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Biomedical subjects

J D Chapman

Publications and source records attributed to J D Chapman.

At least 91 records · Page 5Linked to original sources
PubMed1983

Synthesis and in vivo studies of the radiosensitizer 4-[82Br]bromomisonidazole.

[82Br]Misonidazole ( [82Br]MISO) was investigated as a potential agent for scintillation imaging and indexing of hypoxic areas in tumor masses. [82Br]MISO was prepared by irradiating samples of Br-MISO in a SLOWPOKE reactor for 2 h at a thermal neutron flux of 10(12) n cm-2 s-1. Radiochemical yields ranged from 11 to 16%. [82Br]MISO had a plasma clearance half-life of approximately 40 min in BALB/c mice bearing EMT-6 tumors. The major metabolic product was identified as [82Br]Desmisonidazole. [82Br]MISO showed relatively high tumor uptake and persistently high plasma levels.

Animals↗
PubMed1983

Identification of a hypoxic population of bone marrow cells.

A technique using collagenase has been devised to release and separate, with reproducibility, hematopoietic cells (HC) from various microenvironments of mouse femurs. HC were assayed by an in vitro gel culture technique used traditionally to score granulocyte-macrophage precursor cells (CFU-C). CFU-C which resided in the medullary cavity and endosteal regions were sensitive to ionizing radiation and resistant to misonidazole (MISO) cytotoxicity. CFU-C which resided within the compact bone were resistant to ionizing radiation and sensitive to the cytotoxic action of MISO. These results suggest that HC which reside in the bone are hypoxic and retain clonogenic potential. When animals were exposed to various treatments with MISO followed by myelotoxic doses of cyclophosphamide (CTX) or total body irradiation (TBI), the LD50 of both agents was significantly reduced. This result suggests that a hypoxic component of HC could be important in the regenerative process within the marrow after such myelotoxic trauma.

Animals↗
PubMed1983

The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole.

14C-misonidazole was injected IP into BALB/C mice bearing EMT-6 tumours. Tumour and normal tissue levels of radioactivity were determined by liquid scintillation procedures for times up to 72 h after drug administration. At times longer than 8 h, levels of 14C in tumour were 2-6 times higher than 14C levels measured in other normal tissues, with the exception of liver. The levels of 14C from misonidazole retained in liver tissue were comparable to those retained in the tumours. The clearance of 14C-misonidazole from the tumours and all normal tissues could be characterised by two distinct phases: a rapid phase (0.7 h half-life) followed by a much slower phase (approximately 50 h half-life). The distribution of retained 14C from labelled misonidazole within tumour-bearing mice was also measured by whole animal autoradiographic techniques. This procedure confirmed the biodistribution of 14C-misonidazole determined by liquid scintillation procedures. To enhance binding to hypoxic cells in vivo, 14C-misonidazole was administered in multiple doses over a three-hour period, simulating a prolonged exposure to the drug. The 14C from labelled misonidazole retained in tumour tissue was 4-15 times greater than that retained in normal tissues, liver tissue being again an exception. Myocardial ischaemia was induced by isoproterenol treatment and a two-fold increase of 14C from labelled misonidazole was found in the heart tissue of mice treated by the drug compared to controls. The increased binding of 14C-misonidazole to tumour cells after prolonged exposure to the drug and the increased binding of 14C-misonidazole to ischaemic heart tissue suggests that hypoxia is a factor in sensitiser adduct formation in vivo.

Animals↗
PubMed1983

Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells.

[14C]Misonidazole (MISO) becomes bound to macromolecules of mammalian cells upon hypoxic incubation. Intracellular enzyme processes are implicated since the temperature dependence for this process showed an activation energy of 33.5 kcal/mol. The sensitizer bound to both hypoxic and aerobic cells was associated with the macromolecular fraction and the soluble fraction in the proportion, 23 and 77%, respectively. The initial rate of binding of [14C]MISO to the macromolecular (acid-insoluble) fraction of hypoxic EMT-6 mouse tumor and V-79 hamster cells increased proportionally with the square root of extracellular concentration of MISO up to at least 5mM. High concentrations of dimethyl sulfoxide (an effective OH radical scavenger), allopurinol (an effective inhibitor of xanthine oxidase), and diamide (a chemical which can deplete cellular levels of glutathione) had little or no effect on this metabolism-induced binding process. The addition of high concentrations of exogenous cysteamine to hypoxic cell cultures resulted in almost complete inhibition of binding. Extracellular bovine albumin at high concentration in hypoxic cell cultures had little effect on the production of adducts to cell macromolecules and only small amounts of [14C]MISO were found to bind to the extra-cellular bovine albumin. This result suggests that MISO preferentially binds to molecules within the cell in which it is metabolically activated. In experiments where cells labeled under hypoxic conditions with [14C]MISO were subsequently permitted to proliferate in aerobic monolayers, a half-life of the acid-insoluble addition products of approximately 55 hr was measured. A large number of [14C]MISO adducts (approximately 10(9)/cell) can be generated in hypoxic cells without any evidence of cytotoxicity, and they are slowly cleared from cells. These are favorable characteristics as regards the development of this technique as a marker for hypoxic cells in solid tumors.

Anaerobiosis↗
PubMed1982

Binding of 14C-misonidazole to hypoxic cells in V79 spheroids.

The metabolism-induced binding of 14C-labelled misonidazole (MISO) to hypoxic V79 cells in multicell spheroids has been quantitated using autoradiography. Hypoxia was shown to be the major determinant of the rate of binding. Maximally hypoxic cells bound MISO several times more rapidly than necrotic material in the centre of the spheroids, and up to 50 times more rapidly than well oxygenated cells. The rate of binding to chronically hypoxic cells at the edge of the necrotic centre was 20 times less than to similar cells in other spheroids made maximally hypoxic with N2. This difference is consistent with the greater radio-sensitivity of the chronically hypoxic cells, which is a consequence of their intermediate level of oxygenation. The results indicated that the ability to bind MISO might have considerable potential as a marker for hypoxic cells in tumours. However, some binding patterns cannot be explained by the simplest model of O2 diffusion. It may be necessary to invoke more complex models of O2 diffusion or metabolic gradients within the spheroid which affect the rate of binding.

Autoradiography↗
PubMed1982

Response of the Dunning R3327H prostatic adenocarcinoma to radiation and various chemotherapeutic drugs.

Dunning R3327H prostatic adenocarcinoma was bilaterally transplanted in the flanks of animals at the Papanicolaou Institute in Miami, and the animals were received at the Cross Cancer Institute (Edmonton, Alberta, Canada) each month. The animal flanks were palpated weekly, and when tumor volumes reached a size of approximately 300 mm3 the animals were randomized into treatment groups for the assessment of various therapies. Tumor volumes were determined each week before and after various treatments, and tumor growth was compared to that in untreated controls. Ionizing radiation at relatively small single doses completely inhibits tumor growth for a period of up to 6 months. Some interesting characteristics of this radiation-induced growth arrest are that tumors do not die and shrink away as with some other tumor models but remain static in size and show histologic evidence of viable tumor cells. The hypoxic cell radiosensitizer misonidazole potentiates radiation response in this tumor model. Cisplatin, vincristine, etoposide, and estramustine phosphate administered in drug doses approaching their toxic limits have a partial effect on tumor growth.

Adenocarcinoma↗
PubMed1981

Luteinizing hormone secretion before and after ovariectomy in prepubertal and pubertal beef heifers.

The effects of sham ovariectomy (SOVX) or ovariectomy (OVX) on (1) basal luteinizing hormone (LH) concentrations, (2) number of LH peaks per hour and (3) magnitude of LH peaks were determined in prepubertal and pubertal beef heifers. Basal LH concentrations were not influenced by SOVX of prepubertal or pubertal heifers. However, after OVX, basal LH concentrations increased between 168 and 192 hr in prepubertal heifers and between 72 and 80 hr in pubertal heifers. The number of LH peaks per hour was not influenced by SOVX but OVX caused an increase in the number in both prepubertal and pubertal heifers, and the increase occurred sooner after OVX in pubertal than in prepubertal heifers. The magnitude of LH peaks was similar for both prepubertal and pubertal heifers prior to SOVX and OVX. Magnitude of LH peaks was unchanged after SOVX in prepubertal and pubertal heifers, but increased within the first 24 hr after OVX in pubertal heifers and within 168 to 192 hr after OVX in prepubertal heifers. These data indicate that inhibition of LH secretion by ovaries occurred in both prepubertal and pubertal beef heifers. The time-related differences between prepubertal and pubertal heifers in basal LH concentrations, number of LH peaks per hour and magnitude of the LH peaks after OVX may reflect a difference in endocrine environment in these two reproductive states. However, this hypothesis was not tested in this experiment.

Aging↗
PubMed1979

Radioprotection by DMSO of mammalian cells exposed to X-rays and to heavy charged-particle beams.

Populations of G1-phase Chinese hamster cells in stirred suspensions containing various concentrations of DMSO were irradiated with 250 kV X-rays or various heavy charged-particle beams. Chemical radioprotection of cell inactivation was observed for all LET values studied. When cell survival data were resolved into linear and quadratic components, the extent and concentration dependence of DMSO protection were found to be different for the two mechanisms. The chemical kinetics of radioprotection for single-events were similar for LET values up to those which gave the maximum RBE. DMSO protected to a lesser extent against energetic argon ions at an median LET of approximately 220 keV/micron. These data could indicate the contribution of indirect action by hydroxyl radicals and hydrogen atoms to cell inactivation by single-hit and double-hit mechanisms for various radiation qualities. The decrease in RBE observed at very high LET may result, in part, from reduced yields of water radicals at 10(-9)-10(-8) s resulting from radical recombination mechanisms within the charged particle tracks.

Animals↗
PubMed1978

Peripheral neuropathy related to misonidazole: incidence and pathology.

The human tolerance to multiple dosages of misonidazole (Ro-07-0582) was studied in 28 patients with different types of malignant neoplasias. The mean total dose for this group of patients was 16.2 g. The main toxicity was peripheral neuropathy with an overall incidence of 35%. This neuropathy occurred more frequently and with greater severity when the drug was administered 3 times a week and when patients received total doses of over 18 g. The best tolerated schedule appears to be once or twice a week up to total dosages of 18 g or less (approximately 11 g/m2). Electron microscopy of a sural nerve biopsy from an affected patient revealed residual of previous distal axonal degeneration, with some segmental demyelination and remyelination, which affected both large and small myelinated nerve fibres.

Drug Administration Schedule↗
PubMed1978

Hypoxic cell sensitizers and heavy charged-particle radiations.

Stationary-phase populations of Chinese hamster V-79 cells were irradiated with 250 kV X-rays and the Bragg peaks (spread to a width of 4 cm) of energetic He-, C-, Ne-, and A-ion beams produced at the 184-inch cyclotron and BEVALAC at Lawrence Berkeley Laboratory. Survival curves were generated with each radiation for cells suspended in air-saturated and nitrogen-saturated medium with and without sensitizer present. The oxygen enhancement ratios (OERs) measured for X-rays with 1mM metronidazole and 0.5 mM misonidazole were 2.0 and 1.6 respectively. The OERs without sensitizer for He-, C-, Ne-, and A-ion Bragg peaks were 2.4, 1.7, 1.6 and 1.4 respectively. For each type of radiation tested the presence of hypoxic-cell sensitizers resulted in an additional reduction in the measured OERs, indicating that these drugs should be of benefit in the radiotherapy planned with these and other high LET radiations.

Cell Survival↗
PubMed1978

Nitropyrrole radiosensitizers: structure function relationships.

Nitropyrrole derivatives have been tested as hypoxic cell radiosensitizers in vitro and in vivo. Radiosensitizing potential generally increases with nitropyrrole electron affinity. N-hydroxyethyl substitution decreases toxicity relative to N--CH3, N--CH2 CH3 and N--CH2 CH2 CH3 substitution. The most effective nitropyrrole tested in vivo is N-hydroxyethyl-2-cyano-5-nitropyrrole (NP-1).

Animals↗