Expression and significance of estrogen receptor α and β in prostate cancer and peri-cancer tissue

Objective To investigate the expression of estrogen receptor (ER) α and β in human prostate cancer (PC), peri-cancer tissue and benign prostatic hyperplasia (BPH) tissue, and to discuss the role of estrogen receptor in prostate cancer. Methods The expression of ERα and ERβ in PC (n=28), peri-cancer tissue (n=28) and BPH (n=29) were detected by immunohistochemistry with En vision method. The ERα and ERβ expression were compared among different tissues by chisquare. The relationship between ER expression and related clinicopathologic features was statistically analyzed by spearman rank collection. Results ERα was localized dominantly in the stromal cell of PC. There were significant differences of the expression of ERα in PC, peri-cancer tissue and BPH tissue (epithelial cell 0%, 14%, 24%, P＜0. 05; stromal cell 57%, 68%, 31%,P＜0. 05). ERβ was localized in both epithelial and stromal cell of PC. There were significant differences of the expression of ERβ in PC, peri-cancer tissue and BPH tissue (epithelial cell 39%, 64%, 29%, P＜0.01; stromal cell 50%, 75%, 79%, P＜0.05). There was a significant difference of the expression of ERβ in different Gleason scores of PC tissue. Conclusions ERα is localized in the stromal cell of PC tissue.ERβ is localized in both epithelial and stromal cell of PC tissue. The ERβ might be related to the tumor differentiation of PC.     

Expression and significance of estrogen receptor α and β in prostate cancer and peri-cancer tissue

Objective To investigate the expression of estrogen receptor (ER) α and β in human prostate cancer (PC), peri-cancer tissue and benign prostatic hyperplasia (BPH) tissue, and to discuss the role of estrogen receptor in prostate cancer. Methods The expression of ERα and ERβ in PC (n=28), peri-cancer tissue (n=28) and BPH (n=29) were detected by immunohistochemistry with En vision method. The ERα and ERβ expression were compared among different tissues by chisquare. The relationship between ER expression and related clinicopathologic features was statistically analyzed by spearman rank collection. Results ERα was localized dominantly in the stromal cell of PC. There were significant differences of the expression of ERα in PC, peri-cancer tissue and BPH tissue (epithelial cell 0%, 14%, 24%, P＜0. 05; stromal cell 57%, 68%, 31%,P＜0. 05). ERβ was localized in both epithelial and stromal cell of PC. There were significant differences of the expression of ERβ in PC, peri-cancer tissue and BPH tissue (epithelial cell 39%, 64%, 29%, P＜0.01; stromal cell 50%, 75%, 79%, P＜0.05). There was a significant difference of the expression of ERβ in different Gleason scores of PC tissue. Conclusions ERα is localized in the stromal cell of PC tissue.ERβ is localized in both epithelial and stromal cell of PC tissue. The ERβ might be related to the tumor differentiation of PC.     

Exposure to CB-153 and p,p’-DDE and bone mineral density and bone metabolism markers in middle-aged and elderly men and women

The incidence of osteoporotic fractures is rising in western societies, partly due to unknown reasons. Persistent organochlorine compounds (POC) have in animal studies impaired the normal bone metabolism and resulted in increased bone fragility, which might have health implications for POC-exposed human populations. The aim of the present study was to assess whether a high dietary intake of POC through fatty fish from the Baltic may result in decreased bone mineral density (BMD) or disturbances in biochemical markers of bone metabolism. From a study base of fishermen and fishermens wives from the Swedish east coast who are considerably more POC-exposed than the general Swedish population, 196 men (median age 59 years) and 184 women (median age 62 years) participated in an examination of their forearm BMD, using dual energy x-ray absorptiometry (DXA). Further, POC exposure was assessed by analysis of lipid-adjusted serum levels of 2,2,4,4,5,5-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p-DDE). Cadmium in urine (U-Cd) was also analyzed. Biochemical markers in serum of osteoblastic (osteocalcin) and osteoclastic (CrossLaps) functions were measured. Adjustment for potential confounders was made by employing multiple regression analyses. Univariate analyses showed significant negative associations between CB-153 concentrations and BMD, but after adjustment for age and body mass index, these associations did not remain. None of the POC exposure variables were associated with CrossLaps or osteocalcin. There were no significant associations between U-Cd and BMD or any of the biochemical biomarkers. In conclusion, the results did not provide any support for the hypothesis that the current exposure levels to POC constitute a hazard for impaired bone metabolism in the general Swedish population.     

Hip and pelvic fractures and sciatic nerve injury

Objective:To investigate te influence of hip and pelvic fracture,especially acetanbular fracture complicated by sciatic nerve injury on clinical features and prognosis of sciatic nerve injury.Methods:From January 1987 to January 2000,17 patients(14 male and 3 female) who had hip and pelvic fractures complicated by sciatic nerve injury were treated with operative reduction and internal fixation and followed up from 10 months to 5 years.The average age was 38 years(ranging 23-56 years).The left extremities were involved in 11 patients and the right in 6.Twelve patients underwent primary exploration and neurolysis and 5 patients underwent secondary operation.Results:Preperativelys,8 patients were treated with large doses of oral narcotics to control their severe sciatic pain.Three of the 8 patients underwent patient-controlled analgesia and epidural analgesin.After operation,excellent and good rates of reduction and functional recovery of sciatic nerve were 94.1% and 88% respectively.Four patients still had sciatic pain and 2 patients failed to recover.Sciatic nerve function improved within 3-6 months after surgery in 11 patients.Conclusions:Hip and pelivic fractures can result in sciatic nerve injury,especially common peroneal nerve injury and prognosis is poor.Open reduction and internal fixation combined with nerve exploration and neurolysis should be used as early as possible for severe sciatic pain.     

HIV and tuberculosis – science and implementation to turn the tide and reduce deaths

Introduction

Every year, HIV-associated tuberculosis (TB) deprives 350,000 mainly young people of productive and healthy lives. People die because TB is not diagnosed and treated in those with known HIV infection and HIV infection is not diagnosed in those with TB. Even in those in whom both HIV and TB are diagnosed and treated, this often happens far too late. These deficiencies can be addressed through the application of new scientific evidence and diagnostic tools.

Discussion

A strategy of starting antiretroviral therapy (ART) early in the course of HIV infection has the potential to considerably reduce both individual and community burden of TB and needs urgent evaluation for efficacy, feasibility and broader social and economic impact. Isoniazid preventive therapy can reduce the risk of TB and, if given strategically in addition to ART, provides synergistic benefit. Intensified TB screening as part of the “Three I''s” strategy should be conducted at every clinic, home or community-based attendance using a symptoms-based algorithm, and new diagnostic tools should increasingly be used to confirm or refute TB diagnoses. Until such time when more sensitive and specific TB diagnostic assays are widely available, bolder approaches such as empirical anti-TB treatment need to be considered and evaluated. Patients with suspected or diagnosed TB must be screened for HIV and given cotrimoxazole preventive therapy and ART if HIV-positive. Three large randomized trials provide conclusive evidence that ART initiated within two to four weeks of start of anti-TB treatment saves lives, particularly in those with severe immunosuppression. The key to ensuring that these collaborative activities are delivered is the co-location and integration of TB and HIV services within the health system and the community.

Conclusions

Progress towards reducing HIV-associated TB deaths can be achieved through attention to simple and deliverable actions on the ground. John Donne, Meditation XVII, Devotions upon Emergent Occasions: … any mans death diminishes me because I am involved in Mankinde; And therefore never send to know for whom the bell tolls; it tolls for thee ….     

Post-transplant cyclophosphamide and bortezomib inhibit dendritic cell maturation and function and alter their IκB and NFκB

Impairing dendritic cell (DC) function to prevent graft versus host disease (GvHD) is an appealing concept. DC antigen presentation is NF-κB pathway-dependent and bortezomib might therefore play a role in preventing alloreactivity. We obtained DC from the blood of patients enrolled in a phase I study using post-transplant cyclophosphamide and bortezomib for prevention of GvHD. Control samples were obtained from patients receiving standard GvHD prevention regimen. Pre-treatment samples were also collected from enrolled patients. DC isolated on days + 1, + 4, and + 7 showed progressive decrease in the expression of maturation markers in comparison to control. In a DC–CD4 + mixed lymphocyte reaction (MLR) where DC isolated from the recipient blood before graft infusion were the stimulator cells, T cell proliferation measured by bromodeoxyuridine (BrdU) integration was decreased in samples obtained on days + 14 and + 21 in comparison to control group. Finally, measured by real-time PCR, the expression of IκB progressively increased while the expression of NF-κB decreased in DC on days + 1, + 4, and + 7, in comparison to pre-treatment paired controls. We conclude that our data further justify exploring the role of bortezomib in GvHD prevention and propose a novel mechanism of action of bortezomib in DC.     

Androgens and male aging：current evidence of safety and efficacy

Many signs of aging,such as sexual dysfunction,visceral obesity,impaired bone and muscle strength,bear a close resemblance to features of hypogonadism in younger men. The statistical decline of serum testosterone in aging men is solidly documented. It has been presumed that the above features of aging are related to the concurrent decline of androgens,and that correction of the lower-than-normal circulating levels of testosterone will lead to improvement of symptoms of aging. But in essence,the pivotal question whether the age-related decline of testosterone must be viewed as hypogonadism,in the best case reversed by testosterone treatment,has not been definitively resolved. Studies in elderly men with lower-than-normal testosterone report improvement of features of the metabolic syndrome,bone mineral density,of mood and of sexual functioning. But as yet there is no definitive proof of the beneficial effects of restoring testosterone levels to normal in elderly men on clinical parameters. Few of these studies meet as yet rigorous standards of scientific enquiry：double-blind,placebo-controlled design of the study. The above applies also to the assessment of safety of testosterone administration to elderly men. There is so far no convincing evidence that testosterone is a main factor in the development of prostate cancer in elderly men and guidelines for monitoring the development of prostate disease have been developed. It is of note that there are presently no long-term safety data with regard to the prostate. Polycythemia is another potential complication of testosterone treatment. It is dose dependent and can be managed with dose adjustment.     

Microsurgery and music: Parallel ideas and philosophy?

Can a philosophic analogy be drawn between music, a major formal area and discipline of the fine arts, and microsurgery, a branch of applied medical science and research? Is an interdisciplinary view of value? Should we look for links beyond the stated boundaries of each of these areas? These are questions that fascinate physicians who, apart from their professional scientific activity, are also involved in making music a way to enrich their lives. In this paper a medical researcher, physician, and composer gives words to his thoughts about the parallel ideas and philosophies of these two disciplines. © 2007 Wiley‐Liss, Inc. Microsurgery, 2007.     

Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: a dose-response study

This study evaluated the effects of neonatal exposure to different doses of diethylstilbestrol (DES) or estradiol valerate (EV) on penile morphology, penile skeletal muscles, and fertility. Male pups received DES or EV at a dose of 10 microg, 1 microg, 100 ng, 10 ng, or 1 ng per rat on alternate days from postnatal days 2-12. Fertility was tested at 120 days, and tissues were examined at 150 days. Generally, DES and EV induced similar effects within the 10- and 1-microg groups. Fertility was reduced to 0; the weight, length, and diameter of the penis and the weight of penile skeletal muscles, especially bulbocavernosus muscle, were decreased (P <.05) in a dose-dependent manner; the preputial sheath was partially released or its release was delayed; testicular descent was delayed; and the cavernous spaces and smooth muscle cells in the corpora cavernosa penis were replaced by fat cells. Conversely, all of the above parameters were similar in controls and the lower dose groups, except in the 100-ng DES group, in which 4 of 7 males did not sire pups (compared with 1 of 7 in controls and 2 of 6 in the 100-ng EV group). The loss of fertility in these 4 males of the DES group and 1 male of the EV group was associated with partial release of the preputial sheath and abnormal penile morphology. Plasma testosterone was reduced (P <.05) in the 100-ng and higher dose groups for DES and EV. Hence, neonatal exposure to DES or EV at a cumulative dose of 600 ng per rat or more lowers fertility, which is associated with permanent alterations in penile morphology and penile skeletal muscles and decreased testosterone.     

A dose‐dependent dual effect of oestrogen on voiding in the male mouse?

OBJECTIVES: To explore the effect of different degrees of oestrogenization on male voiding, by treating adult castrated and 5alpha-dihydrotestosterone (DHT)-maintained male mice with different doses of oestrogens, as exposure of male mice to excessive amounts of oestrogens can cause bladder outlet obstruction (BOO); in addition, male mice lacking oestrogen receptor (ER)alpha (ERKO) or ERbeta (BERKO) were studied to assess the importance of ER subtypes. MATERIALS AND METHODS: Castrated, DHT-maintained adult mice were treated with 17beta-oestradiol (E(2); 50 and 250 microg/kg) or oestrone (E(1); 5, 50 and 500 microg/kg) daily for 10 days. Control mice were treated only with the vehicle. BERKO and ERKO mice, and their wild-type littermates used as their controls, remained untreated. Under anaesthesia, the bladder and distal urethra were exposed to record simultaneously the bladder pressure and urinary flow rate from the distal urethra. RESULTS: E(2)-treated mice showed obstructive voiding, seen as increased bladder pressure, decreased average flow rate and prolonged micturition time. This was also evident when a high dose (500 microg/kg) of E(1) was used. After treatment with a dose of 50 microg/kg, the urodynamic variables were similar to those in the control mice. Surprisingly, after treatment with a low dose (5 microg/kg) all urodynamic variables improved. There was a minor increase in the bladder pressure in BERKO mice; ERKO mice had a significantly lower urinary flow rate. CONCLUSIONS: High doses of oestrogens caused BOO in castrated, DHT-maintained male mice. A small dose of E(1) had a positive effect on voiding, suggesting that oestrogens are needed for normal male voiding. Reduced urinary flow rates in ERKO mice suggest that oestrogen effects on voiding are mediated at least partly via ERalpha.     

Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis

The link between endocrine disruptors and altered blood glucose homeostasis has been recently suggested. Epidemiological studies have correlated levels of phthalates, dioxins and persistent organic pollutants with alterations of blood glucose homeostasis in humans. Environmentally relevant doses of the ubiquitous endocrine disruptor bisphenol-A (BPA) have profound effects on mice endocrine pancreas--an essential tissue involved in glucose metabolism. BPA exerts rapid non-genomic effects on insulin releasing beta-cells and glucagon releasing alpha-cells within freshly isolated islets of Langerhans. In vivo, a single BPA injection of 10 microg/kg rapidly increases plasma insulin and concomitantly decreases glycaemia. When mice were treated with BPA 100 microg/kg/day for 4 days, the environmental oestrogen produced an increase in beta-cell insulin content along with a post-prandial hyperinsulinaemia and insulin resistance. The results reviewed here demonstrate that doses well below the current lowest observed adverse effect level considered by the US-EPA, disrupt pancreatic beta-cell function producing insulin resistance in male mice. Therefore, this altered blood glucose homeostasis by BPA exposure may enhance the risk of developing type II diabetes.     

Cuscuta chinensis flavonoids alleviate bisphenol A‐induced apoptosis of testicular cells in male mice offspring

Bisphenol A (BPA) is a widespread environmental endocrine disruptor that has multiple effects on reproductive organ development. To investigate the effect of Cuscuta chinensis flavonoids (CCFs) on testicular apoptosis induced by BPA in male mice offspring, pregnant mice were administered intragastrically with BPA and CCF at gestation day (GD) 0.5–17.5. The testes of male offspring (F1 males) were collected at post‐natal day (PND) 21 and PND 56 for the detection of related indicators. The results showed that compared with the BPA group, the testicular index in CCF groups was significantly increased at PND 21 (p < .01). For the mice of different concentrations of CCF groups, the expression levels of bax, caspase‐9 and caspase‐7 proteins were significantly decreased at PND 21 and PND 56, while the expression level of bcl‐2 protein was significantly increased, and testicular apoptotic cells were also decreased significantly (p < .01 or p < .05). Forty mg/kg CCF has no significant difference compared with the control group. The results indicated that CCF could protect the testis development of F1 male mice by alleviating the apoptosis of testicular cells induced by BPA.     

Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats

Impaired growth in utero predicts a low nephron number and high blood pressure later in life as does slowed or accelerated growth after a normal birth weight. We measured the effects of early postnatal growth restriction, with or without prenatal growth restriction, on blood pressure and nephron number in male rat offspring. Bilateral uterine artery and vein ligation were performed to induce uteroplacental insufficiency (Restricted) on day 18 of pregnancy. Postnatal growth restriction was induced in a subset of sham operated control animals by reducing the number of pups at birth to that of the Restricted group (Reduced Litter). Compared to Controls, Restricted pups were born smaller while Reduced Litter pups weighed less by postnatal day 3 and both groups remained lighter throughout lactation. By 10 weeks of age all animals were of similar weight but the Reduced Litter rats had elevated blood pressure. At 22 weeks, Restricted but not Reduced Litter offspring were smaller and the blood pressure was increased in both groups. Restricted and Reduced Litter groups had fewer glomeruli and greater left ventricular mass than Controls. These results suggest that restriction of both perinatal and early postnatal growth increase blood pressure in male offspring. This study also demonstrates that the early postnatal period is a critical time for nephron endowment in the rat.     

邻苯二甲酸二-(2-乙基)己酯致小鼠隐睾睾丸和附睾的组织病理学改变

目的 :探讨邻苯二甲酸二 (2 乙基 )己酯 (DEHP)引起的小鼠隐睾睾丸和附睾的组织病理学改变。　方法 :妊娠KM小鼠 4 0只 ,随机分成 5组 ,分别为正常对照组 8只、玉米油对照组 8只、己烯雌酚 (DES)组 8只、DEHP低剂量组 [DEHP 10 0mg/ (kg·d) ]9只和DEHP高剂量组 [DEHP 5 0 0mg/ (kg·d) ]7只。自妊娠第 12d开始到分娩后 3d ,分别持续经口给予DEHP 10 0mg/ (kg·d)、5 0 0mg/ (kg·d)和DES 10 0 μg/ (kg·d)及玉米油 ,观察仔代雄小鼠的隐睾发生率及隐睾睾丸和附睾的组织病理学改变。　结果 :DEHP 5 0 0mg/ (kg·d)组染毒小鼠的隐睾发生率显著增高 ,睾丸和附睾的体积明显减小、重量减轻 ;睾丸生精上皮发育明显异常 ,精曲小管变薄、萎缩 ,间质细胞异常增生 ,电镜下其隐睾精曲小管上皮和间质细胞均出现明显的超微结构改变。同时附睾管腔中的精子数显著减少甚至缺乏。　结论 :高剂量 [5 0 0mg/ (kg·d) ]DEHP可能具有与DES类似的作用 ,是一种诱发隐睾的重要因子。小鼠在孕期及哺乳期接触DEHP后可引起雄性仔鼠性分化异常 ,诱导隐睾发生、睾丸生精上皮损害和生精过程障碍 ,从而对雄性仔鼠生育力产生不利影响。以上作用存在明确的量 效关系。     

Renal structure and function evaluation of rats from dams that received increased sodium intake during pregnancy and lactation submitted or not to 5/6 nephrectomy

Adult rats submitted to perinatal salt overload presented renin-angiotensin system (RAS) functional disturbances. The RAS contributes to the renal development and renal damage in a 5/6 nephrectomy model. The aim of the present study was to analyze the renal structure and function of offspring from dams that received a high-salt intake during pregnancy and lactation. We also evaluated the influence of the prenatal high-salt intake on the evolution of 5/6 nephrectomy in adult rats. A total of 111 sixty-day-old rat pups from dams that received saline or water during pregnancy and lactation were submitted to 5/6 nephrectomy (nephrectomized) or to a sham operation (sham). The animals were killed 120 days after surgery, and the kidneys were removed for immunohistochemical and histological analysis. Systolic blood pressure (SBP), albuminuria, and glomerular filtration rate (GFR) were evaluated. Increased SBP, albuminuria, and decreased GFR were observed in the rats from dams submitted to high-sodium intake before surgery. However, there was no difference in these parameters between the groups after the 5/6 nephrectomy. The scores for tubulointerstitial lesions and glomerulosclerosis were higher in the rats from the sham saline group compared to the same age control rats, but there was no difference in the histological findings between the groups of nephrectomized rats. In conclusion, our data showed that the high-salt intake during pregnancy and lactation in rats leads to structural changes in the kidney of adult offspring. However, the progression of the renal lesions after 5/6 nephrectomy was similar in both groups.     

The effect of mahogunin gene mutant on reproduction in male mice: a new sight for infertility?

Mahogunin is an important mediator of chromogenesis and neurodegeneration. Mahoganoid is a mutation of the mahogunin gene, which causes a pleiotropic phenotype that includes suppression of obesity, spongiform neurodegeneration and improvement of insulin sensitivity. Our previous research found that mahoganoid widely expressed in the male rat reproductive system, and mahoganoid‐deficient mice have reduced embryonic viability. But the reproductive change in mahogunin knockout (md^nc) male mice has not been reported previously. Here, we report that the mahogunin mRNA also widely exists in reproductive system of male mice, and its mRNA expression in the testis was in accordance with the first spermatogenesis wave cycle. Moreover, we find that md^nc male mice were able to mate with females but no pups are delivered. Besides, the sperms' active progressive motility and hormone secretion (E2, FSH, LH, PRL) were obviously decreased while abnormal sperm rate showed no significant difference in md^nc compared to wild‐type (WT) male mice. This study indicates the mahogunin deficiency results in the infertility of male mice, disruption of hormones secretion and impaired active progressive motility, which may additionally illuminate the aetiology of male infertility in human.     

用模拟经期内膜组织建立子宫内膜异位症小鼠模型及其生殖能力的研究

目的建立子宫内膜异位症(EM)模型小鼠,观察EM模型小鼠的生殖能力,探讨影响其生殖能力的可能原因。方法将51只8周龄雌性C57BL/6小鼠作为受体,并随机分为模型组(n=21)、假手术组(n=15)和空白组(n=15)。用模拟小鼠经期内膜组织腹腔注射的方法建立EM模型;将同等剂量的供体腹腔脂肪组织碎片注入假手术组小鼠的腹腔中;空白组不进行腹腔注射。观察3组小鼠的动情周期,于动情间期采血。将3组小鼠合笼至出现阴栓,统计各组小鼠的胚胎种植数、妊娠率、吸收胎率等。运用酶联免疫吸附法(ELISA法)检测各组小鼠血清FSH、LH、糖类抗原125(CA125)浓度及腹腔液中白介素-2(IL-2)水平,比较各组间的水平差异。结果成功建立EM小鼠模型,模型组小鼠动情周期规律。模型组小鼠的妊娠率显著低于假手术组、空白组(P0.05);3组小鼠的吸收胎率、畸胎率、胚胎重量、顶臀径等比较无显著性差异(P0.05)。模型组不孕鼠的血清FSH浓度、腹腔液IL-2浓度显著高于妊娠实验前的模型组、假手术组和空白组(P0.01);血清LH、CA125浓度在各组间无显著性差异(P0.05)。结论用模拟经期内膜组织腹腔注射的方法可以成功建立EM模型,模型组不孕鼠的卵巢功能、腹腔免疫微环境受到了影响,可能是造成生殖能力下降的重要原因。     

Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer

PURPOSE: We determined if a single intravesical instillation of gemcitabine (2',2'-difluorodeoxycytidine) could prevent the implantation of urothelial cancer cells in the bladder wall of mice, and if 4 weekly treatments could eliminate early implanted bladder cancer in this model. MATERIALS AND METHODS: Tumor implantation and orthotopic bladder tumors were induced in mice by electrocautery of the bladder wall and subsequent instillation of MB49 bladder cancer cells. In the first experiment the tumor cell suspension was left in place for 30 minutes, immediately followed by bladder irrigation and a single intravesical instillation of 250 or 500 microg gemcitabine for 10, 30, 60 or 120 minutes. In the second experiment dwell time was 2 hours, bladders were not irrigated after tumor cell instillation and mice were treated with 4 weekly instillations starting 24 hours after tumor cell implantation. The animals were monitored for side effects and bladder cancer signs, and autopsied at the end of followup. RESULTS: A single intravesical instillation of 500 microg gemcitabine (10 mg/ml) for 30 minutes decreased tumor outgrowth significantly from 90% (control) to 30% (chi-square test p = 0.022). Gemcitabine at 250 microg and prolonged instillations of 500 microg during 60 or 120 minutes were less effective. In the second experiment a short dwell time (30 minutes) was effective at 500 microg doses, resulting in an outgrowth decrease in 89% (control) to 30% of mice, whereas longer instillations (greater than 120 minutes) resulted in significantly reduced tumor outgrowth (11% at 250 microg). The apparent loss of efficacy as a factor of time could not be fully explained. Prolonged bladder distention caused by increased bladder volume due to diuresis may have resulted in trauma and caused enhanced susceptibility to tumor implantation. In the second experiment prolonged instillations (greater than 120 minutes) at 250 microg or higher doses (500 microg) were effective with 11% and 30% outgrowth, respectively. CONCLUSIONS: If given early (within 30 minutes.) after tumor cell seeding, gemcitabine is effective for preventing tumor cell implantation and the resulting tumor outgrowth.