Biomedical subjects
Publications and source records attributed to J D Chapman.
A nucleoside triphosphate phosphohydrolase activity has been discovered in reovirus virions. This activity converts nucleoside triphosphates to nucleoside diphosphates in vitro. Properties of this enzyme are presented, with evidence that this activity is an integral part of the virion core.
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Azomycin riboside (2-nitro-1-beta-D-ribofuranosylimidazole) (AR), a nucleoside analogue with the base component replaced by a 2-nitroimidazole was studied to determine its potential as a radiosensitizer. In vitro evidence showed that AR is as good as or slightly better than misonidazole (MISO) as a hypoxic cell radiosensitizer. AR was also found to kill hypoxic cells directly and this cytotoxicity was at least as great as MISO cytotoxicity. However, when tumor regrowth delay was used to assess in vivo radiosensitization, AR was found to be inferior to MISO while the LD50 host toxicity assay indicated that AR might be nearly as toxic as MISO. Unless AR proves to be less toxic than MISO or can be selectively distributed with nucleoside transport inhibitors, these preliminary observations have not shown any advantage of AR over MISO as a potential clinically useful radiosensitizer.
Normal bone marrow function was surveyed in animals that received cyclophosphamide after treatment with small, multiple doses of misonidazole. Peripheral blood white cell counts, cell differentials, hematocrits, bone marrow white cell counts and committed granulocyte-macrophage precursors (CFUc) were monitored for several days following treatment with misonidazole and cyclophosphamide. When results obtained from animals treated with physiological saline or misonidazole in advance of cyclophosphamide were compared, no significant differences were noted in routine assays of white blood cell count, cell morphology or hematocrit. Pre-treatment with misonidazole, however, caused a significant reduction in survival and delay in recovery of bone marrow CFUc (p less than .01). The combined use of misonidazole and cyclophosphamide also reduced animal survival (DMF = 1.2), with the majority of deaths being attributable to failure of normal hematopoietic function. These results suggest that misonidazole enhances the myelotoxicity associated with cyclophosphamide use. This additional damage is not detectable using routine hematological assays, but is demonstrable in assays of bone marrow stem cells and animal survival studies.
Metabolism-induced binding of misonidazole was shown previously to be enhanced in hypoxic regions of V79 spheroids. Data are presented to show that the binding of misonidazole to EMT6 spheroids is similar to V79 in some respects and different in others. The binding rate in nitrogen was constant in all cells in EMT6 spheroids, whereas a 5-fold rise was found in binding rate across the outer 100 micrometers of V79 spheroids. A small enhancement of binding to the cells near the necrotic center in EMT6 spheroids in air was found, which was similar to the binding to chronically hypoxic cells in aerobic V79 spheroids. The binding rate in 1--5% oxygen was similar in EMT6 and V79 spheroids. Both showed a large rise in binding rate across the outer 120 micrometers and a constant binding rate to healthy cells interior to this. Since 1.5 oxygen should supply only the outer 40 micrometers of a typical spheroid, something beyond a simple oxygen diffusion limitation is required to explain the data. One possible explanation is the diffusion of some of the reactive product away from the hypoxic cells which produce it. This was tested by incubating a single cell suspension in misonidazole at 0.5% oxygen in the presence of absence of V79 spheroids. No evidence was found for an appreciable loss of reactive product from the spheroids.
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Medicare's method for reimbursing at-risk managed care plans causes potential problems with selection (when beneficiaries with higher-than-expected costs stay in traditional plans) and stinting (the tendency to underprovide health services). Adjusting payment by diagnosis offers substantial improvement. We favor large-scale demonstrations of diagnosis-based reimbursement. Reducing payment, a Clinton administration proposal, would recoup excess payments in the short run but not address the selection problem, which could reemerge. Selection makes current payments vulnerable to upward spirals. We propose not using traditional Medicare to update reimbursement. Basing some payment on enrollees' actual use addresses selection and stinting. Rather than reinsurance, we propose blending traditional Medicare and risk-adjusted capitation. Ceding some cases to traditional Medicare in advance appears to be useful for terminally ill patients.
1-(4-Iodo-4-deoxy-beta-L-xylopyranosyl)-2-nitroimidazole (Iodoazomycin Pyranoside; IAZP) was synthesized, labelled with radioiodine(123I, 125I) and evaluated for non-invasive assessment of tumor hypoxia. A biodistribution study with Balb/c mice bearing EMT-6 tumors showed a tumor-to-blood ratio of 13.9, representing 0.5 percent of injected dose per gram of tissue, at 24 hours post injection. This ratio is the highest for any 2-nitro-imidazole reported to date in this tumor model. Rapid elimination of radioactivity from the whole-body was noted (greater than 97% in 24 hours) and thyroid radioactivity at 24 hours was much lower than with other analogues of this series. No toxicity was observed in Balb/c mice at a dose 100 times higher than the anticipated human dose required for scintigraphic imaging. Planar, whole-body gamma scintigraphic images in the murine Balb/c EMT-6 tumor model clearly delineated tumor tissue at 24 hours post injection. These observations suggest that IAZP may be a suitable agent for non-invasive, clinical assessment of tumor hypoxia.
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