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Biomedical subjects

R B Epstein

Publications and source records attributed to R B Epstein.

At least 37 records · Page 2Linked to original sources
PubMed1986

Radiation-induced hemopoietic death in mice as a function of photon energy and dose rate.

Radiation-induced hemopoietic death was measured in mice exposed to photons of four different energies: 250-kVp X rays, 60Co gamma rays (1.25 MeV), and 6- and 25-MV photons from a linear accelerator. For each radiation source, the lethal dose which killed 50% of the population in 30 days (LD50/30) associated with the hemopoietic syndrome was determined in groups of mice exposed to graded doses from 600 to 1150 cGy at dose rates of 20, 40, and 80 cGy/min. The calculated LD50/30 values for 25 and 6 MV were significantly different from each other at all exposure rates while no difference was observed between 6 MV and 60Co. Using 60Co gamma rays as the standard, the relative biologic effectiveness was as follows: 250 kVp greater than 25 MV greater than 6 MV = 60Co. The data suggest that there may be a greater damage to tissue within the marrow cavities following exposure to very high megavoltage radiation, a factor which must be considered with the increasing utilization of linear accelerators in the clinic and laboratory.

Animals↗
PubMed1985

Treatment of systemic candidiasis in neutropenic dogs with ketoconazole.

The present study evaluated the activity of ketoconazole in neutropenic dogs with systemic candidiasis. Five dog pairs were made neutropenic by intravenous cyclophosphamide (50 mg/kg) and challenged with either 10(6) or 10(7) colony-forming units (CFU) of Candida albicans. Half of the dogs received ketoconazole (10 mg/kg) daily beginning 24 h after challenge. All were killed at 96 h and liver, spleen, and kidney were cultured. Of four dogs given 10(6) CFU, two untreated dogs had 9 X 10(3) to 1 X 10(5) CFU/g wet tissue, compared to 0 CFU in ketoconazole-treated dogs. With inoculum increased to 10(7) CFU, three untreated dogs had 2 X 10(4) to 3 X 10(5) CFU/g wet tissue, while three ketoconazole dogs had 0-5 X 10(3) CFU/g wet tissue. The effect of ketoconazole on autologous marrow reconstitution in dogs with systemic candidiasis was examined by infusing autologous cryopreserved marrow into four dogs one day after lethal whole body irradiation (800 rad). Once neutropenic, they were challenged with 10(7) CFU of C. albicans. Two dogs received no ketoconazole and died of disseminated candidiasis, without marrow reconstitution. Two dogs received ketoconazole for 25 days. Prompt marrow recovery occurred and they remained healthy. There was no evidence of infection at death. These studies quantitatively demonstrate the in vivo effectiveness of ketoconazole in reducing tissue infection with C. albicans in neutropenic dogs. They provide in vivo evidence that ketoconazole can prevent or cure systemic candidiasis in the bone marrow transplant setting without significant inhibition of marrow recovery.

Agranulocytosis↗
PubMed1983

Serum cyclophosphamide activity in patients treated for small cell carcinoma of the lung.

Cyclophosphamide requires in vivo activation for its cytotoxicity. A bioassay of serum cyclophosphamide activity based on inhibition of normal peripheral blood CFU-C by serum from cyclophosphamide-treated patients was developed. Seventeen patients with small cell cancer of the lung were studied before and after cyclophosphamide administration in an attempt to correlate serum cytotoxicity in vitro with clinical response to chemotherapy. A correlation (r = 0.61, p less than 0.01) was discovered between serum cytotoxicity in vitro and subsequent leukopenia in vivo. However, a dose-response relationship was not found between serum cytotoxicity and response to chemotherapy. Besides drug dosage and blood level, other factors govern the sensitivity of small cell lung cancer to chemotherapy.

Biotransformation↗
PubMed1981

Kinetics and effects of activated cyclophosphamide in serum.

The effects of sera containing in vivo activated cyclophosphamide were tested on macrophage granulocyte colony growth (CFUc) and mixed leukocyte cultures (MLC). Bone marrow reconstitution and the growth of a canine tumor after incubation of transplanted cells with active sera were studied in vivo. The following experiments were performed: 1) peripheral blood CFUc values were determined in 6 dogs 5 min to 72 h after intravenous administration of 100 mg/kg cyclophosphamide. Inhibition was apparent at 5 min and lasted for 24 h. 2) Sera samples were obtained from 10 dogs after cyclophosphamide administration. The half life of serum inhibitory activity measured against normal dog cells was approximately 6 h. Inhibitory effects were noted 5 min following drug administration and complete at 30 min. 3) Timed incubation with 1 h postcyclophosphamide sera revealed preferential inhibition of MLC activity compared to CFUc activity, 4) In vitro incubation for 30 min in active sera did not affect the bone marrow repopulating potential of hematopoietic cells compared to nonincubated cells. 5) At least a tenfold reduction in the growth potential of a transplantable canine tumor could be produced by in vitro incubation of tumor cells with active sera. It is concluded that varying sensitivities of hematopoietic, immunocompetent and tumor cell populations to cyclophosphamide metabolites may provide a basis for in vitro chemoseparation of mixtures of these cell types.

Animals↗
PubMed1980

Immunosuppressive effects of rabbit anti-canine brain serum.

Liver absorbed rabbit anticanine brain serum (ABS) was tested for its immunosuppressive capacities in dogs. Single intravenous injection of ABS led to significant decrease in lymphocyte counts and functions after 24 hours, as measured by phytohemagglutinin stimulation and mixed lymphocyte culture. The immunosuppressive effectiveness of ABS could further be documented by prolongation of skin graft survival in unrelated dogs which were treated daily for 12 days with intramuscular ABS injections. The ABS was generally well-tolerated. One dog died of pneumonia. All dogs showed moderate decrease in platelet counts after 10 days of ABS treatment. Autopsies showed normal cerebral histology, moderate lymphoid hypoplasia, and no changes in the bone marrow and liver. The results suggest that liver absorbed anti-canine brain serum is a potent immunosuppressant with limited toxicity.

Animals↗
PubMed1980

Plasmapheresis as immunotherapeutic modality in the treatment of the canine venereal tumor.

Plasmapheresis was evaluated as a treatment modality for the transmissible venereal tumor (TVT) of the dog. The TVT is a unique tumor because of its capability for transplantation as a homograft between untreated randomly bred dogs and is characterized by the presence of dog leukocyte antigen (DLA) determinants on its tumor cells and reactivity in the mixed leukocyte tumor cell culture (MLTC). In the progressing phase, high titers of blocking antibodies measurable in the MLTC were noted. The purpose of this study was to evaluate the influence of plasmapheresis on the growth of established TVT and to correlate tumor response with the removal of blocking factors. Six pairs of DLA-identical dogs were used as experimental and control animals. Plasmapheresis was performed by discontinuous centrifugation using the Hemonetics model 30. An average of 1100 +/- 120 ml of plasma was exchanged on consecutive days during the third week after tumor injection. Consistently lower growth rates were observed in 2 experimental dogs, but there was no early rejection. Sera taken at day 14 of tumor growth contained significant blocking activity in all 12 dogs. Sera obtained post-plasmapheresis showed a decrease of blocking activity in all 6 experimental dogs, P less than 0.001. The TVT appears to be a suitable model for preclinical studies of plasmapheresis alone and in combination with other modalities.

Animals↗
PubMed1980

Autologous bone marrow infusion following high dose chemotherapy of the canine transmissible venereal tumor (TVT).

The present study was undertaken to evaluate infusion of cryopreserved autologous bone marrow following supralethal chemotherapy in canines bearing a solid tumor thought to be moderately sensitive to cytotoxic agents. Initial studies in 5 dogs established a combination of busulfan (Bu) 3 mg/kg X 2 days and cyclophosphamide (Cy) 50 mg/kg on day 3 to produce bone marrow lethality within 14 days (high dose regime). Bu 1 mg/kg, Cy 20 mg/kg produced tolerable toxicity (low dose regime). Eight pairs of dogs were challenged with 3 X 10(8) transmissible venereal tumor cells. Measurable progressive tumor growth occurred in all instances. Marrow aspirated from the femoral shafts of the animals was cryopreserved in 10% DMSO. One dog of each pair received the high dose Bu + Cy regime followed in 30 h by marrow infusion and his partner received the low dose regime without marrow. Tumors were measured serially for at least 2 months. Infusion of marrow resulted in evidence of hematologic recovery within 2 weeks following the high dose regime. Tumor responses occurred in both groups when compared to 8 untreated tumor challenged controls. High dose animals had greater initial responses than low dosed dogs but long term responses were not significantly different. Eight dogs rechallenged with tumor cells after initial successful therapy failed to develop tumors. It was concluded that: a) cryopreserved autologous bone marrow infusion was effective in protecting tumor bearing canines from otherwise lethal chemotherapy; b) the transmissible venereal tumor of canines responded to both high and low dose regimes; c) the rescue of dogs by stored autologous marrow did not offer additional benefits in tumor control over a standard regime; d) chemotherapy treated dogs resisted tumor rechallenge. This model may offer a large animal system to study the autologous marrow rescue concept during controlled periods of tumor evolution.

Anemia, Aplastic↗
PubMed1979

The collection, preservation and function of peripheral blood hematopoietic cells in dogs.

Semicontinuous flow centrifugation (SFC) was employed in canines to obtain adequate numbers of cells for autologous marrow repopulation following supralethal cyclophosphamide administration (100 mg per kg). Four cycles using a 225 ml bowl and 30 ml per minute flow rate were carried out for procurement. Collections averaged 8.4 +/- 0.4 x 10(9) (n = 30) leukocytes. Mononuclear cells (MNC) comprised 75 +/- 2% of the population and granulocyte colony-forming units (CFU-C) totaled 1.9 +/- 0.09 x 10(5) colonies per collection. Eighty-six percent of mononuclear cells were "T" cells in the 30 to 90 second fraction compared to 49% at 150 to 120 seconds. CFU-C fractionation revealed a peak at 30-210 seconds and a second peak at 120-210 seconds. Following programed freezing and rapid thawing 77.7 +/- 11.4% of CFU-C were recovered. Using a dose of 1 x10(9) MNC per kg for reinfusion, marrow repopulation and clinical recovery occurred in four out of four dogs. It was concluded that 1) SFC was effective for obtaining adequate numbers of peripheral blood stem cells for autologous marrow repopulation. 2) A rapid thawing and direct transfusion technique appears satisfactory for administration. 3) Some separation of "T", "B" and CFU-C peripheral blood components is possible by centrifugation.

Animals↗
PubMed1979

Processing of peripheral blood stem cells for transplantation.

Canines were studied to determine the efficacy of peripheral blood collection by semicontinuous centrifugation to procure sufficient numbers of hematopoietic cells for marrow reconstitution. CFU-C assays on fresh and cryopreserved peripheral blood cells were compared to bone marrow aspirates. Attempts were made to partially separate hematopoietic cells from immunocompetent cells during buffy coat collection and by incubation with activated cyclophosphamide. Yields from 4 runs of semicontinuous centrifugation averaged 1.7 x 10(5) CFU-C compared to 1.9 x 10(5) CFU-C for standard marrow aspiration. Ratios of approximately 5/1 marrow to peripheral blood mononuclear cells (MNC) were found. Autologous transplantation with 1.6 x 10(4) CFU-C per kg resulted in evidence of marrow reconstitution within two weeks following otherwise lethal chemotherapy. Recovery of CFU-C following cryo-preservation was 82% for marrow and 78% for peripheral blood. Selective depression of MLC activity occurred when peripheral blood MNC were incubated for 30 minutes with activated cyclophosphamide. MLC was inhibited by greater than 90% while 70% of CFU-Cs were retained. It was concluded that peripheral blood may be a practical alternative to marrow for transplantation studies.

Animals↗
PubMed1979

Isolation and characterization of canine venereal tumor-associated inhibitory and blocking factors.

Spontaneous regression of the canine venereal tumor is associated with the production of a serum factor which inhibits in vitro tumor colony-forming units in agar. Logarithmic or persistent tumor growth, on the other hand, is characterized by a serum factor which protects cells against in vitro inhibition (blocking factor). These factors have been characterized by immunochemical methods. Whole regressor and blocking sera were fractionated by Sephadex G-200 filtration and immunoabsorption with rabbit antiserum specific for canine immunoglobulin G2a. Fractions were characterized by immunoelectrophoresis, radial immunodiffusion, and disc gel electrophoresis. In vitro inhibitory and blocking activity of the whole serum was accounted for by the purified immunoglobulin G2a. Blocking activity was also found in protein eluted from logarithmically growing tumors. Preparative polyacrylamide electrophoresis revealed five major fractions with blocking activity only in the immunoglobulin G fraction. Tumor eluates and immunoglobulin G isolated from serially removed tumors demonstrated with the clinical course of the tumor. Using ultrafiltration and sodium dodecyl sulfate electrophoresis of tumor-associated immunoglobulin G at low pH, it was not possible to identify an antigen complexed to the blocking antibody.

Animals↗
PubMed1978

Cytogenetic evidence for recurrence of acute myelogenous leukemia after allogeneic bone marrow transplantation in donor hematopoietic cells.

A 22-yr-old man with acute myelocytic leukemia received a bone marrow transplant from a genotypically HLA-identical female sibling after cyclophosphamide preparation. He remained in complete remission for 18 mo, when he developed a chloroma in the perineum. The chloroma was treated with local radiotherapy. The chloroma recurred 8 mo later and was treated with radiotherapy followed by combination chemotherapy. At 34 mo after transplant, marrow relapse and chloroma were documented. The first chloroma contained host cells by fluorescent Y-chromatin body analyses of interphase nuclei. All metaphase cells and karyotypes from peripheral blood and marrow samples showed no evidence of host cells from 3 wk after transplant through the time of marrow relapse. Data from autosomal and sex chromosome studies indicate that the marrow relapse occurred in cells of donor origin. A new consistent chromosome abnormality [45, X, -X, t(8;21) (q22; q22)] was observed in a majority of donor cells. The patient received a second bone marrow transplant from the same donor after preparation with busulfan and cyclophosphamide and attained a complete remission with full hematologic engraftment.

Adult↗