PubMed Health⌕ Search

Biomedical subjects

M S Steiner

Publications and source records attributed to M S Steiner.

At least 19 recordsLinked to original sources
PubMed2001

Apoptosis induction in prostate cancer cells by a novel gene product, pHyde, involves caspase-3.

A novel gene, pHyde, was recently cloned from Dunning rat prostate cancer cells. A recombinant adenovirus containing pHyde cDNA gene (AdpHyde) was generated to investigate the biological function of pHyde protein. AdpHyde inhibited the growth of human prostate cancer cells. Apoptosis was induced in AdpHyde transduced cells as demonstrated by DAPI (4', 6-diamino-2-phenylindole), TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) staining, and flow cytometry assays. Apoptosis was also induced in human xenograft prostate cancer tumors growing in nude mice following treatment with AdpHyde. AdpHyde transduction resulted in a dose-dependent stimulation of caspase-3 activity in DU145 cells which was blocked by DEVD (succinyl-Asp-Glu-Val-Asp-aldehyde) and VAD (benzyloxycarbonyl - Val - Ala - Asp -fluoromethylketone), inhibitors specifically against caspase-3. Moreover, cancer cells that lacked expression of endogenous caspase-3 were not or barely inhibited by pHyde. These results taken together suggest that pHyde inhibits cancer growth by inducing apoptosis through a caspase-3 dependent pathway.

Adenoviridae↗
PubMed2001

Gene therapy for prostate cancer.

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression of a variety of diseases including the malignant transformation of prostatic epithelial cells. Initial clinical trials for prostate cancer have thus far shown gene therapy to be relatively safe, although definitive evidence of durable therapeutic efficacy remains to be demonstrated. In this article, recent preclinical research, current therapeutic strategies, and recent results of gene therapy clinical trials for the treatment of prostate cancer are reviewed.

Clinical Trials as Topic↗
PubMed2001

High grade prostatic intraepithelial neoplasia is a disease.

High grade prostatic intraepithelial neoplasia (PIN) is now widely accepted as the main premalignant lesion that has the potential to progress to prostate adenocarcinoma. High grade PIN is a standard diagnosis that must be included as part of the reported pathologic evaluation of prostate biopsies. Premalignant lesions that affect other organs have been identified and are treated when diagnosed such that the premalignant lesions itself are a disease (eg, carcinoma in situ of the bladder, colon polyps, and cervical dysplasia). Urologists should recognize that high grade PIN is a dangerous lesion and that it should be aggressively managed either by saturation biopsies of the prostate following the diagnosis of high grade PIN, or the more common recommendation--repeated prostate biopsies every 3 to 6 months for 2 years, then annually. Treatment of these precancerous lesions would appear to be of clinical benefit notwithstanding the potential for cancer prevention. These clinical benefits would reduce morbidity, enhance the quality of life, delay surgery or radiation, and increase the interval for surveillance requiring invasive procedures.

Adenocarcinoma↗
PubMed2001

Gene therapy for prostate cancer.

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression of a variety of diseases including the malignant transformation of prostatic epithelial cells. Initial clinical trials for prostate cancer have thus far shown gene therapy to be relatively safe, although definitive evidence of durable therapeutic efficacy remains to be demonstrated. In this article, recent preclinical research, current therapeutic strategies, and recent results of gene therapy clinical trials for the treatment of prostate cancer are reviewed.

Genetic Therapy↗
PubMed2001

Neuroanatomy of the female continence complex: clinical implications.

OBJECTIVES: Improved understanding of pelvic neuroanatomy in women has led to modified surgical approaches and additional considerations in pelvic surgery. The innervation of the external urinary sphincter and urethra is not well defined in women, and, as such, the continence complex is not well understood. METHODS: Fourteen pelvic sections from seven fresh female cadavers were dissected to investigate the neuroanatomy of the female continence complex. RESULTS: Neuroanatomic dissections of the continence mechanism revealed that branches of the pelvic nerve travel beneath the fascia of the levator ani muscle and approach the urinary sphincter in near midline position, posterolateral to the rectum. This pelvic nerve branch passes laterally around the vagina and rectum to enter the sphincter musculature at the 5-o'clock and 7-o'clock positions. The pudendal nerve, traveling in the pudendal canal, gives an intrapelvic branch that courses to the urinary sphincter. At the level of the proximal urinary sphincter, it joins the pelvic nerve branch to the urinary sphincter. CONCLUSIONS: These neuroanatomic dissections provide a basis for surgical modifications that may address a variety of concerns regarding urinary continence in female surgical patients. With improved understanding of the female continence complex, we may now have a more precise anatomic explanation for the high failure rates associated with transvaginal urethral suspension procedures. Additionally, awareness and preservation of the continence nerves during cystectomy may allow for greater use of orthotopic bladder replacement in women.

Aged↗
PubMed2001

Selective estrogen receptor modulators for the chemoprevention of prostate cancer.

The ability to interfere with prostate carcinogenesis, and as a consequence, prevent prostate cancer with drugs is the basis for chemoprevention. The prostate contains estrogen receptors in both the stroma and epithelium. Both animal models and human epidemiologic studies have implicated estrogens as an initiator of prostate cancer. In the aging male, prostate cancer occurs in an environment of rising estrogen and decreasing androgen levels. Selective estrogen receptor modulators (SERMs) have shown the ability to prevent (GTx-006 [acapodene]) and treat (GTx-006 and arzoxifene) prostate cancer, suggesting that they may be used in prostate cancer chemoprevention. A phase 2 clinical trial using GTx-006 for prostate cancer chemoprevention is currently being conducted.

Age Factors↗
PubMed2001

Efficacy of first-generation Cavermap to verify location and function of cavernous nerves during radical prostatectomy: a multi-institutional evaluation by experienced surgeons.

OBJECTIVES: To evaluate, using five experienced surgeons, the efficacy of the first-generation Cavermap Surgical Aid to identify the cavernous nerves intraoperatively and to predict the recovery of sexual function. This study was not designed to determine whether this device improves the ability to preserve the nerves or improve outcome. METHODS: Fifty men younger than 60 years old (mean age 52.5 years; range 43 to 59) with clinically localized prostate cancer (76% T1c, mean Gleason score 6, prostate-specific antigen level less than 10 ng/mL) underwent nerve-sparing radical prostatectomy (90% bilateral). Intraoperatively, the Cavermap device was used to test for the presence of the cavernous nerves once the neurovascular bundle was identified visually and to determine whether the nerves were intact after the prostate was removed. Erectile function was evaluated using the International Index of Erectile Function; men were considered potent if they were able to achieve unassisted intercourse in at least one half of their attempts. RESULTS: Before the removal of the prostate, the tumescence response to stimulation of the neurovascular bundle was 87.8%; when tissue not containing the neurovascular bundle was stimulated, no tumescence response occurred in 54%. After prostatectomy, a bilateral response to stimulation occurred in 90%, a unilateral response in 5%, and no response in 5%. Postoperatively, 71% of the patients were potent at 12 months. In the patients who demonstrated bilateral stimulation after removal of the prostate, 78% were potent at 12 months. CONCLUSIONS: After radical prostatectomy performed by experienced surgeons, patient-reported potency rates in men younger than 60 years of age were high. Cavermap stimulation demonstrated an 87.8% sensitivity and 54% specificity in locating the neurovascular bundle as identified by experienced surgeons. The lack of specificity of this first-generation device limits its application for deciding which structures can be safely preserved or excised. Because virtually all patients demonstrated a positive response after removal of the prostate, the value of stimulation to predict the recovery of sexual function is yet to be determined.

Adult↗
PubMed2000

Growth inhibition of prostate cancer by an adenovirus expressing a novel tumor suppressor gene, pHyde.

It has been estimated that there will be > 180,400 new cases of prostate cancer and 31,900 prostate cancer deaths in the United States this year. New therapeutic strategies against locally advanced prostate cancer are desperately needed. A novel gene (pHyde) was identified by an improved cDNA competition hybridization technique for Dunning rat prostate cancer cell lines. A recombinant replication-deficient E1/E3-deleted adenovirus type 5 containing a pHyde gene under the control of a truncated Rous sarcoma virus (RSV) promoter (AdRSVpHyde) was generated. In vitro, AdRSVpHyde significantly inhibited growth of human prostate cancer cell lines DU145 and LNCaP in culture. In vivo, a single injection of AdRSVpHyde (5 x 10(9) plaque-forming units) reduced DU145 tumors in nude mice remarkably compared with untreated control or viral control-treated DU145 tumors. Moreover, AdRSVpHyde induced apoptosis and stimulated p53 expression. These results together suggest that pHyde is a tumor suppressor gene that inhibits growth of prostate cancer and that this inhibition is at least in part due to the induction of apoptosis.

Adenovirus E1 Proteins↗
PubMed2000

Efficacious chemoprevention of primary prostate cancer by flutamide in an autochthonous transgenic model.

Although the etiology of prostate cancer is still not clear, family history, hormones, and age are thought to play a role in its initiation and progression. There is no cure for the advanced disease. Because prostate cancer initially develops as an androgen-dependent tumor, agents with antiandrogen activity have become the focus for chemoprevention of this disease. A pilot study was undertaken to test the efficacy of flutamide (an antiandrogen) in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer. Three groups of mice received s.c. implantation of slow-release flutamide pellets: (a) low-dose flutamide group (6.6 mg/kg); (b) high-dose flutamide group (33 mg/kg); and (c) control placebo group. Efficacy was measured by the absence of palpable tumor formation. Prostate tissues/tumors were harvested for evaluation by molecular and histology techniques. The low-dose flutamide group did not differ significantly from the placebo group, in which palpable tumors initially presented at 17 weeks of age, and by 33 weeks, all of the animals developed palpable tumors. In the high-dose flutamide group, however, tumors did not appear until 24 weeks, a lag of 7 weeks, and by 34 weeks, 42% of the animals were still tumor free. The period of time at which 50% of the animals had tumors was 33 weeks in the high-dose flutamide group, 24.5 weeks in the low-dose flutamide group, and 24.5 weeks in the placebo group. The difference between the placebo and high-dose flutamide groups was statistically significant (log rank, P = 0.0036; Wilcoxon's statistical analysis, P = 0.0060). Tumors from high-dose flutamide-treated animals were more differentiated and retained much of the normal glandular architecture compared with those of the placebo group, whose tumors consisted of sheets of poorly differentiated cells. The expression of T antigen in the prostate tissues of flutamide-treated animals (at 10 weeks age) was lower than that in the comparable placebo-treated group. Flutamide had the ability to suppress T antigen-driven carcinogenesis, resulting in a significant decrease in the incidence of prostate cancer and an increase in the latency period of prostate cancer in TRAMP mice.

Adenocarcinoma↗
PubMed2000

p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways.

Tumor suppressor gene p16 is a cyclin-dependent kinase inhibitor and an important negative cell cycle regulator. The inactivation of p16 appears to be a common event in prostate cancer. Replacement of p16 inhibits prostate tumor cell growth, but the mechanism is not known. Human prostate cancer cell lines PPC-1, which has an inactivated p16, and DU145, which has a nonfunctional retinoblastoma Rb protein (pRb), were used to determine the possible mechanism of p16 mediated growth inhibition. PPC-1 cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, induced p16 expression, inhibited cell growth, and induced senescence. Similarly, PPC-1 cells transduced by an adenoviral vector containing the p16 gene (AdRSVp16) produced a p16 protein that suppressed cellular proliferation and induced senescence. Co-staining of AdRSVp16-transduced PPC-1 cells by p16 immunohistochemistry and by beta-galactosidase substrate X-gal showed that the morphologically enlarged cells expressed both p16 and senescence-associated beta-galactosidase. In contrast, AdRSVp16 did not induce senescence in DU145 cells, but did inhibit its growth. However, when wild-type pRb was introduced in DU145 cells, AdRSVp16 was able to induce senescence. Thus, the mechanism by which p16 suppressed prostate cancer was dependent on the pRb functional status of cells whereby p16 caused pRb+ cells to undergo inhibition by senescence, whereas pRb- cells were also inhibited, but not by senescence.

Antimetabolites, Antineoplastic↗
PubMed2000

Neuroanatomy of the pelvis: implications for colonic and rectal resection.

PURPOSE: Urinary dysfunction remains a common complication of radical pelvic surgery, particularly after abdominoperineal resection. In treating rectal carcinoma, the extent of primary resection and lymphadenectomy are major determinants in the degree of postoperative urologic morbidity. METHODS: Twelve male and eight female hemipelves from fresh cadavers were dissected with reference to the neuroanatomy of the lower genitourinary tract. These cadavers were dissected within twelve hours of thaw from frozen state. The cadavers were hemisected at the level of the sacral promontory for better exposure of neural trunks and vascular structures leading into the pelvis. These structures were followed down sequentially into the true pelvis, using magnified dissection under operating microscope or loupe dissection or both. RESULTS: Coordinated lower urinary tract function relies on both autonomic and somatic nerve activity. Emanating from the inferior hypogastric plexus, the pelvic nerve supplies sympathetic and parasympathetic innervation to the pelvic viscera. The course of the pelvic nerve is as follows: 1) from the inferior hypogastric plexus, it has multiple branches forming a web-like complex within the endopelvic fascial sleeve, some of which innervate the bladder detrusor; 2) a main branch traveling inferolateral to the rectum remains deep to the fascia of the levator ani muscle and courses to the external urinary sphincter; 3) at the level of the prostatic apex (or bladder neck in females), this pelvic nerve branch sends direct branches to the urinary sphincter. The pudendal nerve traverses the pelvis in the pudendal canal, and before leaving the pelvis to enter the perineum, it gives an intrapelvic branch that courses alongside the ischium to enter the external urinary sphincter. In the ischiorectal fossa, terminal branches of the pudendal nerve (i. e., perineal nerve) can be seen inserting into the urinary sphincter. CONCLUSIONS: Urinary retention and urinary incontinence represent two distinct urologic complications after abdominoperineal resection. Injury to detrusor branches of the pelvic nerve can cause detrusor denervation and urinary retention. In addition, injury to intrapelvic branches of the pelvic and pudendal nerves to the urinary sphincter can result in intrinsic sphincter deficiency and urinary incontinence. A better understanding of the neuroanatomy of the lower genitourinary tract can give a physiologic basis for clinical findings of postoperative voiding dysfunction and may help the surgeon refine surgical technique by more precisely determining resection limits to minimize urologic complications.

Aged↗
PubMed2000

Interstitial laser coagulation technique. Executive summary.

In March 1999, it was again my privilege to moderate a meeting of distinguished colleagues organized by Indigo Medical, Inc. as their BPH Advisory Panel. This executive summary highlights the most important conclusions of our day-long session. Details can be found in the subsequent sections of the publication. Our discussion of ILC technique is based on several exciting new concepts in prostatic anatomy. These concepts are derived from anatomical studies using fresh cadavers that have revealed the structures of the prostate in greater detail than ever before. Such findings are important because the great majority of descriptions of this anatomy are incomplete or inaccurate. An overview of the current clinical anatomy is found in Section VI.

Clinical Trials as Topic↗
PubMed2000

Transcriptionally regulated adenoviruses for prostate-specific gene therapy.

Most virally based vectors for gene therapy contain viral promoters that are tissue-nonspecific. Consequently, unintended expression of toxic therapeutic genes in normal tissues may potentially occur. We have constructed adenoviruses that contain a bacterial beta-galactosidase (beta-gal) gene (lacZ) under the control of three different prostate-specific promoters: prostate-specific antigen (PSA), probasin, and the mouse mammary-tumor-virus long terminal repeat (MMTV; prostate-specific Ad-lacZ). In general, these prostate-specific Ad-lacZ can effectively transduce and express beta-gal in prostate cells and display weak, if any, expression of beta-gal in nonprostate cells in vitro. In vivo, these adenoviruses showed a high level of beta-gal expression in canine prostate but also disseminated to tissues other than prostate after intraprostatic (i.p.) injection. However, none of the prostate-specific Ad-lacZ expressed beta-gal in these nonprostate tissues. Furthermore, prostate-specific Ad-lacZ expressed beta-gal only in xenograft tumors grown in nude mice, derived from human prostate-cancer cells DU145 and PPC-1, but showed no beta-gal expression in tumors derived from human bladder-cancer cells RT4. These results indicate that adenoviruses containing prostate-specific promoters may express intended transgenes specifically in prostate in vivo.

Adenoviridae↗
PubMed2000

Adenovirus p16 gene therapy for prostate cancer.

Surgery, radiation, or hormone deprivation alone does not adequately affect local control of clinical or pathologic stage T3 prostate cancer. Lack of local cancer control ultimately leads to a higher incidence of morbidity, distant metastasis, and decreased survival, with patients having disease-specific mortality exceeding 75%. Other novel therapies against this devastating and common disease are needed for the achievement of long-term local cancer control. For this purpose, therapeutic interventions should target prostate-cancer cells at the molecular and cellular level in ways not possible by current modalities of cancer treatment. Any strategy that can modify the biologic behavior of these cells may potentially have the most significant clinical impact. As prostate cancer represents an accumulation of genetic mutations that causes a prostate cell to lose the ability to control its growth, one new approach against prostate cancer may be gene therapy. Identification of key missing or mutated tumor-suppressor genes that, when replaced, may inhibit or destroy prostate-cancer cells may have the best chance of clinical success. One such gene appears to be tumor-suppressor gene p16 (also known as MTS1, INK4A, and CDKN2). Tumor-suppressor gene p16 is an important negative cell-cycle regulator whose functional loss may significantly contribute to malignant transformation and progression. Alterations in the p16 gene and its protein expression often occur in prostate cancer. An adenoviral vector containing wild-type p16 (Adp16) had a high transduction efficiency in prostate-cancer cells both in vitro and in vivo. Moreover, prostate tumors injected with Adp16 expressed p16 and the adenoviral vector expressed the transgene for up to 14 days. Wild-type p16 inhibited prostate-cancer proliferation in vitro and markedly suppressed tumors in vivo. Pathologic evaluation of the Adp16-treated tumors showed dose-dependent necrosis and fibrosis. Although the mechanism of p16 inhibition in cancer remains to be elucidated, senescence and apoptosis may both be important; however, the data suggest that p16-induced growth inhibition can function independently of the retinoblastoma gene product.

Adenoviridae↗