Needs for animal models of human diseases of the nervous system.
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Biomedical subjects
Publications and source records attributed to F S Vogel.
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To investigate the pathologic consequences of therapeutic radiation, this morphologic study evaluated the brains of 25 patients with intracranial gliomas treated both with and without this form of therapy. Although beneficial effects such as the retardation of tumor growth were evident in these studies, among the seventeen patients who received from 5000--6000 rads for malignant gliomas, four developed "late delayed" radiation necrosis. The strong predilection of this tissue response for the white matter adjacent to the neoplasm suggests a local sensitivity which may have been engendered or enhanced by cerebral edema. A fifth case disclosed focal demyelination in the mid-brain suggesting "early delayed" radiation necrosis, and an additional case had distinctive foci of necrosis within the brain stem. Changes of diffuse cerebral edema were noted in many of the radiated brains. It is concluded that radiation therapy in commonly employed dosages for malignant gliomas carries a risk of injury to surrounding cerebral tissues.
A study was made of tissues from 130 pocket mice after a single head-only exposure to high-LET 20Ne particle radiation at 1000, 100 or 10 rad (nominal surface dose) with the view of obtaining base"line data regarding the effectiveness of HZE (cosmic-ray) particles during spaceflight. First seen at 2-3 weeks after exposure, necrotic neurons in the cerebrum reached peak incidence (0 . 04 per cent at 1000 rad, 0 . 003 per cent at 100 rad and less than 0 . 0005 per cent at 10 rad) after 4-5 weeks and decreased to low levels thereafter. Incidence in the cerebellum was lower. Neuroglia, cells of the subependymal matrix and dentate gyrus precursor cells suffered acute damage at 1000 and at 100 rad. At 1000 rad, enlarged hyperchromatic neuroglia, first noted at 3 weeks, increased in number up to 7 months, then declined. Alterations in the retina and olfactory epithelium were seen at 1000 rad, and reaction in the scalp at 100 rad. Damage was incurred by dentinoblasts at 10 rad. Changes similar to those observed in pocket mice were found in the brains of gerbils and C57B1 mice.
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The s.c. administration of gamma-L-glutaminyl-4-hydroxybenzene (GHB) to neonatal black mice produced a prompt, generalized, and selective swelling and lysis of the melanocytes of the hair follicles. The findings indicate that this cytotoxic effect was dependent upon the intracellular activation of GHB by tyrosinase. Supportive of this conclusion were: (a) an absence of comparable cytological alterations in adjacent keratinocytes; (b) a lack of response by melanocytes of albino mice; and (c) patterns of deficient pigmentation produced by GHB in juvenile black mice, suggesting that susceptible follicles were those in the tyrosinase-producing growth phase. The administration of GHB also induced condensation, or "apoptosis," of individual follicular keratinocytes of both black and albino mice and in the melanocytes in the latter. This response was apparently independent of tyrosinase. It was transitory and without appreciable effect on hair growth. The findings further characterize the selective cytolytic properties of GHB for mammalian cells that possess tyrosinase and suggest a potential for this natural compound as a chemotherapeutic agent against melanocarcinoma.
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The quinone intermediates resulting from tyrosinase-mediated oxidation of tyrosine were evaluated as sulfhydryl reagent inhibitors of purified calf thymus DNA polymerase alpha in order to determine which of these might be cytotoxic. Dopachrome and an oxidation product of 2,4,5-trihydroxyphenylalanine were relatively ineffective as inhibitors of DNA polymerase alpha. On the other hand, a dopaquinone analogue, 4-(2-N-acetylaminoethyl)-1,2-benzoquinone, synthesized from N-acetyl dopamine, was demonstrated to have marked affinity for this sulfhydryl enzyme. This property was shared by 1,2-benzoquinone. These studies point to dopaquinone as a significant toxic metabolite in melanin biosynthesis.
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Extensive areas of hemorrhagic softening developed in the cerebral white matter in three critically ill patients. The anatomic peculiarities of the vasculature of this region, as well as the possible roles of edema and vasospasm, are weighed as factors in the pathogenesis of these unusual lesions.
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Gliomas, derived from astrocytes, oligodendroglia, or ependyma, are each united into a continuum by a graduation of anaplasia. Neoplasms originate at all levels of each continuum; subsequently, some move along its declivity. Conversely, neuroblastic tumors may differentiate, whereas concomitantly in the same lesion, the glial stroma may dedifferentiate. Anaplastic glia, as in a glioblastoma multiforme, can initiate malignant transformation in alien cells.
A stable phenol, gamma-L-glutaminyl-4-hydroxybenzene (GHB), is oxidized by tyrosinase in the gill tissues of the mushroom Agaricus bisporus to a quinone and a second oxidation product which together suppress mitochondrial energy production and the synthesis of proteins and nucleic acids in the zygote, thus establishing dormancy in the spores. Brief incubation of cultured murine L1210 leukemia and B-16 melanoma cells with muM concentrations of the purified quinone notably prolonged survival times or blocked tumor growth in histocompatible mice inoculated i.p. with high concentrations of the exposed cells. The instability of the quinone precluded in vivo administration. The short incubation of cultured B-16 melanoma cells with mM concentrations of GHB markedly prolonged survival times or abolished tumor growth in histocompatible C57BL/6J mice inoculated i.p. with 5 X 10(6) exposed cells. This response did not occur with L1210 leukemia cells, which lack the enzyme tyrosinase. The survival times of mice bearing B-16 melanoma, but not of those with L1210 leukemia, were slightly prolonged by a single injection and were significantly extended by daily i.p. injections of GHB. Normal C57BL/6J mice, given GHB i.p. as single or multiple 400-mg/kg doses, manifested no systemic toxicity but showed depigmentation of the hair after 2 to 3 weeks. These studies provide evidence that GHB exerts cytotoxicity specifically for cells that by their content of tyrosinase convert the phenol to the quinone. This targeted response minimizes systemic toxocity and underscores the potential therapeutic application of this agent to melanocarcinoma.
The histopathologic diagnoses in 718 brain tumor patients entered in the Brain Tumor Study Group were reviewed, as well as those for 53 of these patients who were reviewed, as well as those for 53 of these patients who were autopsied later. This review documented instances of progression of histologic analplasia. Of particular interest in the autopsied cases were several instances of extensive necrosis in white matter distant from persisting glioma following chemotherapy and radiotherapy. This observation suggested the presence of a structural and/or metabolic alteration in the diseased hemisphere that perhaps makes it more susceptible to further alterations secondary to the adjunctive therapy.
The 490 quinone, a natural sulfhydryl-arylating reagent from the mushroom, Agaricus bisporus, markedly inhibited L1210 murine leukemia DNA polymerase alpha while resulting in little inhibition of DNA polymerase beta from this source. This quinone was more strongly inhibitory than p-chloromercuri-benzoate or N-ethylmaleimide and was less readily neutralized by sulfhydryl-containing molecules such as dithioerythritol. Preliminary experiments indicate that DNA protects DNA polymerase alpha from inhibition by the 490 quinone. The inhibition of DNA synthesis by quinone 490 may contribute significantly to the cytotoxicity of this compound and to the potential of gamma-L-glutaminyl-4-hydroxybenzene as an antitumor agent.