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Biomedical subjects

W D Heston

Publications and source records attributed to W D Heston.

At least 73 records · Page 4Linked to original sources
PubMed1991

Is combined modality therapy appropriate for apparently localized carcinoma of the prostate?

In a pilot study at the authors' institution, 17 patients with stage C carcinoma of the prostate had preoperative therapy with diethylstilbestrol. After 8 to 12 weeks of DES at 3 mg per day, the surgical margins, seminal vesicles, and pelvic lymph nodes were free of tumor in seven patients. In one patient, no residual tumor could be found despite an extensive search, and in two other cases, only small foci of atypical cells could be found. The authors suggest a trial of the proper role of neoadjuvant hormonal therapy in stages B2 and C prostatic carcinoma.

Animals↗
PubMed1991

Future developments of nonhormonal systemic therapy for prostatic carcinoma.

Prostate cancer is the most common type of cancer in men. Despite increased public awareness and new screening methods, a significant proportion of men continue to present with metastatic disease. Most men will respond initially to hormonal intervention; however, given time, the majority will have recurrences of hormonally unresponsive tumor on which present therapies have little impact. Research continues to identify new cellular and molecular aspects of prostate cancer with implications as possible sites of therapeutic intervention.

Animals↗
PubMed1989

Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue.

Using Northern blot analysis, we have demonstrated that mRNA for transforming growth factor alpha (TGF-alpha) was expressed in five malignant kidney tissue specimens but was not detected in their autologous nonneoplastic homologues. In addition, the expression of epidermal growth factor (EGF) receptor mRNA in these malignant tissues was 2- to 3-fold greater than in nontransformed tissues. In two cases examined using immunohistochemistry, we were able to correlate the increased expression of the mRNA with an increase in protein expression. Since TGF-alpha is known to bind to the EGF receptor, the finding of an increased expression of both TGF-alpha and EGF receptor mRNA in kidney tumor tissue suggests that interaction between TGF-alpha and the EGF receptor may play a role in promoting transformation and/or proliferation of kidney neoplasms, perhaps by an autocrine mechanism.

Blotting, Northern↗
PubMed1989

Effect of coumarin on the normal rat prostate and on the R-3327H prostatic adenocarcinoma.

Coumarin, the parent compound of warfarin, has been observed to stimulate macrophages, increase phagocytosis, and induce changes in lymphocyte-mitogen responsiveness in cancer patients. Coumarin has been reported to have antitumor activity in human melanomas and renal cancer when used in conjunction with the H-2 antagonist, cimetidine. We have observed that coumarin has antiprostatic activity in rats. When coumarin was given to mature rats at a dose of 40 mg/kg, a significant decrease in the size of the prostate, seminal vesicles, and testes was observed. Testosterone levels were unchanged or slightly elevated, consistent with an antiandrogenic-like activity. Similarly, coumarin significantly inhibited the androgen-induced increase in prostatic size when administered to castrated rats receiving testosterone. Coumarin given to rats bearing the R-3327H androgen-sensitive, prostate-derived tumor decreased the size of the primary tumor. The effect was greater than that produced by castration. Coumarin is worthy of further consideration as an agent for use in controlling the normal and abnormal growth of the prostate.

Adenocarcinoma↗
PubMed1989

Cytotoxicity of high energy shock waves: methodologic considerations.

In vivo and in vitro experimentation with high energy shock waves (HESW) is necessary to further our understanding of the biologic effects and potential application of this novel energy form. Factors are identified which are critical to the design and subsequent interpretation of HESW experimentation. First, the nature of the containment vessel and the presence or absence of acoustic interfaces are shown to significantly alter the outcome of cell suspension experiments. Second, the effects of HESW are shown to differ markedly for cells in suspension versus cells in tissue making comparisons between the two uncertain. Finally, the need for appropriate negative controls is demonstrated with in vivo experiments to control for the generalized toxicity which occurs when small animals are exposed to such an intense force distributed over a relatively large area. These findings affect the interpretation of previously reported work which investigated the cytotoxic potential of HESW.

Animals↗
PubMed1988

Anticarcinoma activity of rhodamine 123 against a murine renal adenocarcinoma.

The mitochondria of carcinoma cells retain the permeant cationic compound rhodamine 123 longer than the mitochondria of normal epithelial cells. The possibility of exploiting this difference in the chemotherapy of a murine renal adenocarcinoma was investigated. Rhodamine 123 exhibited anticarcinoma activity in mice and this activity was potentiated by 2-deoxyglucose and methylglyoxal bis(guanylhydrazone), a chemotherapeutic agent that is toxic to mitochondria. Prolonged retention of rhodamine 123 by renal tumor cells compared with normal renal epithelial cells was demonstrated by flow cytometry, perhaps explaining its antitumor activity. A combination of both mitochondrial toxins, rhodamine 123 and methylglyoxal bis(guanylhydrazone) produced the longest survival and had the greatest antitumor effect.

Adenocarcinoma↗
PubMed1988

Heparin-binding growth factor isolated from human prostatic extracts.

Prostatic tissue extracts from patients with benign prostatic hyperplasia (BPH) and prostatic carcinoma were fractionated using heparin-Sepharose chromatography. The mitogenic activity of eluted fractions on quiescent subconfluent Swiss Albino 3T3 fibroblasts was tested employing a tritiated-thymidine-incorporation assay. Two peaks of activity were consistently noted--one in the void volume and a second fraction which eluted with 1.3-1.6 M NaCl and contained the majority of the mitogenic activity. Both non-heparin- and heparin-binding fractions increased tritiated incorporation into a mouse osteoblast cell line (MC3T3), while only the heparin-binding fractions stimulated a human umbilical vein endothelial cell line (HUV). No increased uptake of thymidine was seen using a human prostatic carcinoma cell line (PC-3). Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of lyophilized active fractions showed a persistent band at 17,500 daltons. The purified protein demonstrated angiogenic properties using the chick embryo chorioallantoic membrane (CAM) assay. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) or acidic FGF (aFGF) demonstrated that the former, but not the latter, bound to prostatic growth factor (PrGF), and inhibited its mitogenic activity as well. It appears that PrGF shares homology with basic fibroblast growth factors.

Allantois↗
PubMed1988

Expression of basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma.

In our previous work we demonstrated that prostate-derived growth factor (PrGF) is homologous to basic fibroblast growth factor (bFGF), not acidic fibroblast growth factor (aFGF). Using Northern blot analysis we now show that the messenger RNA for bFGF but not aFGF is expressed in benign prostatic hyperplastic (BPH) tissue as well as in carcinoma of the prostate (CAP). This not only corroborates our previous results, but suggests that PrGF is produced locally and not merely stored in the prostate. The demonstration of local production of bFGF by prostate tissue may indicate that this growth factor plays a role, either alone or in conjunction with other factors, in the etiology of benign hyperplasia or prostatic cancer.

Animals↗
PubMed1988

The effect of high energy shock waves (HESW) on human bone marrow.

The effect of High energy shock waves (HESW) on the viability and proliferation of normal human bone marrow cells was evaluated. A dose dependent increase in cytotoxicity with an increase in the number of HESW was demonstrated. In general 700 HESW immediately reduced the cell viability of bone marrow cells by 50%. The CFU-GM assay provides a method to evaluate the effect of HESW on the proliferative capacity of bone marrow. Following HESW treatment the colony forming ability of trypan blue excluding cells also felt in a dose dependent fashion, but some variation in sensitivity was noted. By comparing the sensitivity of various cells, the cells of normal human bone marrow were felt to be less sensitive to HESW effects than those of other tissue cultured cells or malignant cell lines.

Bone Marrow↗
PubMed1988

Characterization of a heparin-binding growth factor from adenocarcinoma of the kidney.

A polypeptide isolated from tissue extracts of renal adenocarcinoma was mitogenic for BALB/c 3T3 cells and human umbilical vein (HUV) cells in culture. It also demonstrated angiogenic ability using the chorioallantoic membrane bioassay. Using heparin-sepharose affinity chromatography the purified protein eluted with a NaCl concentration between 1.4 and 1.8 M and demonstrated a molecular weight of approximately 17,000 daltons based on SDS polyacrylamide gel electrophoresis. Half maximal stimulation of tritiated thymidine incorporation into BALB/c 3T3 cells was achieved by 1.6 ng./ml. of the heparin binding material. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) only or acidic FGF (aFGF) only demonstrated that the purified protein binds to the former and not the latter. The characteristics of this material, in effect the elution profile off heparin-Sepharose, the molecular weight, angiogenic activity and the results of western blot analysis, suggest that this growth factor is similar to the family of basic fibroblast growth factors.

Angiogenesis Inducing Agents↗
PubMed1988

Free radical production by high energy shock waves--comparison with ionizing irradiation.

Fricke chemical dosimetry is used as an indirect measure of the free radical production of ionizing irradiation. We adapted the Fricke ferrous sulfate radiation dosimeter to examine the chemical effects of high energy shock waves. Significant free radical production was documented. The reaction was dose dependent, predictably increased by acoustic impedance, but curvilinear. A thousand shocks at 18 kilovolts induced the same free radical oxidation as 1100 rad cobalt-60 gamma ionizing irradiation, increasing to 2900 rad in the presence of an air-fluid zone of acoustic impedance. The biological effect of these free radicals was compared to that of cobalt-60 ionizing irradiation by measuring the affect on Chinese hamster cells by clonogenic assay. While cobalt-60 irradiation produced a marked decrease in clonogenic survivors, little effect was noted with high energy shock waves. This suggested that the chemical effects produced by shock waves were either absent or attenuated in the cells, or were inherently less toxic than those of ionizing irradiation.

Animals↗
PubMed1987

Effects of intermittent diethylstilbestrol diphosphate administration on the R3327 rat prostatic carcinoma.

Clinical trials have utilized intermittent diethylstilbestrol diphosphate (DES) therapy in advanced symptomatic prostatic carcinoma to diminish the morbidity of standard endocrine therapy. To determine the effect of intermittent DES administration on the Dunning R3327 rat prostatic adenocarcinoma 60 days following tumor implant, 6 groups were randomly assigned: control (N = 8), castrate (N = 10), high dose DES (N = 8, 1.6 micrograms/ml DES continuously in drinking water), low dose DES (N = 10, 0.4 microgram/ml continuously in drinking water), intermittent high dose DES (N = 10, 1.6 micrograms/ml DES in drinking water for 1 week, then off for 3 weeks), and intermittent low dose DES (N = 10, 0.4 microgram/ml DES for 1 week, then off for 3 weeks). Results indicate that low or high dose DES, and intermittent low or intermittent high dose DES during the week of administration were able to reduce serum testosterone to castrate levels (0.1 ng/ml). After withdrawal of intermittent DES, serum testosterone returned toward control levels (1.0 ng/ml). Initial mean tumor burden between control and treatment groups was not significantly different. All DES exposed rats had a tumor volume at death (range, 15.6-18.3 cm3) smaller than control (mean, 25.4 cm3) or castrate (mean, 40.8 cm3) rats. Despite this significant survival advantage from the time of randomization was achieved only in castrate (median survival, 331 days) or high dose DES (median survival, 359 days) groups compared to control (median survival, 225 days). Similarly, significant prolongation in tumor doubling time was achieved only by rats receiving castration or high dose DES. Intermittent DES administration controls tumor volume but does not provide a survival advantage. In this respect, intermittent DES is inferior to castration.

Animals↗
PubMed1987

Cytotoxic activity of a polyamine analogue, monoaziridinylputrescine, against the PC-3 human prostatic carcinoma cell line.

We have previously demonstrated that prostate and prostate-derived rodent tumors can be manipulated into increasing their accumulation of radiolabeled putrescine by alpha-difluoromethylornithine (DFMO)-induced depletion of intracellular putrescine and spermidine. As methods which increase intracellular accumulation of cytotoxic agents often increase the chemotherapeutic effectiveness of the agent, we examined whether an alkylating derivative of putrescine would be cytotoxic to tumor cells. We present here our findings on the cytotoxicity of the aziridinyl derivative of putrescine (AZP) against prostatic cancer cells. The apparent Km for putrescine was 2.5 microM with or without DFMO pretreatment and the apparent Ki for AZP was 1 microM with or without DFMO pretreatment. Intracellular polyamine depletion by DFMO pretreatment resulted in a 3.7-fold greater accumulation of AZP compared to non-DFMO-treated cells. The growth inhibitory activity of AZP was increased with prior polyamine depletion by DFMO with the 50% effective dose decreasing from 18 microM to 2.1 microM. Putrescine was able to block the cytotoxic effect of AZP. Putrescine was also able to rescue the AZP-treated PC-3 cells for up to 6 h following a 1-h exposure to AZP. It appears that aziridinylputrescine behaves like putrescine in that it competes with putrescine for uptake into the cell and, like putrescine, has its uptake into the cell increased by prior polyamine depletion. It differs from putrescine in that it expresses cytotoxic activity and inhibits the growth of the human prostate-derived PC-3 cell line. This cytotoxic activity is also increased by prior polyamine depletion. The cytotoxic behavior of AZP is dependent both on the concentration and duration of exposure. Putrescine can rescue the cells from the effect of AZP. AZP is a potentially useful cytotoxic analogue that utilizes the polyamine transport system for its uptake into the cell.

Cell Line↗
PubMed1987

Histopathologic and ultrastructural correlates of tumor growth suppression by high energy shock waves.

High energy shock waves (HESW) are cytotoxic to tumor cells as determined by vital staining and impaired ability of viable cells to form colonies in a clonogenic assay. In addition, direct exposure of tumor nodules to HESW results in suppression of tumor growth rate. In order to identify histopathologic and ultrastructural correlates of these observations, R3327AT-3 prostatic tumor cells were exposed to HESW in vitro and in vivo. Damage to cells in suspension was manifested by fragmentation of cells to form debris. At the ultrastructural level, mitochondria were swollen and contained distorted cristae following exposure of tumor cells to HESW. In vivo exposure of tumor nodules to HESW did not cause a distinct histopathologic or ultrastructural effect that could be qualitatively distinguished from spontaneously occurring cell death. Hemorrhage and necrosis were observed in muscle and fibroadipose tissue adjacent to tumor. The mechanism of HESW-induced cytotoxicity is not clear from our studies. Evidence of damage of normal tissues exposed in vivo and tumor cells in vitro is reflected in histomorphological changes.

Animals↗
PubMed1986

Etoposide in prostatic cancer: experimental studies and phase II trial in patients with bidimensionally measurable disease.

Etoposide, a semisynthetic derivative of podophyllotoxin, was evaluated concurrently in vitro against a human derived hormone-resistant cell line, PC-3, and in vivo in bidimensionally measurable hormone-resistant human prostatic cancer. In vitro, a dose-response relationship was observed, with 74% inhibition at 10 micrograms/ml (1 h incubation) and greater than 99% inhibition at 90 micrograms/ml, both in the range of clinically achievable concentrations. In vivo, 1 PR (5%, 95% confidence limits 0-12%) of 18+ months was observed in 20 adequately treated patients. The results confirm the limited role of etoposide in hormone-refractory disease and the need for new model systems for evaluation of potential chemotherapeutic compounds in this disease.

Adenocarcinoma↗