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D S Coffey

Publications and source records attributed to D S Coffey.

At least 91 records · Page 5Linked to original sources
PubMed1988

Aromatase inhibition in the dog. I. Effect on serum LH, serum testosterone concentrations, testicular secretions and spermatogenesis.

Chronic treatment of intact male beagles with an orally active nonsteroidal aromatase inhibitor (4-(5,6,7,8-tetrahydroimidazo [1,5a] pyridin-5-yl) benzonitrile hydrochloride; CGS 16949; CIBA-GEIGY) at a dosage of 2.5 mg./kg. per day for six months resulted in increased (p less than 0.01) serum LH and testosterone concentrations compared to placebo-fed controls. The increases in serum LH and testosterone concentrations occurred by one week of treatment and were maintained over the six month period. Testes of CGS 16949A fed dogs obtained at termination of the experiment when perfused in vitro in the presence of a maximally stimulating concentration of LH secreted nondetectable amounts of estradiol and estrone and higher (p less than 0.01) amounts of testosterone, androstenedione and dihydrotestosterone than testes of control dogs. Despite these changes in androgen secretion there was no evidence on any effect of aromatase inhibition upon spermatogenesis. These data support the hypothesis that in the dog, estrogens play a major role in negative feedback of the hypothalamic-pituitary-testicular axis.

Animals↗
PubMed1988

Aromatase inhibition in the dog. II. Effect on growth, function, and pathology of the prostate.

To evaluate the role of aromatase inhibitors in the treatment of benign prostatic hyperplasia (BPH), the effects of a potent, oral, nonsteroidal aromatase inhibitor [4-(5,6,7,8-tetrahydroimidazo[1,5a]pyridin-5yl)benzonitrile; CGS-16949A, CIBA-GEIGY] on canine BPH have been studied. Twelve mature beagles with enlarged prostates were divided into two groups of similar age, prostatic size, and prostatic histology. Dogs were given either CGS-16949A at a dosage of 2.5 mg./kg./day p.o. (n = 6) or an oral placebo (n = 6) for 25 weeks. Treatment with aromatase inhibitor had no significant effect on prostatic weight nor on total DNA content when compared to controls (p greater than 0.1). Semen volume did not change with treatment, and prostatic tissue concentrations of testosterone, dihydrotestosterone (DHT), and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were similar for the treated and control beagles (p greater than 0.1). Protein concentration in the ejaculate, however, was significantly greater for the dogs receiving CGS-16949A (p less than 0.01). Histologically, there was no difference in the incidence or type of BPH between the two treatment groups. Beagles treated with aromatase inhibitor, however, did have a more severe inflammatory infiltrate of the prostatic parenchyma than the control dogs (p less than 0.01). The mean serum testosterone concentration for the beagles treated with aromatase inhibitor was 10 times greater than that for the control animals (p less than 0.01). The endocrine effect of this aromatase inhibitor in the male canine is presented in the preceding paper. Taken together, these results suggest that inhibition of endogenous aromatase activity is not an effective treatment for spontaneous BPH in the intact canine.

Animals↗
PubMed1988

Nuclear roundness factor measurement for assessment of prognosis of patients with prostatic carcinoma. I. Testing of a digitization system.

Standard pathological grading systems for prostatic carcinoma based upon glandular architectural pattern or nuclear anaplasia have failed to predict the prognosis of individual patients. Quantitative morphometric analysis of nuclear shape has predicted the outcome of patients with prostatic carcinoma when evaluated by some but not all reported studies. Calculation of nuclear roundness factor by different investigators was complicated by equipment differences and lack of standardized methods for acquiring and reporting data. We have improved our system for nuclear contour digitization and determined its theoretical limitations by digitizing standardized objects. Measurement errors were independent of orientation or location of an object within a microscopic or digitizer tablet field, speed of digitization and introduction of a microscope extension tube and light emitting diode cursor. Perimeters and areas of circles and squares of actual or digitizer-projected diameter or sidelength greater than five mm. were measured with a reproducibility and accuracy of greater than or equal to 90%. When a microscopic circle of diameter similar to prostatic carcinoma nuclei was digitized at a magnification of 2580 X, perimeter and area measurements differed within or between observers by less than 5% and were more than 95% accurate. In order to calculate accurately and evaluate NRF for use in assessing the prognosis of patients with prostatic carcinoma investigators must precisely describe their digitization system, standardization method and observer reproducibility and accuracy when measuring circles that approximate the projected size of prostatic carcinoma nuclei.

Carcinoma↗
PubMed1988

Nuclear roundness factor measurement for assessment of prognosis of patients with prostatic carcinoma. II. Standardization of methodology for histologic sections.

A nuclear shape descriptor, nuclear roundness factor, predicted outcome in patients with prostatic carcinoma whereas standard pathological grading by Gleason's architectural pattern did not. The inability of others to duplicate those successes warranted a reevaluation of the technique for NRF measurement. We previously described our digitization system and measured the perimeter and area of a microscopic circle similar in size to prostatic carcinoma nuclei with a reproducibility and accuracy of greater than 95%. We have applied our improved system to nuclear contour digitization and standardized our method for NRF measurement. In order to calculate accurately the NRF for prostatic carcinoma, the histologic section must have been reviewed by a pathologist and 150 nuclei traced after random selection. NRF measurement reproducibility within and between observers exceeded 90%. This system for NRF measurement successfully predicted outcome in 13 of 15 patients with stages A2, B1, and B2 prostatic carcinoma. Our success with a carefully tested and improved system for NRF determination warrants further evaluation of NRF for assessment of prognosis of patients with prostatic carcinoma.

Carcinoma↗
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

Growth-related elevations of DNA topoisomerase II levels found in Dunning R3327 rat prostatic adenocarcinomas.

The relationship between DNA topoisomerase II expression and mammalian cell proliferation has been evaluated by determining enzyme levels in normal and neoplastic rat prostate tissues. By activity assay and by immunoblot analysis using anti-topoisomerase II antiserum, topoisomerase II levels were found to be elevated in both the Dunning R3327-H and the Dunning R3327-G rat prostatic adenocarcinomas over levels assayed in the normal rat dorsal prostate. Immunohistochemical studies using the antitopoisomerase II antiserum revealed that a greater fraction of nuclei contained detectable levels of topoisomerase II in tissue sections prepared from each of the Dunning tumors than in rat dorsal prostate tissue sections. The Dunning R3327-H and R3327-G tumors grow at different rates in vivo (J. T. Isaacs and D. S. Coffey, Clin. Oncol., 2: 479-498, 1983). When measured topoisomerase II levels were compared to known growth parameters for each of the tissues studied, topoisomerase II expression was found to be correlated with tissue growth rate.

Adenocarcinoma↗
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

Prediction of metastatic potential by a new grading system of cell motility: validation in the Dunning R-3327 prostatic adenocarcinoma model.

Many grading systems for prostatic carcinoma exist; however, none allows pathologists to accurately predict the prognosis of individual patients. Examination of dead fixed histological sections of malignancies may not be the best way to predict the biological behavior of living dynamic tumors. We have developed a grading system that reproducibly characterized the motility of living cancer cells. In the Dunning R3327 rat prostatic adenocarcinoma model, three sublines of high metastatic potential (greater than 90%) were distinguished from four sublines of low metastatic potential (less than 10%). Individual cells from these sublines were correctly identified as high or low metastatic in 96% of cases by grading membrane ruffling, pseudopodal extension, and vectoral translation.

Adenocarcinoma↗
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

Time lapse videomicroscopic identification of Dunning R-3327 adenocarcinoma and normal rat prostate cells.

A method for accurate prediction of prognosis in human prostatic cancer does not exist. The limitations of pathologic grading systems may result from the failure of standard pathological examination of fixed dead tissue to accurately assess the biological behavior of live tumor cells. Many of the sublines of the Dunning R-3327 rat adenocarcinoma are histologically similar yet differ widely in their metastatic potential. The nonmetastatic G, occasionally metastatic AT-1 and AT-2, and highly metastatic AT-3 and MAT-Lu Dunning sublines, and normal dorsal prostate were grown in culture and filmed by time-lapse videomicroscopy. Cell membrane ruffling, undulation and pseudopodal extension, vectoral translation, irregularity of pathway, and overall subjective motility (gestalt) were visually graded. Intra-assay, intra-observer, and inter-observer reproducibility were 75, 80 and 75% respectively. The combination of ruffling, pseudopodal extension and vectoral translation was most successful in identifying the six sublines. To validate this technique prospectively, five tumor sublines and two normal prostates were graded by 10 observers unfamiliar with the technique. Fifty-nine percent of unknowns were correctly identified when motility profiles were compared to previously developed standards by least sum of squares analysis. We devised a new technique for characterizing the motility of living prostate cells which was more accurate in identifying normal rat prostate and the Dunning sublines than standard pathological examination. Prostatic cancer cell motility may reflect biological behavior and metastatic potential and thus contribute to the assessment of an individual patient's prognosis.

Adenocarcinoma↗
PubMed1987

Light-microscopic stereologic analysis of spontaneous and steroid-induced canine prostatic hyperplasia.

A combined light-microscopic and stereologic analysis of the canine prostate was performed under the following experimental conditions: intact and castrated dogs, spontaneous benign prostatic hyperplasia, intact and castrated dogs after treatment with testosterone, 5 alpha-dihydrotestosterone or 3 alpha-androstanediol in combination with estradiol. Regarding the absolute amounts of the glandular and stromal parts of the prostate as well as the glandular cells, no difference was found among the testosterone, 3 alpha-androstanediol and 5 alpha-dihydrotestosterone treated castrated dogs. Treatment with 5 alpha-dihydrotestosterone or 3 alpha-androstanediol in combination with 17 beta-estradiol induced a four-fold increase in glandular and a two-fold increase in stromal tissue. The glandular to stromal tissue ratio equals that found in spontaneous canine hyperplasia, which is indicative of the glandular type of spontaneous canine hyperplasia. Therefore, it can be stated that treatment with 5 alpha-dihydrotestosterone or 3 alpha-androstanediol combined with 17 beta-estradiol not only induces prostatic overgrowth but also leads to prostatic hyperplasia of the glandular type. However, the stereologic analysis of canine prostates following steroid administration shows that canine hyperplasia is primarily a glandular disease, while human benign prostatic hyperplasia shows more stromal activation.

Androstane-3,17-diol↗
PubMed1987

Structural aspects of mammalian DNA replication: topoisomerase II.

The dynamic biology of mammalian DNA requires structural complexity. Previous studies on the structure and function of mammalian DNA have suggested that mammalian cell nuclei contain DNA organized into loop-domains by a nuclear structural subcomponent termed the nuclear matrix. The loop-domains, functioning as replicons during DNA synthesis, appear to be replicated by biosynthetic complexes located at fixed sites within the nuclear matrix milieu. Recently, we have found the mammalian DNA topoisomerase II enzyme to be associated with newly replicated DNA, and we speculate that the enzyme may be strategically positioned to untangle topologically intertwined daughter loop-domains before mitotic segregation. Further studies demonstrating growth-related elevations of DNA topoisomerase II levels in rat prostatic adenocarcinoma tissues support a role for the enzyme in cellular proliferation in vivo. The possible participation of DNA topoisomerase II in mammalian DNA replication and the proliferation-dependent appearance of the enzyme in neoplastic tissues may have important implications for therapeutic strategies directed at DNA topoisomerase II.

Animals↗
PubMed1987

Correlation of prognosis to nuclear roundness and to flow cytometric light scatter.

The application of quantitative pathology to the study of malignant tumors is discussed, with emphasis on the correlation between nuclear roundness and prognosis in prostatic carcinoma. Stage A2 prostatic carcinoma patients with 4-year follow-ups and surgically treated stage B1 and B2 prostatic carcinoma patients with 15-year follow-ups were characterized by manual digitization of cancerous nuclei. A form factor that assessed nuclear shape produced an accurate separation of those patients who developed metastatic disease from those who did not. The digitized nuclear roundness correlated with the perpendicular light scatter measured by flow cytometry. When combined with forward light scatter, perpendicular light scatter separated four tumor cell lines of different metastatic potential in an animal model of prostatic cancer; a relative grading index based on these findings seemed capable of identifying human patients with more extensive disease in a preliminary study. The observation of freshly aspirated viable prostatic carcinoma cells led us to appreciate membrane ruffling, pseudopodal extension and translational movements that appear to distinguish these cells from their benign counterparts. Time-lapse cinematography, image digitization and Fourier analysis allow for the objective description of cell motion and should provide new and exciting tools for the pathologist.

Cell Movement↗
PubMed1986

Effect of age, castration, and testosterone replacement on the development and restoration of canine benign prostatic hyperplasia.

An experiment was designed to test the effect of castration and testosterone replacement on the development of benign prostatic hyperplasia (BPH) in young and on the restoration of BPH in old beagles. Twenty beagles were divided by age into young (1.5-2.5-yr) and old (6.0-8.5-yr) groups. Each of these groups was further divided randomly into two additional groups of age-matched, intact, untreated control and castrate beagles. The latter were then treated with testosterone-filled Silastic implants designed to clamp serum testosterone at concentrations similar to those observed in adult beagles for 7 months beginning 5 months after castration. Histopathologic characterization of each prostate was completed on biopsy material obtained at the beginning and end of the experiment. Prostate weights were determined each month for 12 months via a noninvasive two-dimensional X-ray procedure. Testosterone treatment for 7 months allowed BPH to develop in young and restored BPH in old beagles. These results suggest that testosterone in the adult beagle acts permissively to allow BPH to develop in the prostate of the aging dog. Some other testicular product may be required for the continued growth of BPH in aged beagles.

Age Factors↗