Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine.

OBJECTIVE: To assess the involvement of the multidrug resistance-associated protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR) phenotype of prostate cancer in vitro. MATERIALS AND METHODS: Chemoselection of human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye viability assays. Western blot analysis of MRP1 expression and glutathione content were measured, and MRP1 function assessed in fluorescence assays. RESULTS: MRP1 was increased in the MDR models; the glutathione content was significantly higher in PC3-R but there was no increase in glutathione in DU-R. Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited with MK-571 in the MDR models. CONCLUSION: MRP1 and glutathione mediate MDR in newly developed prostate cancer models.

Multidrug resistance in prostate cancer.

Advanced hormone-refractory prostate cancer remains a therapeutic challenge, because all available pharmaceutical concepts have been ineffective in improving cancer-specific survival. Failure of chemotherapy may be caused by multidrug resistance (MDR) mechanisms protecting cancer cells against cytotoxic drugs, and the question arises whether prostate cancer is also using MDR principles resulting in resistance against chemotherapeutic agents. In consequence, an array of diverse pathways known to lead to MDR such as MDR1, MRPs, glutathione, and apoptosis have been examined and partially established at varying degrees in hormone-refractory prostate cancer. Thus, evidence keeps accumulating for the involvement of some MDR mechanisms in the chemoresistance of prostate cancer in vitro and in vivo. For some of them, e.g. MRP1, functional expression appears to be probable. This lends credit to the idea that reversal, circumvention, or overcoming of MDR pathways in advanced prostate cancer may be feasible and will lead to new avenues with improved treatment efficacy in otherwise intractable disease.

Rational selection of a control arm for randomised trials in metastatic renal cell carcinoma.

OBJECTIVE: Immunotherapy, and only immunotherapy, has reproducible, albeit limited efficacy in metastatic renal cell cancer (MRCC). Further improvement is warranted and progress will have to be investigated in randomised clinical trials, because the variable natural history of this disease precludes firm conclusions outside the context of controlled clinical studies. Currently, there is no general accepted standard arm to compare for those randomised clinical protocols. This needs to be established, which is the goal of this project. MATERIALS AND METHODS: Interferon-alpha (IFN-alpha) or interleukin-2 (Il-2) are registered for the use in MRCC. Taking this regulatory affair into consideration, a systematic literature research using Medline Sources was carried out to identify large controlled clinical studies in MRCC, in which one or both of the registered drugs were involved. Scientific value of the trials was weighed, and the applicability, efficacy, and safety of the control arm was analysed. RESULTS: 13 large controlled studies qualified for this purpose, and a total of 3065 patients were included. IFN-alpha monotherapy, the combination of IFN-alpha and Il-2, and the combination of IFN-alpha, Il-2 and 5-fluorouracil (5-FU) were used as a standard treatment in decreasing frequency, respectively. There is no valid scientific proof that a combination of immunotherapies prolongs survival over monotherapies, but the combination of surgery and immunotherapy leads to a clear survival benefit over immunotherapy alone. IFN-alpha monotherapy has considerable less side effects than Il-2 based regimens. CONCLUSION: An appealing safety profile, the applicability in an outpatient regimen, the possibility of less stringent selection criteria, and the proven life prolonging effect will make adjuvant monotherapy, in particular IFN-alpha monotherapy, after a tumournephrectomy currently the control-arm of choice in randomised trials for MRCC.

The plication procedure for penile curvature: surgical outcome and postoperative sexual functioning.

OBJECTIVE: This study evaluates the patients' judgement of the surgical outcome of the plication procedure, as described by Schröder and Essed, and the postoperative sexual functioning of patients with congenital curvatures and Peyronie's disease. PATIENTS AND METHODS: Of 98 patients treated for penile curvatures between 1985 and 1996, 85 patients received postoperatively a 'Questionnaire Assessing the Outcome of Surgery' and a short version of the 'Questionnaire for Screening Sexual Dysfunctions'. RESULTS: 28 patients with congenital curvatures and 31 with Peyronie's disease were evaluated. 75% of the patients with congenital curvatures and 58% of the patients with Peyronie's disease were satisfied with the result. Patients treated for Peyronie's disease reported diminished penile length and inability to have sexual intercourse more often than patients with congenital curvatures (90 vs. 64%, and 29 vs. 0%). After correction for age, patients with Peyronie's disease were less satisfied with their present sex life, had more frequent erectile problems and more trouble with considerable sexual desire than a group of 42 controls. For patients with Peyronie's disease satisfaction with the result was positively correlated with satisfaction with their present sex life and negatively correlated with the frequency of erectile problems. For patients with congenital curvatures satisfaction with the result was negatively correlated with both a postoperative curvature and a repeat operation. CONCLUSIONS: Some patients with Peyronie's disease may not benefit from surgical correction (alone). Because of the occurrence of sexual problems, future evaluation of the role of pre- and postoperative sexological counselling in achieving better results is recommended.

Principles of nephrectomy for malignant disease.

For many years the prevailing belief was to advocate'radical' nephrectomy via a transperitoneal approach as the standard surgical procedure for renal cell carcinoma (RCC). because the early control of the renal vessels before manipulating the kidney should minimize the likelihood of disseminating tumour cells during surgery. This philosophy was based on retrospective data which were never confirmed in a controlled trial. Since then,evidence has accumulated that some patients maybe better served by an extraperitoneal (translumbar)approach, providing similar oncological efficacy with the added advantage of reduced morbidity. However,these results are again either retrospective or statistically insignificant, and therefore do not allow firm conclusions. Nevertheless, if there is any difference in the possible intraoperative dissemination of tumour, depending on the type of surgical approach, it will be small, requiring analysis in a large randomized multicentre trial. The treatment of choice for disease that is not disseminated is surgery, although the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvements will probably have to rely on the development of more effective systemic therapy and the application of combined treatments to counter the relatively many patients presenting with advanced stages. Concepts and progress in this field appear to be of major interest for modern uro-oncologists after the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.

A phase II trial of methotrexate-human serum albumin (MTX-HSA) in patients with metastatic renal cell carcinoma who progressed under immunotherapy.

INTRODUCTION: Renal cell carcinoma (RCC) has a poor prognosis when metastasized to distant sites, although immunotherapy may offer a prolongation of survival in selected patient groups. Unfortunately, no treatment options remain when immunotherapy fails. In this phase IIa trial the tolerability and efficacy of the antifolate drug methotrexate-human serum albumin (MTX-HSA) were evaluated in patients with metastatic RCC who progressed after first-line immunotherapy. PATIENTS AND METHODS: A total of 17 patients started treatment, and 14 (12 men, 2 women) were evaluable for response according to the phase IIa Gehan design. Patients had had prior tumor nephrectomy, were in relatively good general condition, had no impairment of renal, liver or bone marrow function, and had progressive metastatic disease after treatment with interferon-alpha (IFN-alpha) with or without cis-retinoic acid (EORTC protocols 30951 and 30947). MTX-HSA was given once a week intravenously on an outpatient basis at a dose of 50 mg/m(2). The treatment interval was prolonged in those patients who had not yet recovered from previous toxicities. RESULTS: Toxicity was manageable, relatively mild to moderate and reversible in most cases. Grade 2/3 mucositis (10/17) and grade 3 elevated transaminase levels (4/17) were most frequent, and in only one patient was a grade 4 thrombocytopenia reported. Of three inevaluable patients, one discontinued treatment due to drug-related toxicities. The mean administration interval was 12.1 days, and 7 of 14 evaluable patients had treatment intervals of 1 or 2 weeks. No objective responses were seen, although eight patients had stable disease (stabilization >2 months) for up to 8 months (median 121 days). CONCLUSION: MTX-HSA was generally well tolerated and can be given on an outpatient basis, but no objective responses were seen in patients with metastatic RCC who had progressed after previous immunotherapy.