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Biomedical subjects

R B Alexander

Publications and source records attributed to R B Alexander.

At least 55 records · Page 3Linked to original sources
PubMed1990

Transplantation in miniature swine: analysis of graft-infiltrating lymphocytes provides evidence for local suppression.

Previous studies from this laboratory have demonstrated that swine tolerant of class I disparate renal allografts show peripheral antidonor cellular reactivity which can be augmented by skin grafting. To assess the possibility of local suppression, cell-mediated lymphocytotoxicity of graft-infiltrating lymphocytes was compared to that of peripheral blood lymphocytes from three tolerant and four acutely rejecting recipients of class I--disparate renal allografts. Mixed lymphocyte cultures using peripheral blood lymphocytes or graft-infiltrating lymphocytes and an equal number of irradiated peripheral blood lymphocyte stimulators were incubated for 6 days and tested in a 6-hr 51Cr release assay. Graft-infiltrating lymphocytes from rejecting animals had potent antidonor cell-mediated lymphocytotoxic activity with or without in vitro stimulation. Anti-third-party reactivity was seen with appropriate stimulation, suggesting heterogeneity of graft-infiltrating lymphocyte cultures. Peripheral blood lymphocytes from rejectors generated donor-specific cell-mediated lymphocytotoxicity. Graft-infiltrating lymphocytes from tolerant animals generated no antidonor cell-mediated lymphocytotoxicity with or without in vitro stimulation, but generated an anti-third-party response. Peripheral blood lymphocytes from tolerant animals displayed both antidonor and anti-third-party reactivity with appropriate in vitro stimulation. These data support the hypothesis that local suppression may contribute significantly to maintenance of tolerance to class I disparate renal allografts in miniature swine.

Animals↗
PubMed1989

Pathological stage is higher in older men with clinical stage B1 adenocarcinoma of the prostate.

We examined the relationship between age and pathological stage in 444 consecutive patients who underwent pelvic lymphadenectomy and radical retropubic prostatectomy for clinically localized adenocarcinoma of the prostate. Pathological stage of cancer was determined postoperatively as organ-confined, capsular penetration (cancer through prostatic capsule), seminal vesicle involvement or lymph node metastases. Patient age ranged from 34 to 75 years. The majority of the patients had clinical stage B1 disease with induration confined to less than 1 lobe of the gland. In this group a statistically significant (p equals 0.001, chi-square test for trend) correlation between increased age and higher pathological stage was found. We also found that older men with clinical stage B1 disease had a statistically significant trend toward higher Gleason grade. An explanation for our findings might be the masking of prostatic induration by benign prostatic hypertrophy, clearly a disease of aging men. We suggest that increased age is a relative risk factor for advanced pathological findings in men with clinical stage B1 prostatic cancer.

Adenocarcinoma↗
PubMed1987

Future developments and new research in genitourinary cancers. Perspectives.

Significant advances in the therapy of genitourinary cancers have occurred, yet the challenge of metastatic disease in many of these tumors remains unsolved. The great success achieved in the treatment of testicular cancer has been in large part due to the development of effective systemic therapy. Effective treatment for metastatic transitional cell carcinoma is just beginning to be described. Advanced renal and prostatic carcinomas remain a major clinical problem with no effective curative therapy. Novel new approaches to systemic therapy developed on sound basic experimental principles are needed. Several potential approaches such as angiogenesis factor, interleukin II, lymphokine activated killer cells, and tumor necrosis factor are discussed.

Angiogenesis Inducing Agents↗
PubMed1987

Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II.

Recombinant human tumor necrosis factor (rHTNF) alone had no effect on L929 tumor cells at 100 units/ml for 20 h of continuous exposure. However, under the same conditions, rHTNF markedly enhanced the cytotoxicity of Adriamycin, actinomycin D, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, teniposide (VM 26), and etoposide (VP 16), all targeted at DNA topoisomerase II. The rHTNF had a minimally enhancing effect on the cytotoxicity of bleomycin, hydroxyurea, and 1-beta-D-arabinofuranosylcytosine and no effect on the cytotoxicity of cis-platinum, mitomycin C, vincristine, and vinblastine, all chemotherapeutic drugs with dose-related cytotoxic effects on L929 cells but mechanisms of action which do not appear to involve topoisomerase II. Treatment with rHTNF first and then topoisomerase-targeted drugs yielded no enhanced cytotoxicity, whereas pretreatment with drug followed by rHTNF yielded marked enhancement of cytotoxicity. Topoisomerases have previously been implicated in cell kill phenomena following treatment with certain chemotherapeutic agents [K.M. Tewey, et al., Science (Wash. DC), 226:466-468, 1984]. The data suggest that the lethality to the cell from topoisomerase-targeted drug treatment is increased by rHTNF in vitro. We suggest that rHTNF may be a useful adjuvant to this class of drugs which has well-known antitumor activity.

Animals↗
PubMed1987

Tumor necrosis factor enhances the in vitro and in vivo efficacy of chemotherapeutic drugs targeted at DNA topoisomerase II in the treatment of murine bladder cancer.

Recombinant human tumor necrosis factor (rTNF) is a macrophage secretory protein with antitumor activity. The murine bladder tumor cell line MBT-2 was used to evaluate the in vitro and in vivo antitumor effects of rTNF in combination with chemotherapeutic drugs targeted at DNA topoisomerase II. These drugs, such as adriamycin and etoposide (VP 16), are in widespread use in the treatment of human cancer. The rTNF significantly enhanced the cytotoxic efficacy of the topoisomerase-targeted drugs actinomycin D, adriamycin, etoposide (VP 16) and teniposide (VM 26) against MBT-2 cells in vitro. The rTNF alone had no effect upon the cells in the same assay. When examined in vivo using MBT-2 tumor-bearing C3H/HeJ mice, these same antitumor relationships were seen. The addition of rTNF to actinomycin D or VP 16 resulted in a significant reduction in tumor volume at 20 days compared to untreated animals. Actinomycin D, VP 16 or rTNF treatment alone had no significant effect on 20 day tumor volume. The data provide a reasonable basis for the addition of rTNF to experimental protocols for the treatment of human bladder cancer using topoisomerase-targeted drugs such as adriamycin both intravesically and systemically. These observations may also be relevant to other human cancers currently treated with these drugs.

Animals↗
PubMed1987

Estrogen receptors in the nuclear matrix: direct demonstration using monoclonal antireceptor antibody.

Estradiol-binding sites, as assayed by exchange with radiolabeled steroid, become associated with the nuclear matrix of estrogen-responsive tissues after treatment with estrogen in vivo. Using monoclonal estrogen receptor antibodies, we have now obtained direct evidence that these matrix-associated estradiol-binding sites are estrogen receptor proteins similar to those found in the cytosol before estrogen treatment. Proteins of the liver nuclear matrix from untreated or ethinyl estradiol-treated female rats were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose paper, and probed with the monoclonal estrogen receptor antibody H222Sp gamma. A single prominent immunoreactive 67,000 mol wt band, indicating the presence of estrogen receptors, was found in the liver nuclear matrix of estrogen-treated animals. This band was detectable, but of much lower intensity, in the liver nuclear matrix of untreated animals. Liver cytosol estrogen receptor from untreated rats also migrated as a 67,000 mol wt band. These immunoreactivity data corroborated data obtained by [3H]estradiol-binding assays. Scatchard analysis of specific high affinity [3H]estradiol-binding sites showed high levels of these sites in the liver nuclear matrix of estrogen-treated rats and low levels in untreated rats. Therefore, both direct and indirect methods of receptor identification demonstrate the specific association of estrogen receptors with the nuclear matrix after estrogen treatment in vivo.

Animals↗
PubMed1985

Comparison of anticonvulsive properties of eboracin and phenytoin in mice.

The in vivo effects of phenytoin (diphenylhydantoin, Dilantin) and the experimental anticonvulsant, eboracin, a substituted indenopyrrole, were compared in mice. Pretreatment with varying dosages of either agent followed by challenge with the chemoconvulsant pentylenetetrazol (Metrazol) indicated that eboracin provided slightly less protection against seizures than phenytoin and was much less toxic. Intermediate doses of either agent led to a form of clonic status epilepticus which persisted for an average of 18 min in phenytoin-treated and 58 min in eboracin-treated mice. Pretreatment with higher or lower doses did not lead to these manifestations. Animals in which this syndrome had been induced should be of value in studies of the chemistry and physiology of the clonic state.

Animals↗
PubMed1985

Immunogold probes for electron microscopy: evaluation of staining by fluorescence microscopy.

A method is presented whereby the staining of intracellular structures with immunogold probes for electron microscopy can be evaluated at the light microscopic level. Methanol-fixed monolayers of cultured Dunning R-3327-H rat prostatic adenocarcinoma cells were stained for cytokeratins using a two-step immunogold technique consisting of primary anti-keratin antibody followed by gold-labeled secondary antibody. Bound immunogold probe was then visualized with a fluorescent tertiary anti-immunogold probe antibody. Fluorescence microscopy of the whole cell monolayers showed a typical keratin cytoskeleton. The extra staining step did not interfere with subsequent fixation, embedding, and sectioning for electron microscopy, which showed cytoplasmic intermediate filaments decorated with colloidal gold. Using this method, it should be possible to manipulate parameters critical to staining with immunogold probes and to evaluate the labeling without necessitating repeated time-consuming electron microscopic processing. The method also provides a useful correlation between the light microscopic and ultrastructural labeling patterns of immunogold probes.

Adenocarcinoma↗
PubMed1981

Metrazol thresholds in inbred and non-inbred audiosensitive mice.

Mice of the O'Grady strain which were inbred for susceptibility to audiogenic seizures were found to be more sensitive to pentamethylenetetrazol (Metrazol) convulsions than mice of the parent Swiss-Webster strain from which they were originally derived. A dose of 35 mg/kg Metrazol was required to produce a 50% convulsive response (CD50) in O'Grady mice and 50 mg/kg in the control parent strain. No differences in convulsive thresholds to Metrazol were obtained, however, between untreated Swiss-Webster mice and mice of the same strain made audiosuseptible by rubidium chloride intake or magnesium deficiency.

Acoustic Stimulation↗
PubMed1980

Serotonin and norepinephrine: long-term decrease in rate of synthesis in brain of rats primed with p-chlorophenylalanine.

Rats which had been primed with the serotonin depletor, p-chlorophenylalanine, and sacrificed months later were found to have the same resting levels of brain serotonin and norepinephrine as unprimed controls. However, when treated with the monoamine oxidase inhibitor, tranylcypromine, the former showed a significantly lower accumulation of these biogenic amines than their tranylcypromine-treated unprimed counterparts. These findings indicate that brain serotonin, which had been lowered at the outset by p-chlorophenylalanine, had returned to normal levels but that the priming procedure might have resulted in a long-term decrease in the turnover rates of serotonin as well as norepinephrine. Primed animals may prove suitable as models of disturbed biogenic amine metabolism with possible relevance to schizophrenia and other brain dysfunctions.

Animals↗
PubMed1978

Alcohol consumption in rats treated with lithium carbonate or rubidium chloride.

Wistar-NTRU rats, offered a free choice between tap water and a 10% ethanol solution (v/v) in the absence of reinforcement, were injected for five days with Li2 CO3, RbCl or placebo. Lithium-treated group consumed 25% more liquid per day but chose to take 14.5% less alcohol than controls (p less than 0.05). By contrast, rubidium-treated animals consumed 15% less liquid but 70% more alcohol than control animals (p less than 0.005). Rubidium-treated rats were strikingly more active than the other two groups: their motility index was 60.0 as compared to 33.6 for lithium-treated and 29.4 for control rats. Serum glucose and urea nitrogen concentration were not significantly affected by the treatment but serum alcohol content was low in lithium-treated and high in rubidum-treated animals.

Alcohol Drinking↗
PubMed1967

LSD: injection early in pregnancy produces abnormalities in offspring of rats.

One of five rats given a single subcutaneous injection of lysergic acid diethylamide (LSD) early in pregnancy appeared to abort early; two delivered stunted stillborn offspring at term, one delivered a littler of seven healthy and one underdeveloped young, and the last one delivered an apparently normal litter. All five matched controls, given saline injections, went to term and delivered healthy litters of 11 to 16 offspring; there were no abortions and no stillbirths. In a replicate experiment, one of five rats given LSD on the 4th day of gestation aborted, two delivered some stillborn offspring, one gave an abnormally small litter of four, and the last one produced an apparently normal litter of ten. All matched controls delivered healthy litters, totaling 66. Some surviving offspring treated with LSD failed to develop as well as control animals. Treatment of five additional rats with LSD late in pregnancy had no obvious effect on the offspring.

Abnormalities, Drug-Induced↗