolismo , Fatores de TempoAssuntos
Compostos Organofosforados/metabolismo , Ribavirina/metabolismo , Ribonucleosídeos/metabolismo , Triazóis/metabolismo , Animais , Carcinoma de Ehrlich/enzimologia , Bovinos , Hipoxantina Fosforribosiltransferase/metabolismo , Técnicas In Vitro , Camundongos , Nucleosídeos , Nucleotídeos , Fosfotransferases/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Ratos , Ribavirina/análogos & derivadosRESUMO
A general reaction of glycosyl cyanides with liquid hydrogen sulfide in the presence of 4-dimethylaminopyridine to provide the corresponding glycosylthiocarboxamides is described. These glycosylthiocarboxamides were utilized as the precursors for the synthesis of 2-D-ribofuranosylthiazole-4-carboxamide and 2-beta-D-ribofuranosylthiazole-5-carboxamide (23). The structural modification of 2-beta-D-ribofuranosylthiazole-4-carboxamide (12) into 2-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)thiazole-4-carboxamide (15), 2-beta-D-ribofuranosylthiazole-4-thiocarboxamide (17), and 2-(5-deoxy-beta-D-ribofuranosyl)thiazole-4-carboxamide (19) is also described. These thiazole nucleosides were tested for in vitro activity against type 1 herpes virus, type 3 parainfluenza virus, and type 13 rhinovirus and an in vivo experiment was run against parainfluenza virus. They were also evaluated as potential inhibitors of purine nucleotide biosynthesis. It was shown that the compounds (12 and 15) which possessed the most significant antiviral activity were also active inhibitors (40-70%) of guanine nucleotide biosynthesis.