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Biomedical subjects

R M Sutherland

Publications and source records attributed to R M Sutherland.

At least 163 records · Page 9Linked to original sources
PubMed1980

Effect of acute and chronic misonidazole administration on peripheral-nerve electrophysiology in mice.

I.p. administration at several dose levels over periods of up to 12 weeks, or continuous i.v. infusion of high doses of misonidazole (MISO) for 15 h, produced no significant change in peripheral nerve conduction velocity (NCV) and did not prevent the normal increase in NCV as the animals matured from 12 to 24 weeks of age. Peripheral NCV (sural nerve) was reduced in both MISO-treated and control mice with hind-limb tumour implants, presumably owing to physical pressure due to tumour growth. In addition, neither the medial nerves nor the tibial nerve in the normal limbs of the tumour-implanted, drug-treated animals showed any change. Consequently our earlier and present studies do not confirm the recent reports of changes in NCV following either acute or chronic MISO administration to mice.

Animals↗
PubMed1980

The effect of misonidazole on some physiologic parameters in mice.

The physiologic effects of misonidazole (Ro-07-0582) were studied in BALB/cKa mice injected i.p. at 0.5 to 1.5 mg/g b.wt. A 2--4 degree C reduction of body core temperature was observed in unanesthetized mice: the duration and degree of effect were dependent on dose. Normal core temperatures were restored when the serum level of misonidazole had fallen to 0.5 microM (100 micrograms/ml). Misonidazole (1 mg/g) produced a rapid postinjectional drop of heart rate (40%), respiration (45%) and body core (4 degrees C) temperatures which gradually returned to preinjection values 6 to 8 hr later. In addition, misonidazole administration (1 mg/g) enhanced the overall effect on body temperature induced by hexobarbital anesthesia by a factor of approximately 3. These results are discussed in relation to the use of mouse model tumor systems to give an estimate of the magnitude of the cytotoxic effect of misonidazole expected in humans.

Animals↗
PubMed1980

Cytotoxicity of hypoxic cell sensitizers in multicell spheroids.

Multicell tumor spheroids of EMT6/Ro cells were used to evaluate the cytotoxicity of several hypoxic cell sensitizers. The number of clonogenic cells per spheroid was determined after different exposure periods and concentrations of misonidazole, Ro-05-9963, and SR 2508 which have similar electron affinities. The kinetics of cytotoxicity were similar for each drug and the clonogenic fraction was reduced by about 0.5 to a plateau level after 24 hours at 3.0 mM for spheroids grown in 20% O2. Extended exposure periods caused additional cytotoxicity for both Ro-05-9963 and SR 2508. Lower concentrations (0.5 mM) of these sensitizers were not cytotoxic even in spheroids grown in low concentrations of oxygen (2.5% O2) to increase the hypoxic fraction. However, at cytotoxic concentrations (3.0 mM) spheroids grown in this low oxygen concentration exhibited almost twice as much cytotoxicity. No cytotoxicity was produced at 3.0 mM misonidazole in small spheroids without necrotic centers and hypoxic cells. In addition to being cytotoxic, continuous exposure of spheroids to high concentrations (3.0 mM) of misonidazole were cytostatic. The spheroid experiments were predictive of the relative effectiveness of the different sensitizers for EMT6/Ro tumors in vivo but the rate and extent of cytotoxicity was greater in tumors especially at low concentrations. In both spheroids and tumors there was little change in growth rate after 24 hours or single intraperitoneal exposures respectively, even with concentrations which reduced the clonogenic fraction by 0.9. This was related to a rapid repopulation of cells and increase in growth fraction after misonidazole cytotoxicity. Addition of adriamycin immediately after misonidazole cytotoxicity resulted in an apparent supra-additive overall response. The significance of these results for interpretation of tumor properties and responses in vivo and for tumor therapy were discussed.

Animals↗
PubMed1980

Selective dissociation and characterization of cells from different regions of multicell tumor spheroids.

A technique has been developed which takes advantage of the spherical symmetry of EMT6/Ro multicellular tumor spheroids to isolate subpopulations of cells originating from various locations in the spheroid structure. The method involves gently exposing spheroids to a dilute trypsin solution at 18 to 20 degrees in specially designed dishes on a rotary shaker. Under these conditions, cells are released only from the outer spheroid surface; successive trypsin treatments dissociate cells from increasing depths in the spheroid. Measurements of the spheroid diameter and rate of cell dissociation demonstrated the reproducibility of the technique. Observations of histological sections showed that trypsin was active only over a small distance into the spheroid. Characterization of the cells isolated indicated that cell volume, membrane integrity, and clonogenic capacity all decreased for cells located in inner spheroid regions. Autoradiography and DNA content analysis by flow cytometry established that outer region cells were actively proliferating while inner region cells were in a nonproliferative state. There was a significant number of cells arrested with S- and G2-phase DNA contents as well as a large number arrested with a G1 DNA content, similar to recent findings for nonproliferating cells in tumors.

Animals↗
PubMed1979

Morphological and functional characteristics of cells infiltrating and destroying tumor multicellular spheroids in vivo.

EMT6 mammary sarcoma cells were grown in vitro as multicellular spheroids to model for the heterogeneity of microenvironments and structural changes which develop in many tumors, including micrometastases. Spheroids of 700-900 micron diameter were implanted into and recovered at different times from the peritoneal cavities of sensitized or nonsensitized allogeneic and syngeneic mice. The colony forming efficiency of spheroid tumor cells recovered at 24 and 48 h from sensitized allogeneic mice was markedly decreased as compared with those from nonsensitized allogeneic or syngeneic animals. These recovered spheroids were extensively infiltrated by both lymphocytes and macrophages, which ultrastructurally had very close membrane associations with tumor cells. Host cells recovered from spheroids exhibited cytotoxic activity in an in vitro 51Cr release assay. Thus, multicellular spheroids in vivo provide a unique experimental model to study the functional capacity of host cells within a spheroical tumor. Although lacking the stroma and the vasculature of in vivo solid tumors, this model does have many similarities to in vivo tumors and is thus suitable for studying the tumor cell-host cell interactions within the tumor microenvironment. In addition, the system offers the potential for quantitative study of the effects of treatment modalities on tumor cell-host cell interactions.

Animals↗
PubMed1978

Effect of weak magnetic fields on growth of cells in tissue culture.

Normal Chinese hamster V79 cells were grown in vitro for more than one year in a magnetic field of 10(-7) tesla to test recently hypothesized effects of weak magnetic fields on biological systems. No significant difference was observed between growth rate in such fields and that in the ambient geomagnetic field.

Cell Division↗
PubMed1977

Multicellular spheroids: a new model target for in vitro studies of immunity to solid tumor allografts.

Multicellular spheroids of EMT6 mammary sarcoma cells of BALB/c origin were incubated with normal spleen cells or alloimmune spleen cells generated in vitro in mixed leukocyte cultures (MLC). After 24 hours, spheroids were trypsinized and assayed for surviving tumor cells by use of a cloning technique. Under these conditions a 60-80% reduction in clone-forming tumor cells was observed after incubation of spheroids with immune lymphocytes as compared to normal lymphocyte controls. This cytotoxic effect occurred in situ, and alloimmune cells sensitized against unrelated antigens were much less cytotoxic than were specifically sensitized cells. In parallel autoradiographic studies, some immune lymphoid cells that had been labeled with tritiated thymidine during the proliferative phase of the MLC could be demonstrated within spheroids after 24 hours. These results suggested that multicellular spheroids will be a useful in vitro model for more detailed analysis of the factors controlling infiltration in in situ destruction of solid tumor grafts.

Animals↗
PubMed1977

Effect of metronidazole on the C3H/HeJ mouse and growth of the C3HBA mammary adenocarcinoma.

Metronidazole (0.6 mg/gm) was injected intraperitoneally at 12 hour intervals for 10 days into C3H/HeJ mice with established C3HBA mammary adenocarcinomas. Tumor growth, total white cell count and body weight were decreased by 3 days. Heart rate and rectal temperature were depressed most following the initial injections but were less depressed by 10 days. Hemoglobin and hematocrit were not changed. Plasma assays of total protein, uric acid, bilirubin, alkaline phosphatase and calcium were not affected. It was not possible to separate the tumors treated with metronidazole from control tumors, based on cellular differences. Blood vessels in most of the tumors in the drug treated animals were larger and appeared engorged with blood.

Adenocarcinoma↗