Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy.

PURPOSE: We evaluated the safety and efficacy of exisulind for delaying disease progression in men with increasing prostate specific antigen (PSA) after radical prostatectomy. MATERIALS AND METHODS: A total of 96 men with increasing PSA after radical prostatectomy were randomized to receive placebo (49) or 250 mg. exisulind twice daily (47) for 12 months. The primary efficacy parameter was the difference in change from baseline PSA between the placebo and exisulind groups. The PSA doubling time was also evaluated before and during study. A subgroup analysis classified patients based on the risk of developing metastatic disease. RESULTS: Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients (p = 0.017). The results were also statistically significant in men at high risk for metastasis (p = 0.0003) and those who could not be classified according to risk (p = 0.0009). In addition, median PSA doubling time was lengthened in high risk patients on exisulind (2.12 month increase) compared with those on placebo (3.37 month decrease, p = 0.048). Exisulind was well tolerated. CONCLUSIONS: Exisulind inhibited the increase in PSA overall and prolonged PSA doubling time in high risk patients compared with placebo. These results suggest that Exisulind has the potential to extend the time from biochemical recurrence to the need for androgen deprivation therapy. Exisulind was well tolerated in this patient population. Our results support further study of Exisulind in the treatment of patients with prostate cancer.

Cure of undifferentiated small cell carcinoma of the urinary bladder with M-VAC chemotherapy.

Small cell carcinoma (SCC) of the urinary bladder is a rare, aggressive malignancy with approximately 135 cases reported in the literature. Treatments have included chemotherapy, radical surgery, radiotherapy, and combinations of these. We present the apparent cure of a 73-year-old man who presented with clinical stage T2 SCC of the urinary bladder. He was treated with three cycles of methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin (M-VAC) chemotherapy. Subsequent radical cystoprostatectomy revealed no pathologic evidence of tumor. The patient is alive and well with no evidence of recurrence 3 years post cystectomy. A brief review of the literature is also presented.

New approaches to the treatment of advanced prostate cancer.

Several presentations by attendees of the 11th International Prostate Cancer Update addressed recent advances in prostate cancer treatment. A study that examined whether a relationship exists between neuroendocrine (NE) cell differentiation and hormone-refractory prostate cancer (HRPC) concluded that the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC. Exisuland, a selective apoptotic antineoplastic drug, was compared to placebo in a recent study and was found to significantly inhibit the increase of prostate-specific antigen in patients who had undergone radical prostatectomy. A new dosing regimen for flutamide (500 mg daily) was found to have no significant differences from the currently recommended dose (250 mg every 8 hours); the new, single daily dose could meet with greater compliance and would reduce drug cost by 30%. The antiproliferative effect of vitamin D on prostatic carcinoma cells was discussed, along with the possible role of vitamin D supplementation during prostate cancer treatment. Finally, a presentation on hospice care acknowledged that referral for such care is unfortunately at times delayed by physicians, patients, and patients' families, leaving insufficient time for all the benefits of that stage of care to be realized.

Exisulind, a selective apoptotic antineoplastic drug.

Exisulind (Aptosyn, Cell Pathways, Inc.) is the first of a new class of targeted, pro-apoptotic drugs that show promise in the treatment of cancer. These agents induce apoptosis (i.e., programmed cell death) in a broad range of pre-cancerous and cancerous tissues without affecting normal cells. The antineoplastic effect of exisulind appears to be the result of activation of protein kinase G (PKG) which leads to multiple downstream effects culminating in apoptosis. Exisulind has demonstrated antineoplastic activity in solid tumour and haematological cancer cell lines and is an inhibitor of tumour growth in rodent models of colon, prostate, bladder, mammary and lung cancer. Preclinical data evaluating selective apoptotic antineoplastic drugs (SAANDs) in combination with various chemotherapy drugs indicates additive or synergistic antineoplastic effects. In clinical studies, exisulind prevented colorectal polyp formation in patients with familial adenomatous polyposis (FAP) over 24 months. In a randomised, placebo-controlled study of prostate cancer patients, exisulind inhibited the rise of prostate-specific antigen (PSA) in men with PSA progression after radical prostatectomy. Exisulind has been well-tolerated by most patients in clinical trials. In conclusion, preclinical evidence and early clinical results suggest that exisulind and other drugs in this class may have wide applications in treating cancer both as monotherapy and in combination with chemotherapy and other targeted agents.

A recombinant defective adenoviral agent expressing anti-bcl-2 ribozyme promotes apoptosis of bcl-2-expressing human prostate cancer cells.

Over-expression of bcl-2, a potent anti-apoptosis protein, is likely to be one of the genetic mechanisms through which human prostate cancer cells develop resistance to hormonal and other forms of therapy. To develop a therapeutic agent for hormone-resistant prostate cancer based on suppression of bcl-2 expression, we had previously designed and synthesized a dual-hammerhead ribozyme capable of recognizing and specifically cleaving human bcl-2 mRNA in vitro as well as in vivo. To increase the efficiency by which the anti-bcl-2 ribozyme can be delivered to target cells, we have created a recombinant replication-deficient (defective) adenoviral agent capable of expressing the anti-bcl-2 ribozyme upon infection. This viral agent effectively reduces intracellular levels of bcl-2 mRNA and protein in cultured LNCaP prostate cancer cells following standard infection procedures. Likewise, the defective adenovirus-anti-bcl-2 ribozyme induces extensive apoptosis in several androgen-sensitive (LNCaP) and androgen-insensitive (LNCaP/bcl-2 and PC-3) human prostate cancer cell lines that express differing amounts of bcl-2 protein. One androgen-insensitive prostate cancer cell line, DU-145, lacking in bcl-2 expression, was found to be completely refractory to the effects of the virus ribozyme, supporting the concept that the cytotoxic effects of the ribozyme are based solely on its effects on bcl-2 expression. Our results support further development of this adenovirus/anti-bcl-2 ribozyme for potential gene therapeutic purposes in certain forms of hormone-resistant prostate cancer where over-expression of bcl-2 proto-oncogene is indicated.

Rising risk of testicular cancer by birth cohort in the United States from 1973 to 1995.

PURPOSE: Recent epidemiological studies have demonstrated an increasing incidence of testicular cancer in white men which appears to be correlated with the period of birth. Because this birth cohort phenomenon can explain etiological factors in testicular cancer, we determine whether this trend is present throughout the United States based on an analysis of testicular cancer incidence by birth cohort. MATERIALS AND METHODS: Testicular cancer incidence was obtained from the National Cancer Institute Surveillance, Epidemiology and End Results database from 1973 to 1995. Numbers of cases were extracted and grouped by 5-year birth cohorts for all testicular germ cell neoplasms. Poisson regression analysis with variables of age, time of diagnosis and birth cohort were used to determine relative risk. Poisson models were compared using computer log linear model software. RESULTS: Between 1973 and 1995 the incidence of testicular cancer in the United States increased 51% (3.61 to 5.44/100,000). Analysis of Poisson models revealed that birth cohort was strongly associated with relative risk of testicular cancer (p = 0.001). In addition, peak age at diagnosis decreased for each successive birth cohort. CONCLUSIONS: The overall incidence of testicular cancer in white men and the relative risk of testicular cancer have been increasing in the United States. This trend is strongly associated with birth cohort in concordance with previously reported European data. Moreover, testicular cancer is being diagnosed at a younger age as evidenced by a shift to the left in the age of peak incidence. These unique epidemiological patterns offer a basis for analysis of potential etiological factors.

Early effects of castration on the vascular system of the rat ventral prostate gland.

Recent studies have found that blood flow to the rat ventral prostate gland is drastically reduced at an early time after castration. These observations caused us to reevaluate the effects of castration on the various cell populations of the ventral prostate, especially those in the prostatic vascular system. Sections of ventral prostate glands obtained at different times after castration were analyzed using the TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick END labeling) staining method to quantify apoptosis in different cell types. The results of this analysis showed a significant increase in TUNEL staining of prostate endothelial and (nonendothelial) stromal cells as early as 12 h postcastration that continued to 24 h after castration. In contrast, TUNEL labeling of prostate epithelial cells was not significantly increased compared with control values until 72 h after castration. The use of dual immunohistochemical staining procedures (anti-CD31 for endothelial cells or antismooth muscle actin for smooth muscle cells combined with TUNEL labeling) allowed us to confirm that the TUNEL-positive vascular cells at these early times after castration were endothelial in nature, whereas smooth muscle cells surrounding the prostate glands or portions of the afferent vascular endothelium were rarely TUNEL labeled. Electron microscopic evaluation of ventral prostate tissues at 48 h after castration provided further morphological evidence for the occurrence of apoptosis in prostate endothelial cells. Finally, the Lendrum-Fraser histochemical procedure used to identify fibrin leakage in tissues with vascular damage was applied to sections of the ventral prostate gland. This stain revealed diffuse fibrin accumulation in periglandular areas outside the capillaries and blood vessels in prostates from 24-h castrated rats, but not in prostates of sham-operated rats. Our results confirm an early effect of castration on the vascular system of the rat ventral prostate identified by increased apoptosis of endothelial cells and vascular leakiness. As these changes temporally precede the loss of epithelial cells, we propose that they may be causal rather than incidental to regression of the rat ventral prostate after castration.

Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis.

OBJECTIVES: Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. METHODS: Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. RESULTS: Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells. CONCLUSIONS: This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

Declining sperm counts in the United States? A critical review.

PURPOSE: Recent reports suggest declining sperm counts in the United States. These reports did not include all available data and did not account for geographic variations noted in prior studies. We examined all available data on U.S. sperm counts and evaluated whether geographic variations account for the decline suggested. MATERIALS AND METHODS: We reviewed all 29 U.S. studies from 1938 to 1996 reporting manually counted semen analyses of 9,612 fertile or presumably fertile men. We determined mean sperm concentrations by geographic location with weighted analysis of variance, and assessed any changes with time by linear regression analysis. RESULTS: Mean sperm concentrations from New York were significantly higher than from all other U.S. cities (98.6 versus 71.6 x 10(6) sperm per cc, respectively, p = 0.006). There has been no statistically significant change with time for mean sperm concentrations reported from New York (p = 0.49) or from U.S. cities other than New York (p = 0.62). Analysis without separating by location revealed a decline (p = 0.047). CONCLUSIONS: Sperm concentrations are highest in New York compared to other U.S. cities. When accounting for this geographic difference and examining all available data, there appears to be no significant change in sperm counts in the U.S. during the last 60 years. Further studies addressing the causes of geographic variations are needed.

Influence of free-to-total prostate specific antigen variability on the early diagnosis of prostate cancer: a comparative study of three immunoassays.

OBJECTIVE: To compare three immunoassays for total prostate specific antigen (tPSA), free PSA (fPSA), free-to-total PSA ratio (f/tPSA), and the f/tPSA thresholds for optimal differentiation between benign prostatic hypertrophy (BPH) and prostate cancer in 141 consecutive patients referred for prostatic disease. PATIENTS AND METHODS: The study included 43 patients with prostate cancer and 98 with BPH, all confirmed histologically. PSA levels were assessed using the following assay kits just before histological analysis of the prostate; Hybritech (Tandem-R PSA, normal values, NV, < 4 ng/mL, and Tandem-R free PSA), Cis Bio (PSA-RIACT, NV < 2.5 ng/mL and fPSA-RIACT) and Immunocorp (PSA-IRMA, NV < 4 ng/mL and Free PSA-IRMA). The results were assessed to determine the sensitivity, specificity and threshold values of the different assays to differentiate patients with BPH and cancer. RESULTS: The mean tPSA and f/tPSA ratio were statistically different in assays with different NVs. The mean fPSA values differed significantly between the Hybritech and Cis Bio, between the Hybritech and Immunocorp but not between the Cis Bio and Immunocorp assays. With receiver operator curve analysis, there were no statistically significant differences among the three immunoassays in f/tPSA (0.72 for Hybritech, 0.73 for Cis Bio and 0.64 for Immunocorp) or between the tPSA and fPSA curves for each manufacturer. With the sensitivity fixed at 90%, different f/tPSA thresholds were defined (0.22, 0.34 and 0.25 for Hybritech, Cis Bio and Immunocorp, respectively). The specificities (i.e. the percentage of unnecessary biopsies spared) were 22%, 21% and 31%, respectively (not significantly different). CONCLUSION: Each immunoassay could be used to distinguish prostate cancer and BPH at different f/tPSA thresholds, with 21-30% of unnecessary biopsies spared. There was no difference in overall performance among the different assays. Further studies are needed to better define the exact use of the f/tPSA ratio in the routine diagnosis of prostate cancer.

Urinary continence after radical prostatectomy: the Columbia experience.

PURPOSE: We determine the incidence of urinary incontinence after radical prostatectomy and the factors that may influence this incidence. MATERIALS AND METHODS: A total of 615 men who underwent radical retropubic prostatectomy performed by 1 of us (C. A. O. or M. C. B.) at our center between 1988 and 1996 were mailed a questionnaire regarding preoperative and postoperative voiding habits. Data collected included preoperative and postoperative continence status, interval to postoperative continence status, associated urinary symptoms, willingness to undergo radical prostatectomy again if given the chance and additional postoperative procedures. Patient age, date of surgery and duration of followup were also noted. RESULTS: Of the 615 patients 480 (78.2%), a mean of 62.6 years old, responded to the questionnaire. Mean followup was 3.3 years (range 1 to 8.8). Continence was defined as no regular use of pads. Of the respondents 91.8% were considered continent, 92% had achieved final continence status by 6 months postoperatively, 10.6% required 1 or more additional procedures related to urinary control and 90% would undergo surgery again if given the chance. Of the patients considered incontinent postoperatively 44% had associated urgency. Age, year of surgery and preoperative urinary leakage or post-void dribbling had no significant impact on postoperative continence status. CONCLUSIONS: Using an anonymous self-administered questionnaire we found an 8.2% incontinence rate after radical prostatectomy. This rate was similar to that in large, single institutional studies in which physician interview was used to elicit responses but significantly less than that in a national sample of Medicare patients also given a self-administered questionnaire. With minimal potential for adverse consequences in the hands of experienced surgeons, radical prostatectomy remains well tolerated with excellent patient satisfaction.

MacLeod revisited: sperm count distributions in 374 fertile men from 1971 to 1994.

OBJECTIVES: There has been an enormous amount of interest as to whether sperm counts are declining over time. We sought to compare a contemporary group of fertile men to those from the MacLeod study of 1951 to ascertain whether sperm counts in fertile men have changed over time. METHODS: We obtained sperm count data from 374 fertile men who banked sperm in Minnesota prior to vasectomy from 1971 to 1994 and compared them to sperm count distributions from the 1000 fertile men of MacLeod's study. Semen analyses were performed as per World Health Organization guidelines using identical techniques in both the present and MacLeod studies. RESULTS: The contemporary group had a mean sperm count of 102 +/- 81 x 10(6)/mL (median 85 x 10(6)/mL) compared to 107 +/- 74 x 10(6)/mL (median 90 x 10(6)/mL) for MacLeod's data. There are no significant differences in mean or median sperm counts or sperm count distributions between the groups. CONCLUSIONS: We find remarkable similarities in sperm count distributions in cohorts of fertile men from 1951 and 1971 to 1994. Sperm counts in fertile men have not changed appreciably in the 40 years since MacLeod's report.

Development of a hammerhead ribozyme against BCL-2. II. Ribozyme treatment sensitizes hormone-resistant prostate cancer cells to apoptotic agents.

BACKGROUND: Several lines of evidence strongly implicate a crucial role for the apoptosis suppressing bcl-2 oncogene in the genesis of hormone-refractory human prostate cancer. By efficiently destroying the intracellular bcl-2 mRNA, one might be able to make the prostate cancer cell responsive again to conventional apoptotic stimuli such as androgen withdrawal. To achieve this end, we have devised a catalytic antisense RNA strategy (Ribozyme) for bcl-2 and evaluated its gene therapeutic potential. METHODS AND RESULTS: Bcl-2 overexpressing LNCaP prostatic carcinoma cells (LNCaP/bcl-2) were transfected with the anti-bcl-2 ribozyme RNA using a polyamine-based transfection reagent and the reduction in the intracellular bcl-2 mRNA levels was followed by a ribonuclease protection assay. Using a cell viability assay, prior ribozyme transfection and subsequent application of apoptotic stimuli such as serum starvation or phorbol ester treatment caused a 30% increase in cell death by apoptosis than with these apoptotic stimuli alone. CONCLUSIONS: The results obtained strongly support the ability of a potential anti-bcl-2 ribozyme therapy to synergize with other agents in inducing apoptosis of hormone-resistant human prostate cancer cells.

Pretreatment prostate specific antigen doubling times: use in patients before radical prostatectomy.

PURPOSE: We determined whether pre-radical prostatectomy prostate specific antigen (PSA) doubling time could predict pathological stage at radical prostatectomy or PSA failure postoperatively. We also sought to compare PSA doubling times from men with prostate cancer treated with radical prostatectomy to a group treated with radiation therapy. MATERIALS AND METHODS: Detailed followup was available for 150 patients with clinically localized prostate cancer who underwent radical prostatectomy from January 1993 to August 1995. PSA doubling time was calculated for all patients with 3 or more pre-radical prostatectomy PSA levels using linear regression. We assessed the association between PSA doubling time and PSA failure, pathologic stage at radical prostatectomy, final PSA before treatment and Gleason score. We compared our PSA doubling time values and distribution to a published series of patients with prostate cancer who had undergone radiation therapy. RESULTS: A total of 56 patients had 3 or more PSA values before treatment. Median followup was 17.3 months. PSA doubling time did not correlate with PSA failure, final PSA or Gleason score, but it did with pathological stage at radical prostatectomy (p = 0.0035 for positive margins, p = 0.025 for positive seminal vesicles). Our PSA doubling time and PSA failure rates did not differ from the radiation therapy population with similar followup times. CONCLUSIONS: Although studies from the radiation literature have shown PSA doubling time to be useful in predicting PSA failure after treatment for prostate cancer, our results do not confirm this finding. We did find a correlation with pathologic stage at radical prostatectomy, and so longer followup with more patients may confirm this in the future. We also found no significant differences in PSA doubling time between our patients and a group treated with radiation. At least for this parameter, patients with prostate cancer referred for radical prostatectomy and radiation therapy may be similar.

The relationship of sperm counts to birth rates: a population based study.

PURPOSE: We determined if a statistical relationship exists between changes in sperm counts and birth rates by comparing data from a single geographic location for a 24-year period. MATERIALS AND METHODS: We retrospectively analyzed data from 660 men who banked 1,972 semen samples before vasectomy in Minnesota from 1971 to 1994. Using general linear models, annual variations in sperm count were determined after adjusting for age, duration of abstinence and seasonal (monthly) effects. Adjusted annual mean sperm count was then correlated with regional birth rate data obtained from The National Center for Health Statistics. RESULTS: Multiple regression analysis revealed a significant linear increase in mean annual sperm count at an estimated rate of 1.03 x 10(6) sperm per ml. per year (b = 0.14, t = 5.641, p < 0.0001). There was no effect of age (t = -0.814, p = 0.4156) but there were significant effects of abstinence (b = 0.14, t = 8.808, p < 0.0001) and month of sperm banking (b = 0.025, t = 5.00, p < 0.0001) on sperm counts. Using analysis of covariance there was a significant, nonlinear (year-to-year) fluctuation in mean sperm counts (F = 8.63, p < 0.001). For the study period mean birth rates in Minnesota (live births per 1,000 population) fluctuated yearly from 13.8 in 1973 to 16.7 in 1981. There was a strong correlation between adjusted mean yearly sperm count and annual birth rates (r = 0.63, p = 0.001). CONCLUSIONS: We found a statistically significant correlation between yearly variations in mean sperm counts and birth rates. Our data suggest that variations in male reproductive function may affect population based birth rates and, therefore, may be more important than previously understood.

Worldwide variations in sperm counts.

OBJECTIVES: Based on the premise that various human disease processes manifest differently depending on geography, we set out to determine whether sperm counts vary from different nations and different regions within the United States. METHODS: We reviewed the literature of all significant population-based studies that evaluated sperm counts from fertile or presumably fertile men from 1930 to the present. RESULTS: We found that sperm counts did, in fact, vary greatly. Throughout the United States, average sperm counts ranged from a low of 48 million/cc in lowa to a high of 134 million/cc in New York, with multiple values in-between from Texas, Minnesota, Washington State, and California. Internationally, average sperm counts ranged from a low of 52.9 million/cc in Thailand to a high of 102.9 million/cc in France. CONCLUSIONS: We conclude that sperm counts are subject to a wide range of variation among geographic locations.

Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma.

OBJECTIVES: We assessed the frequency of bone metastases, their association with serum alkaline phosphatase (AP), and prognostic capabilities of AP in patients with renal cell carcinoma (RCC), using bone scan as the reference standard for diagnosis. METHODS: We conducted a retrospective review of patients with metastatic RCC treated with either autologous ex vivo activated T-lymphocytes and cimetidine (ALT) or cimetidine alone. RESULTS: Twenty-eight of 90 patients (31%) had evidence of bone metastases by bone scan. With 100 mg/ dL as the upper limit of normal, 11 of 28 (39%) patients with bone metastases had normal AP levels. Of these 11 patients, 8 had bone pain. Of the 3 asymptomatic patients with bone metastasis and normal AP levels, only 1 had bone as the only site of metastasis and would have been incorrectly staged without the scan. Patients with bone metastases had a significantly shorter median survival than those without bone metastases (13.8 versus 25.3 months; P < 0.05). Among patients without bone metastases who had elevated AP levels, those treated with ALT had significantly longer median survivals than those treated with cimetidine alone (27.6 versus 14.5 months; P < 0.05). Overall, patients treated with ALT had a significantly longer median survival than the ones treated only with cimetidine (21 versus 8.5 months; P < 0.05). Overall, the median survival for patients with elevated AP levels (10 months) was not significantly different from that of those with normal AP levels (13 months). CONCLUSIONS: In a high-risk group of patients with metastatic RCC, 31% had bone metastases. Elevated AP levels, the presence of bone pain, or the presence of other metastases correctly predicted bone metastasis in all but 1 patient. A bone scan may safely be omitted in patients with RCC, normal AP levels, and no bone pain. However, AP elevation itself had little prognostic capability in these patients.

External beam radiation therapy does not offer long-term control of prostate cancer.

In the absence of large, contemporary, randomized series comparing external beam radiation and radical prostatectomy, definitive conclusions regarding relative efficacy are difficult to establish. This article examines series in which an objective, comparable end point was used and prostate-specific antigen (PSA) response was assessed. With follow-up of less than 5 years, PSA-based recurrence rates are similar for external beam radiation and radical surgery; however, the 10- and 15-year control rates are significantly lower in the population of patients treated with external beam radiation. The authors conclude that external beam radiation therapy as a single modality does not equal radical prostatectomy in comparably staged and followed patients.