Joel B. Nelson

Identification of endothelin–1 in the pathophysiology of metastatic adenocarcinoma of the prostate

Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone–refractory disease is characterized by painful osteoblastic bone metastases. Endothelin–1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin–1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin–1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin–1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.

Laparoscopic nephrectomy for renal cell cancer: evaluation of efficacy and safety: a multicenter experience

OBJECTIVESnAlthough laparoscopic radical nephrectomy is a safe and minimally invasive alternative to open surgery, the long-term disease-free outcome of this procedure has not been reported. We evaluated our experience with the laparoscopic management of renal cell carcinoma to assess the clinical efficacy of this surgical modality.nnnMETHODSnBetween February 1991 and June 1997, 157 patients at five institutions were retrospectively identified who had clinically localized, pathologically confirmed, renal cell carcinoma and had undergone laparoscopic radical nephrectomy. Operative and clinical records were reviewed to determine morbidity, disease-free status, and cancer-specific survival. Of the patients followed up for at least 12 months (n = 101), 75% had an abdominal computed tomography scan at their last visit.nnnRESULTSnThe mean age at surgery was 61 years (range 27 to 92) and all patients were clinical Stage T1-2,NO,MO. Fifteen patients (9.6%) had perioperative complications. During a mean follow-up of 19.2 months (range 1 to 72; 51 patients with 2 years or more of follow-up), no patient developed a laparoscopic port site or renal fossa tumor recurrence. Four patients developed metastatic disease, and 1 patient developed a local recurrence. The 5-year actuarial disease-free rate was 91%+/-4.8 (SE). At last follow-up, there were no cancer-specific mortalities.nnnCONCLUSIONSnThe laparoscopic surgical management of localized renal cell carcinoma is feasible. Short-term results indicate that laparoscopic radical nephrectomy is not associated with an increased risk of port site or retroperitoneal recurrence. Longer follow-up is necessary to compare long-term survival and disease-free rates with those of open surgery.

New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade

OBJECTIVESnThe osteoblastic response of bone to metastatic prostate cancer is both characteristic and enigmatic. The potent vasoconstrictor endothelin-1 (ET-1), produced by prostate cancer, has been identified as a potential factor in new bone formation.nnnMETHODSnUsing a novel method to quantitate new bone formation induced by the WISH tumor, we examined the effects of ET-1 overexpression and endothelin receptor antagonists on the osteoblastic response.nnnRESULTSnWISH, a human tumor cell line derived from amnion, produces ET-1 mRNA and protein and induces abundant new bone formation and splenomegaly in vivo. Stable transfection of WISH with an ET-1 overexpression cDNA construct produced clones that secreted 18-fold more bioactive ET-1 than vector-only controls. After 14 days of growth in the lower leg of nu/nu mice, ET-1 overexpressing tumors produced significantly more new bone than vector-only controls. Conversely, areas of new bone formation were significantly less in animals treated with a selective endothelin A (ET(A)) receptor antagonist A127722.nnnCONCLUSIONSnThe activity of ET-1 in this osteoblastic model provides a unique target for therapy.

Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics

PURPOSEnEndothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients.nnnPATIENTS AND METHODSnPatients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief.nnnRESULTSnThirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset.nnnCONCLUSIONnAdverse events were consistent with atrasentans pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular tumors

OBJECTIVESnTo assess retrospectively whether laparoscopic retroperitoneal lymph node dissection (RPLND) in patients with clinical Stage I nonseminomatous germ cell testicular tumor (NSGCT) provides useful pathologic staging information on which subsequent management can be based. Approximately 30% of patients with clinical Stage I NSGCT will have pathologic Stage II disease.nnnMETHODSnA retrospective review of 29 patients with clinical Stage I NSGCT who underwent transperitoneal laparoscopic RPLND by a single surgeon was performed. Selection criteria included the presence of embryonal carcinoma in the primary tumor or vascular invasion. A modified left (n = 18) or right (n = 11) template was used.nnnRESULTSnPositive retroperitoneal nodes were detected in 12 (41%) of 29 patients. Ten of these patients received immediate adjuvant platinum-based chemotherapy, and 2 patients refused chemotherapy. The nodes were negative in 1 7 (59%) of 29 patients; all but 2 patients (one with recurrence in the chest, the other with biochemical recurrence) have undergone observation. No evidence of disease recurrence has been found in the retroperitoneum of any patient (follow-up range 1 to 65 months). Prospectively, the dissection was limited if grossly positive nodes were encountered; therefore, the total number of nodes removed was significantly different if the nodes were positive or negative (14 +/- 2 and 25 +/- 3, respectively; P <0.004). Two patients required an open conversion because of hemorrhage. Complications included lymphocele (n = 1) and flank compartment syndrome (n = 1).nnnCONCLUSIONSnLaparoscopic RPLND is a feasible, minimally invasive surgical alternative to observation or open RPLND for Stage I NSGCT. Disease outcomes are favorable to date. Longer follow-up in a larger series is necessary to determine therapeutic efficacy.

Caveolin expression is decreased following androgen deprivation in human prostate cancer cell lines

Increased expression of caveolin has been associated with prostate cancer progression. In a mouse reconstitution model of prostate cancer, expression of caveolin was inversely related to androgen sensitivity: androgen independent clones had high caveolin expression; low caveolin expression was associated with sensitivity to androgen withdrawal. In contrast, several independent observations support the hypothesis that caveolin functions as a tumor suppressor.

Dynamics of prostate cancer cell invasion studied in vitro by NMR microscopy

Understanding the dynamics and pathogenesis of invasion is vital for developing strategies to prevent cancer metastasis. Conventional invasion assays provide information for a single time point. NMR microscopic imaging as used in the current study to measure cell invasion in vitro provides a nondestructive method for scoring cell invasion thus offering a unique possibility to study this process dynamically. An additional advantage is that cells can be retrieved for metabolic and physiological characterization. Two prostate cancer cell lines, DU‐145 and Mat‐Ly‐Lu, preselected for differences in invasive behavior, were studied. Cells were seeded in 12‐mm culture plate inserts containing a 15‐μm‐thick porous membrane with 3.0 μm pore size that was coated with a 100 μm Matrigel layer. Cell invasion in the Matrigel layer was obtained from the profile of intracellular water measured with diffusion‐weighted 1D imaging. Additional experiments were also performed with confocal microscopy to validate the NMR results. Significant differences were detected between the invasive behavior of DU‐145 and Mat‐Ly‐Lu cells. The obtained results show that NMR microscopy can be used to dynamically study invasion by cancer cells. The noninvasive nature of NMR microscopy permits determination of cell migration dynamically for any given sample, which is especially important if cell availability is limited to the unique sample, such as for biopsy specimens. Magn Reson Med 42:277–282, 1999.

Alternatives to death: Understanding androgen-independent prostate cancer

Decreased levels of caveolin promote sensitivity to androgen withdrawal in prostate cancer cells, suggesting another therapeutic target for the treatment of prostate cancer (pages 1062–1064).

PROSTATE-SPECIFIC ANTIGEN AND OTHER MARKERS OF THERAPEUTIC RESPONSE

Several new agents and combinations demonstrate significant activity in the treatment of patients with hormone refractory prostate cancer. Prostate-specific antigen (PSA) is being used increasingly as the key marker of a therapeutic response in trials of new agents. This article reviews data that support this marker as a surrogate endpoint, and it discusses the issues around the appropriateness of PSA as an intermediate marker with evolving noncytotoxic agents. Other biomarkers of prostate cancer progression are not uniformly elevated in men with advanced disease; to date, they are of limited clinical use. This article also discusses the rationale and results of novel and alternative biomarkers of prostate cancer progression.