RESUMO
A human medulloblastoma (BN-2) and a glioblastoma (BN-3) which were previously established in nude mice were used to determine the effect of combined modality therapy with gamma-radiation, and three chemotherapeutic agents, procarbazine, 1,4-cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)-3,6-dioxo diethylester (AZQ), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The tumor cells were grown in tissue culture and implanted intracranially in the right cerebral hemisphere of NIH Swiss nude mice to a depth of 3 mm. The mice were randomized, and treatment was started 3 days after tumor implantation. Procarbazine and AZQ were injected i.p. every 5 days for three treatments. BCNU was injected one time for a single treatment. Radiation was localized to the head. A 60Co unit was used for irradiation at the rate of 125 rads/min 3 days after tumor implantation. Ten experiments were performed using six to nine mice per group and different drug-radiation dose combinations. The drug dose ranged from 400 to 500 mg/kg/injection for procarbazine, 7.5 mg/kg/injection for AZQ, and 10 to 20 mg/kg/injection for BCNU. The radiation dose ranged from 320 to 1050 rads/mouse (whole head). The day of death was recorded for each animal, and the mean of each treatment group was used to calculate the percentage increase in life span (ILS) compared to the untreated control group. Chemotherapy alone produced a minimal effect, while radiation alone produced minimal effects at 320 to 640 rads with progressively positive effects at 800 and 1050 rads. When the combination treatment of the human medulloblastoma xenograft with procarbazine was used, the ILS was significantly increased in all four experiments, ranging from 25 to 41%, and was superior to single-modality treatment in all but the 1050-rad treatment, where it showed an equal effect. The combination treatment using AZQ and BCNU showed no ILS for the medulloblastoma tumor. Combination treatment of the human glioblastoma xenograft using BCNU produced significant ILSs of 105 and 119% and was superior to single-modality treatment with a drug dose of 10 mg/kg and radiation doses of 540 and 800 rads, respectively. The nude mouse-human tumor xenograft model was found to be useful for combined modality studies and should give valuable information for the experimental design of pilot Phase III clinical studies against a variety of brain tumors.
Assuntos
Benzoquinonas , Glioma/radioterapia , Meduloblastoma/radioterapia , Animais , Aziridinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Carmustina/uso terapêutico , Linhagem Celular , Glioma/tratamento farmacológico , Humanos , Meduloblastoma/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Procarbazina/uso terapêutico , Fatores de Tempo , Transplante HeterólogoRESUMO
This is the first report of an experimental intraorbital ligature producing papilledema characterized by axonal swelling and accumulation of mitochondria in the lamina retinalis of the optic disc of rhesus monkeys subjected to immediately retrobulbar ligature of a portion of the optic nerve. This is an improved technique for investigating the pathogenesis of papilledema and optic neuropathy.
Assuntos
Nervo Óptico/fisiopatologia , Papiledema/fisiopatologia , Animais , Axônios/ultraestrutura , Haplorrinos , Ligadura , Métodos , Dilatação Mitocondrial , Atrofia Óptica/patologia , Disco Óptico/ultraestrutura , Nervo Óptico/ultraestrutura , Papiledema/patologia , Retina/ultraestruturaAssuntos
Cannabis/farmacologia , Corticosterona/metabolismo , Sistema Límbico/metabolismo , Glândulas Suprarrenais/fisiologia , Adrenalectomia , Animais , Córtex Cerebral/metabolismo , Dronabinol/farmacologia , Hipocampo/metabolismo , Sistema Límbico/efeitos dos fármacos , Masculino , Ratos , Fatores de Tempo , TrítioAssuntos
Encéfalo/enzimologia , Núcleo Celular/enzimologia , Neuroglia/metabolismo , RNA Nucleotidiltransferases/metabolismo , Acetilcolinesterase/análise , Animais , Química Encefálica , Centrifugação com Gradiente de Concentração , DNA/análise , L-Lactato Desidrogenase/análise , Fígado/metabolismo , Microscopia Eletrônica , Microscopia de Contraste de Fase , Proteínas do Tecido Nervoso/análise , Neuroglia/análise , Neurônios/metabolismo , Nucleotídeos/análise , RNA/análise , Ovinos , Succinato Desidrogenase/análise , TrítioRESUMO
The histology, ultrastructure, and nuclear RNA polymerase activity are described in a murine primitive neuroectodermal tumor derived by serial transplantation from a tumor originally induced with methylcholanthrene and classified as an ependymoblastoma. The light microscope and ultrastructural studies show that this tumor does not contain the distinguishing morphological features of differentiated ependymal cells which are also commonly seen in human ependymomas. One outstanding feature is the size and number of the nucleoli. The mean number of nucleoli/nucleus is 4 which is two to four times that of the normal neuroglial cell. The nucleolar diameter is about twice that found in normal neuroglial cells. The nucleolar diameter is about twice that found in normal neuroglial cells. The nuclear RNA synthesizing activity is the highest of the chemically induced animal tumors we have studied. The alpha amanitin inhibition is the lowest seen in any of these tumors which suggests that RNA polymerases inhibited by alpha amanitin contribute less to the total nuclear RNA synthesis. Adriamycin significantly inhibits the nuclear RNA polymerase activity of this tumor.
Assuntos
RNA Polimerases Dirigidas por DNA/análise , Ependimoma/induzido quimicamente , Metilcolantreno , Animais , Nucléolo Celular , Núcleo Celular/enzimologia , Doxorrubicina/farmacologia , Ependimoma/enzimologia , Ependimoma/ultraestrutura , Camundongos , Microscopia EletrônicaRESUMO
A nucleolar isolation procedure was developed for the murine primitive neuroectodermal tumor originally induced with methylcholanthrene. This procedure utilizes sonication for breakage of the nuclei at a magnesium concentration which disperses the extranucleolar chromatin. The nucleoli retain RNA synthetic activity which is inhibited to about 90% by actinomycin D and the chemotherapeutic drug adriamycin.
Assuntos
Nucléolo Celular/enzimologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Ependimoma/ultraestrutura , RNA Polimerase I/antagonistas & inibidores , Amanitinas/farmacologia , Animais , Fracionamento Celular , Núcleo Celular/enzimologia , Dactinomicina/farmacologia , Doxorrubicina/farmacologia , Ependimoma/enzimologia , Magnésio/metabolismo , Camundongos , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/ultraestruturaRESUMO
Nuclear RNA polymerase activity was studied in homotransplanted rat glial tumors where the primary tumor was produced by transplacental injection of ethylnitrosourea. Alpha amanitin, cycloheximide, and rifampicin were tested as inhibitors of this activity. Alpha amanitin significantly inhibited RNA polymerase activity in all tumors. This indicated that the major nuclear RNA polymerase activity seen in vitro in the tumor nuclei was RNA polymerase II. This is similar to the activity seen in normal glial nuclei. Cycloheximide and rifampicin which have no effect on RNA polymerase activity in normal glial nuclei inhibited about 20% of the polymerase activity in three of the tumors. The size and multiplicity of the nucleoli in these tumor cells suggests that RNA polymerase I could account for the activity which is inhibited by cycloheximide.
Assuntos
Neoplasias Encefálicas/enzimologia , RNA Polimerases Dirigidas por DNA/metabolismo , Amanitinas/farmacologia , Animais , Autorradiografia , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/patologia , Nucléolo Celular/ultraestrutura , Núcleo Celular/enzimologia , Cicloeximida/farmacologia , DNA de Neoplasias/biossíntese , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Retículo Endoplasmático/ultraestrutura , Etilnitrosoureia , Fibrossarcoma/enzimologia , Glioma/enzimologia , Glioma/patologia , Guanosina Trifosfato/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/enzimologia , Neurofibroma/enzimologia , Ratos , Rifampina/farmacologia , Transplante HomólogoRESUMO
Two human brain tumors which were previously established in nude mice were used to determine antitumor efficacy of various therapeutic agents. These tumors were a medulloblastoma (TE-671) and a glioma (U-251) with mass doubling times of 3.5 and 5.5 days respectively as subcutaneous implants in nude mice. Intracranial (i.c.) tumor challenge was accomplished by inoculating tissue culture-grown cells of either tumor into the right cerebral hemisphere to a depth of 3 mm. Median survival time (MST) in untreated mice with 10(5) i.c. injected TE-671 cells was approximately 30 days and 53 days in the U-251 tumor. With 2 X 10(5) U-251 tumor cells the MST was 27-31 days. Groups of mice which had been inoculated with tumor were treated with various doses and schedules of antineoplastic compounds by the i.p. route. The TE-671 tumor responded to AZQ treatment with an increase in life span (ILS) of 37% compared to untreated controls and an ILS of 30% with CCNU treatment. BCNU and PCNU were ineffective. With the U-251 tumor BCNU produced an ILS of greater than 60%, with 75% cures, greater than 112% ILS with PCNU and 49% ILS with CCNU. Neither tumor responded to procarbazine, PALA, dianhydrogalactitol, D-O-norleucine or dibromodulcitol. The U-251 tumor was treated on various schedules and doses with BCNU and found to respond well on late as well as early treatment. A new drug (rapamycin) being investigated by the NCI was found to be very effective against the U-251 tumor. This model system should prove valuable in assessing the effects of various chemotherapeutic modalities against brain tumors.