Biomedical subjects
Publications and source records attributed to A Begleiter.
Four steroidal nitrosoureas with structures which may permit specific binding to estrogen receptor were synthesized. Inhibitory activity was observed against the growth of the DMBA-induced transplantable rat mammary tumor 13762.
Chondrosarcomas of the jaws are rare tumors; an additional case in the maxilla is described. The literature that discusses the pathogenesis of the tumor, its biological behavior, and the preferred treatment is reviewed. The histologic differentiation between chondrosarcoma and benign cartilagenous tumors is discussed.
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The mechanism of uptake of nitrosoureas by L5178Y cells in vitro was investigated. A time course of the uptake of radioactivity on incubation of L5178Y lymphoblast with [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea was linear for 30 min and then entered a plateau phase; it was markedly temperature dependent. A similar time course for cells incubated with [14C]ethylene-labeled 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea reached equilibrium rapidly, was temperature independent, and resulted in a relatively low level of uptake of radioactivity. However, cells treated with 3-[cyclohexyl-14C]-1-(2-chlorethyl)-1-nitrosourea had a time course that was linear for 30 min, resulted in much higher levels of uptake of radioactivity, and was strongly temperature dependent. These findings, at least for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, suggest that some drug decomposition precedes uptake. The percentage of radioactivity found in the cell sap fraction was at least 85% of total cell activity when cells were incubated with any of the three 14C-labeled nitrosoureas. Furthermore, thin-layer chromatography of the cell sap fraction revealed the presence of free intact drug. These findings indicate that intracellular uptake of intact nitrosoureas occurred. A time course of uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea reached equilibrium rapidly with cell/medium distribution ratios of 0.2 to 0.6 and was temperature independent. The addition of excess unlabeled 1,3-bis(2-chlorethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea had no effect on uptake of [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea, These findings suggest that uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea was by passive diffusion. A time course of the uptake of intact 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with either [14C]ethylene- or ring-labeled drug rapidly reached equilibrium, was temperature independent, and attained a cell/medium ratio greater than unity. Uptake of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was sodium independent and was unaffected by the metabolic inhibitors (sodium fluoride, sodium cyanide, or 2,4-dinitrophenol) or by urea, a potential physiological competitor. Furthermore, addition of unlabeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1,3-bis(2-chlorethyl)-1-nitrosourea had no effect on uptake of labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. These findings suggest that uptake of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea also occurs by passive diffusion.
Mechanism of transport of the alkylating agent [14C]melphalan was investigated in L5178Y lymphoblasts in vitro. A time course of melphalan uptake was approximately linear for 5 to 10 min and thereafter entered a plateau region. Evidence that unidirectional influx of melphalan is carrier mediated was that uptake obeyed simple Michaelis-Menten kinetics, that it demonstrated chemical specificity, and that the cell/medium distribution ratio of drug decreased with increasing extracellular drug concentration. The kinetic parameters for melphalan transport consisted of a Km (mean +/- S.E.) of 1.53 +/- 0.18 X 10(-4) M and a transport capacity (Vmax) of 3.48 +/- 0.31 X 10(-17) mole/min/cell. Findings suggesting that transport was at least in part energy dependent and not simply a passive process were that drug uptake was temperature sensitive and sodium dependent. Analysis of cell sap constituents indicated the presence of intact drug within the cell. The percentage of radioactivity (mean +/- S.D.) found in the cell sap fraction was 95.8 +/- 2.2% of total cell activity, and 92.6 +/- 4.1% of this was trichloroacetic acid soluble. Thin-layer chromatography of the cell sap fraction and medium each revealed that the majority of radioactivity migrated as a single peak with an RF value identical with that obtained for free drug. The alkylating potential of intact drug complicated interpretation of the finding of apparent uphill transport against a concentration gradient. This observation, together with the relatively low cell-medium ratio (mean +/- S.D.) of 3.07 +/- 1.07, favors the concept that melphalan transport occurs by a facilitated diffusion process, although an active transport system has not been entirely excluded. The relative insensitivity of melphalan uptake to a wide range of metabolic inhibitors also suggests that transport is by a facilitated diffusion mechanism rather than an active process. Other alkylating agents and several amino acids including the L and D isomers of phenylalanine did not inhibit melphalan transport; thus a native substrate was not identified for the melphalan carrier and transport was by a mechanism separate from that of other alkylating agents.
Psoriasis is a chronic, recurrent, inflammatory disease of the skin. The occurence of psoriatic lesions in oral mucous membranes is a subject of controversy, and some investigators have stated that such lesions do not occur at all. In the present investigation 100 psoriatic patients were examined for the presence of oral lesions. No patient exhibited oral lesions of psoriasis; however, there was a relatively high incidence of angular cheilosis (11 per cent), fissured tongue (6 per cent), and benign migratory glossitis (5 per cent). The possibility that benign migratory glossitis is an oral manifestation of psoriasis is discussed.
The cytotoxic action of the antitumor antibiotic mitomycin C occurs primarily at the level of DNA. Using highly sensitive fluorescence assays which depend on the enhancement of ethidium fluorescence only when it intercalates duplex regions of DNA, three aspects of mitomycin C action on DNA have been studied: (a) cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. Cross-linking of DNA is determined by the return of fluorescence after a heat denaturation step at alkaline pH's. Under these conditions denatured DNA gives no fluorescence. The cross-linking was independently confirmed by S1-endonuclease (EC 3.1.4.-) digestion. At relatively high concentrations of mitomycin the suppression of ethidium fluorescence enhancement was shown not to be due to depurination but rather to alkylation, as a result of losses in potential intercalation sites. A linear relationship exists between binding ratio for mitomycin and loss of fluorescence. The proportional decrease in fluorescence with pH strongly suggests that the alkylation is due to the aziridine moiety of the antibiotic under these conditions. A parallel increase in the rate and overall efficiency of covalent cross-linking of DNA with lower pH suggests that the cross-linking event, to which the primary cytotoxic action has been linked, occurs sequentially with alkylation by aziridine and then by carbamate. Mitomycin C, reduced chemically, was shown to induce single strand cleavage as well as monoaklylation and covalent cross-linking in PM2 covalently closed circular DNA. The inhibition of this cleavage by superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6), and by free radical scavengers suggests that the degradation of DNA observed to accompany the cytotoxic action of mitomycin C is largely due to the free radical O2. In contrast to the behavior of the antibiotic streptonigrin, mitomycin C does not inactivate the protective enzymes superoxide dismutase or catalase. Lastly, mitomycin C is able to cross-link DNA in the absence of reduction at pH 4. This is consistent with the postulated cross-linking mechansims.
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Electrophysiological recordings from human visual cortex were carried out with electrodes chronically implanted in 13 patients for localization of an epileptogenic focus. Visual evoked potentials (VEPs) elicited by red or blue checkerboard stimuli were recorded using an adaptation stimulus-test stimulus design in which color was the most salient feature. A "significant color effect," defined as a statistically significant effect of the adaptation stimulus on test stimulus VEPs evoked by the same or a different color, was determined for various cortical regions: medial lingual gyrus, 20%; lateral lingual gyrus, 38%; posterior fusiform gyrus, 50%; anterior fusiform gyrus, 0%; inferior temporal gyrus, 5%; occipital pole, 30%; lateral surface of non-visual cortex, 6%; inferior parietal and temporal cortex, 5%. The time course of the significant color effects suggests that wave length-selective neuronal activity occurs initially at the first stage of cortical processing in the medial lingual gyrus, followed by progressively later activation of the lateral lingual gyrus, the posterior fusiform gyrus, and the inferior temporal gyrus. In two patients, stimulation of the lateral lingual and fusiform gyri elicited color sensations in the contralateral half-field, whereas stimulation of the medial lingual and cuneate gyri evoked retinotopically appropriate quadrantic "shimmering" devoid of color. These results suggest that a region of inferior occipital cortex, primarily the posterior portion of the fusiform gyrus, is involved in color perception and may be homologous with area V4 in monkeys. There is also a region of dorsolateral surface cortex which exhibits a fairly high percentage of significant color effects and when stimulated may evoke sensations of color. This region may be the same as the dorsolateral region thought to be involved in selective attention to color.
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