Paclitaxel and cisplatin as intravesical agents against non-muscle-invasive bladder cancer.

OBJECTIVES: To investigate the effects of cisplatin and paclitaxel against human bladder cancer cells in vitro, and to obtain both pharmacokinetic and pharmacodynamic data after intravesical administration in mice. MATERIALS AND METHODS: Six bladder cancer cell lines (J82, KU7, RT4, SW780, T24, UMUC3) were treated with various combined doses of both drugs and cell proliferation was evaluated 3 days later. In vivo, solutions of cisplatin and micellar paclitaxel were instilled transurethrally in female mice and pharmacokinetic data were acquired using high-performance liquid chromatography-mass spectrometry and atomic absorption methods. To obtain efficacy data, mice with orthotopic KU7-luc tumours were administered cisplatin and/or micellar paclitaxel intravesically, and the tumour burden quantified using bioluminescence imaging. RESULTS: In vitro, both cisplatin and paclitaxel potently decreased the proliferation of all cell lines tested, and in combination had an additive but not a synergistic effect. After intravesical instillation, mouse serum concentrations of cisplatin and paclitaxel were in the low microgram/millilitre range and bladder tissue concentrations achieved were 82 and 241 microg/g, respectively. Similar drug levels were reached using combined therapy. In vivo, all chemotherapeutic agents significantly inhibited bladder tumour growth, with the best results for combined therapy and micellar paclitaxel alone. However, there was toxicity in the combined treatment arm. CONCLUSIONS: Both cisplatin and paclitaxel were absorbed at effective amounts into bladder tissues. As intravesical agents, paclitaxel had slightly stronger anticancer potency than cisplatin. Due to increased adverse events, caution should be exercised when combining both cisplatin and paclitaxel intravesically.

Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy.

OBJECTIVES: To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re-introduce chemosensitivity in a docetaxel-resistant, androgen-independent human prostate cancer model. PATIENTS AND METHODS: A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG-P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC-3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel-resistant cell subline (PC-3dR) was developed and analysed. RESULTS: sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5-fold in the newly developed docetaxel-refractory PC-3dR cell line compared with parental PC-3 cells. There was a dose-dependent and sequence-specific decrease in sCLU levels in PC-3dR cells using OGX-011, an antisense oligonucleotide against human sCLU. OGX-011 and small-interference RNA both chemosensitized PC-3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC-3dR cells were significantly increased when OGX-011 was combined with docetaxel. In vivo, growth of PC-3dR xenografts in nude mice was synergistically inhibited by OGX-011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively). CONCLUSION: The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel-refractory cells, and provide preclinical proof of principle for clinical trials testing OGX-011 in second-line chemotherapy regimens for patients with docetaxel-refractory prostate cancer.

Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin.

Therapeutic resistance is the underlying cause for most cancer deaths and a major problem associated with treatment of metastatic prostate cancer. HTI-286, a fully synthetic analog of the natural tripeptide hemiasterlin, inhibits tubulin polymerization and circumvents transport-based resistance to taxanes. In our study, we evaluated its inhibitory effects on human prostate cancer growth in vitro and in different in vivo models. Androgen-dependent and androgen-independent prostate cancer cell lines including a docetaxel-refractory PC-3 subline (PC-3dR) were treated with HTI-286. Transcriptional profiling was carried out to screen for changes in gene expression induced by HTI-286 and compared to docetaxel. In vivo, nude mice with established PC-3 or PC-3dR xenografts were given HTI-286 intravenously. Additionally, mice bearing hormone-sensitive LNCaP tumors were treated with castration in combination with early or delayed HTI-286 therapy. In all cell lines tested, HTI-286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI-286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds. Invivo, HTI-286 significantly inhibited growth of PC-3 and LNCaP xenografts and retained potency in PC-3dR tumors. Simultaneous castration plus HTI-286 therapy was superior to sequential treatment in the LNCaP model. In conclusion, HTI-286 showed strong antitumor activity both in androgen-dependent and androgen- independent tumors and may be a promising agent in second- line treatment strategies for patients suffering from docetaxel- refractory prostate cancer.

Novel targets and approaches in advanced prostate cancer.

PURPOSE OF REVIEW: The development of therapeutic resistance is the underlying cause for most cancer deaths. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in prostate cancer, the rational design of targeted therapeutics is possible. We review new treatment options for men with advanced prostate cancer. RECENT FINDINGS: Although the taxanes currently represent the most active chemotherapeutic agents and standard of care for first-line treatment of metastatic hormone-refractory prostate cancer, most patients eventually progress because of intrinsic or acquired drug resistance. In recent years, increased knowledge of cancer progression and therapeutic resistance has identified many gene targets that regulate apoptosis, proliferation, and cell signalling. To date, numerous novel compounds have entered clinical trials as either single agents or in combination with cytotoxic chemotherapy. SUMMARY: Even though hormone-refractory prostate cancer is still incurable, it is not untreatable. As cancer cells are proficient at adapting to therapeutic stressors, a combination regimen with drugs that target crucial cellular networks like the apoptotic rheostat may be more promising than treatment with highly selective single-target agents. Recent findings are very hopeful, but challenges remain to demonstrate effective antitumour activity in phase III trials with survival as the principal endpoint.

Therapeutic options in advanced prostate cancer: present and future.

Patients with advanced prostate cancer now have many treatment options available including first- and second-line hormonal therapy, radiotherapy, bisphosphonate therapy with zoledronic acid, and taxane-based chemotherapy. These options now give clinicians an opportunity to offer their patients symptomatic relief and most importantly improve overall survival. This article reviews the current treatment options available for men with advanced prostate cancer. In addition, novel treatment options under development, including calcitriol, immunotherapies, small molecule inhibitors, and nucleotide-based targeted therapy, are discussed.

Parameters affecting urologic complications after major joint replacement surgery.

INTRODUCTION AND OBJECTIVES: Peri-operative bladder management after major arthroplasty procedures remains controversial. The purpose of this study was to assess the risk of urological complications in those patients undergoing hip or knee joint replacement. As well, we identified those factors that may affect the likelihood of developing complications. METHODS: Two hundred and twenty-one consecutive patients receiving a total knee or hip arthroplasty were reviewed. The outcomes measured were prolonged urinary retention, as well as urinary tract infections and the development of a septic prosthesis. Statistical significance of any predisposing factors identified was determined using a two-tailed Fisher exact test. RESULTS: Urological complications in the cohort were common at 47%, with patients having hip arthroplasty being at higher risk (p < 0.03). Despite this there was a low incidence of documented infections. Increased rates of urinary retention were identified in those who received intrathecal narcotics (p < 0.02), as well as those who suffered from hypertension (p < 0.05). Gender and anesthetic techniques (general or regional) did not affect the rate of complications. There was a decrease in urological complications when bladder management included peri-operative catheterization rather than expectant management. CONCLUSIONS: Bladder management is a significant problem for patients after hip and knee arthroplasty as urinary retention was identified in almost half of the patients. Parameters that may identify those with higher risks include patients with hypertension and those who receive intrathecal narcotics. In high-risk patients, the practice of utilizing a catheter peri-operatively may decrease the risk of multiple post-operative catheterizations without increasing the rate of infections.

Experimental intraprostatic injection of bacillus Calmette-Guerin: a feasibility and safety study.

PURPOSE: We investigated the feasibility and safety of intraprostatic administration of bacillus Calmette-Guerin (BCG) and determined the histological changes induced by this approach. MATERIALS AND METHODS: A total of 36 healthy male beagle dogs 2.2 to 3.6 years old weighing 10.0 to 14.8 kg were randomly assigned to 6 experimental groups. Four groups were given intradermal BCG vaccination and 6 weeks later they were given 0 (group 1), 10 (group 2), 5 x 10 (group 3) or 10 (group 4) BCG organisms intraprostatically. An additional group received prevaccination, followed 6 weeks later by a dose of 10 BCG organisms intraprostatically and then 6 weeks of antibiotics (group 5). Another group receiving no prevaccination and 5 x 10 BCG organisms intraprostatically at week 6 were included (group 6). RESULTS: Adverse reactions (ARs) were seen in 12 dogs, including inguinal lymphadenopathy in 3, an anal lesion in 5, constipation in 7 and dysuria in 3. There was a trend toward an increased incidence of ARs in high dose groups 3 and 4, fewer ARs in group 5 and no ARs in group 6. There was minimal evidence of systemic dissemination of BCG in any group. Post-necropsy histological analysis indicated higher inflammation as well as glandular destruction in high dose groups 3 and 4. Antibiotics did not seem to lessen the histological response to intraprostatic BCG injection (group 5). Interestingly in nonvaccinated group 6 the level of inflammation as well as glandular destruction was higher. CONCLUSIONS: Our results indicate that intraprostatic BCG administration in dogs is a safe and well tolerated procedure. It is free of major or long lasting serious complications.

Growth characteristics of renal cortical tumors in patients managed by watchful waiting.

OBJECTIVE: To characterize tumor growth of patients managed conservatively for renal cell carcinoma. METHODS: Patients electing conservative management of radiographically determined renal cell carcinomas were referred to a surveillance database. Exclusion criteria consisted of locally advanced disease (>T2) and those with metastatic disease. Clinical follow-up included renal imaging with ultrasound or computed tomography at least every 6 months. RESULTS: Twenty-two patients were originally managed conservatively, two of whom subsequently underwent nephrectomy because of rapid tumor growth. Mean follow-up was 26 months. Mean tumor volume and diameter at presentation was 62.4 cc and 4.08 cm respectively. Overall tumor growth was 24 cc/year by volume or .86 cm/year diameter. CONCLUSIONS: Given the stage migration of incidentally detected renal masses, the natural history of these tumors remains incomplete. Overall tumor growth in selected populations appear to be slow even in those diagnosed with larger masses. These data may be useful in counseling patients and directing further trials on conservative therapy for renal cell carcinoma.

Long-term penile incarceration by a metal ring resulting in urethral erosion and chronic lymphedema.

A patient presented with a metal ring around the base of his penis. The ring had been placed 3 years prior to presentation. Intra-operative findings revealed a ventral erosion with complete transection of the urethra and massive fixed lymphedema of the penile skin distal to the ring. Treatment consisted of removal of the ring with metal shears and bolt cutters. Small reduction of the edema was seen 3 months following removal, and the patient refused further treatment. The most interesting part of the outcome was the preservation of penile urethral voiding although intromission was not possible.