Molecular urology最新文献

{"title":"Cytokine gene therapy for cancer with naked DNA.","authors":"Masaaki Nishitani, T. Sakai, H. Kanayama, K. Himeno, S. Kagawa","doi":"10.1089/10915360050138576","DOIUrl":"https://doi.org/10.1089/10915360050138576","url":null,"abstract":"Plasmid DNA vectors (naked DNA) can easily be purified and transferred in vivo by intramuscular or intradermal injection. Naked DNA is stable in vivo, and long-term expression of the encoded protein is seen without chromosomal integration. Gene gun-mediated delivery of an expression plasmid is slightly more complicated but more efficient. These techniques have been applied to DNA vaccination or cytokine gene therapy for various diseases, including infections, autoimmune disorders, and cancer. We review cytokine gene therapy for cancer with naked DNA in animal models and present our preliminary data on gene gun-mediated in vivo transfection with the interleukin-12 gene in a murine renal cancer model. Because of its safety, simplicity, and low cost, cytokine gene therapy with naked DNA may become an important cancer treatment.","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 2 1","pages":"47-50"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/10915360050138576","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60626335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nephron-sparing surgery is still controversial for patients with renal cell carcinoma and normal contralateral kidney: risks predictable by AgNOR counts in satellite lesions.","authors":"M Kobayashi,&nbsp;S Hashimoto,&nbsp;A Tokue","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To determine whether nephron-sparing surgery is appropriate for patients with renal cell carcinoma (RCC) and a normal contralateral kidney.</p><p><strong>Materials and methods: </strong>We prepared whole-area histologic sections from 58 cases of RCC to examine the features of satellite tumor lesions (STLs), the proliferative potential of which was evaluated by counting argyrophilic nucleolar organizing regions (AgNORs).</p><p><strong>Results: </strong>We found three types of microscopic lesions: STLs, adenomas, and dysplastic foci, the latter two of which appeared to be preneoplastic. Of the 58 cases, STLs were observed in 27 (47%) and either adenomas or dysplastic foci in 19 (33%). At least one of the three types of lesion was found in 37 cases (64%). No correlation was found between the incidence of STL and the size of the main tumor, but the incidence tended to be higher in lesions of higher grade or stage. The STLs were located >2 cm from the margin of the main tumor in 6 of the 27 cases (22%). The mean number of AgNORs per high-power field was 5.09 +/- 1.53 (SD) in the main tumors, 4.21 +/- 1.36 in the STLs, and 2.27 +/- 0.07 in the adenomas and dysplastic foci.</p><p><strong>Conclusions: </strong>These findings suggest that nephron-sparing surgery risks leaving STLs, which have considerable proliferative potential. Thus, nephron-sparing surgery must still be considered adventurous treatment in elective cases but can be recommended for patients who require nephron preservation.</p>","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 1","pages":"21-9"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21694791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-course androgen ablation combined with external-beam radiation therapy and low-dose-rate permanent brachytherapy in early-stage prostate cancer: a matched subset analysis.","authors":"J Sylvester,&nbsp;J C Blasko,&nbsp;P D Grimm,&nbsp;R Meier,&nbsp;W Cavanagh","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background and purpose: </strong>In order to evaluate the effect of short-term androgen blockade on biochemical control rates for high-risk patients receiving a combination regimen of external-beam radiation therapy and low-dose-rate permanent seed implant brachytherapy, a retrospective matched subset analysis was performed.</p><p><strong>Patients and methods: </strong>Inclusion in the high-risk cohort required at least two of the following poor prognostic factors: serum prostate specific antigen (PSA) concentration > or = 10.0 ng/mL, Gleason score > or = 7, or clinical stage T(2c) or T(3a) disease. Twenty-one patients who underwent androgen ablation between June 1991 and December 1995 in addition to combined-modality radiation therapy qualified as high risk, as did 77 patients who underwent combined-radiation therapy only. There was no statistically significant difference between the two groups in terms of follow-up (mean 44.6 v 47.8 months, respectively), pretreatment PSA, clinical stage, biopsy Gleason score, or the presence of all three poor prognostic factors.</p><p><strong>Results: </strong>The overall rates of freedom from biochemical failure at 5 years were 77% in the hormonally treated group and 58% in the nonhormonally treated group. The difference was not statistically significant by log rank test (P = 0.08).</p><p><strong>Conclusion: </strong>Longer follow-up with larger patient numbers is needed to define the role of adjuvant androgen ablation combined with radiation therapy.</p>","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 3","pages":"155-9;discussion 161"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent androgen suppression for prostate cancer: Canadian Prospective Trial and related observations.","authors":"N Bruchovsky,&nbsp;L H Klotz,&nbsp;M Sadar,&nbsp;J M Crook,&nbsp;D Hoffart,&nbsp;L Godwin,&nbsp;M Warkentin,&nbsp;M E Gleave,&nbsp;S L Goldenberg","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The Canadian Prospective Trial of intermittent androgen suppression was a prototype therapeutic initiative started in 1995 for the management of patients in biochemical relapse after radiation for localized prostate cancer. An interim analysis has yielded several observations on the relations between baseline serum prostate specific antigen (PSA), nadir serum PSA, Gleason score, and time off-treatment. In a typical androgen-dependent tumor, the response of serum PSA to androgen withdrawal is biphasic, but with early tumor progression, plateauing of serum PSA is observed. Ligand-independent activation of the androgen receptor, a mechanism subserving the initiation of androgen independence, can be counteracted experimentally with decoy molecules and clinically with nonsteroidal antiandrogens. In some patients, it is possible to lengthen the off-treatment interval by inhibiting the enzyme 5 alpha-reductase, an effect that can be reinforced by lowering serum testosterone with an antigonadotropin. Serial measurements of serum PSA indicate that intermittent androgen suppression engenders a more diverse range of hormone-related responses than previously appreciated. These include: (1) repeated differentiation of tumor with recovery of apoptotic potential; (2) inhibition of tumor growth by rapid restoration of serum testosterone; and (3) restraint of tumor growth by subnormal levels of serum testosterone. These responses are aspects of regulation that should be taken into account when planning long-term treatment of prostate cancer with intermittent androgen suppression.</p>","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 3","pages":"191-9;discussion 201"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The case for neoadjuvant androgen suppression before radiation therapy.","authors":"A L Zietman","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neoadjuvant androgen suppression (NAS) can reduce the number of tumor clonogens prior to radiation, thus increasing the tumor control probability. Also, NAS may sensitize tumor cells to radiation if cell kill by both modalities follows a common pathway. The timing and sequence of NAS and radiation are important, with radiation being most effective if given at the point of maximal tumor regression. The biologic rationale for NAS + radiation has been reinforced by results from randomized trials, in particular RTOG 8610. However, many murine adenocarcinomas respond to androgen deprivation by a reduction in the proliferation rate and arrest in G(0), and in vitro data suggest that this arrest may interfere with radiation-induced cell killing. The mechanism of cell killing after low-dose-rate radiation (brachytherapy) may be different from that after high-dose-rate treatment. There are no reported experimental data assessing the interaction of NAS and brachytherapy to determine whether the combination offers a theoretical advantage or is potentially deleterious. Whether we understand the mechanism or not, clinical trials seem to support a positive interaction of NAS with external-beam radiation, but we have only begun to explore the timing and sequence that will provide the maximal effect. It cannot be assumed that the same advantage will hold with brachytherapy.</p>","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 3","pages":"203-8;discussion 215"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative study of the clinical efficacy of two dosing regimens of flutamide.","authors":"J B Thrasher,&nbsp;J Deeths,&nbsp;C Bennett,&nbsp;P Iyer,&nbsp;M K Dineen,&nbsp;S Zhai,&nbsp;W D Figg,&nbsp;D G McLeod","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>We performed a randomized trial to compare the efficacy and toxicity of a new dose of flutamide (500 mg QD) with the currently recommended dose (250 mg q8h) in the treatment of advanced prostate cancer. The primary endpoints were percent of patients having normalization of prostate specific antigen (PSA), time to normalization, and percent change from baseline. Secondary endpoints were quality of life and toxicity.</p><p><strong>Patients: </strong>Altogether, 440 men aged 46 to 94 years (mean 71 years) with confirmed stage M(1) disease, documented PSA rise >0.2 ng/mL, ECOG status 0 to 2, no second neoplasm, no liver function tests > or = 1.5-fold normal values, and no previous treatment for metastatic disease were entered in the trial.</p><p><strong>Results: </strong>The PSA normalized by week 12 in 71% of the patients receiving 500-mg dose and 75% of those receiving the standard dose. The percent change in PSA was 89% and 96%, respectively. The treatment groups were not significantly different with respect to the incidence of adverse events: 71% v 68% in the 500-mg and 250-mg arms, respectively (P = 0.337).</p><p><strong>Conclusions: </strong>When combined with castration, 500 mg of flutamide appears to be equally effective in lowering serum PSA and is not significantly more toxic than conventional dosing. The use of 500 mg QD instead of the standard 250 mg q8h would result in a cost savings of 30%.</p>","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 3","pages":"259-63;discussion 265"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21890487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational Research Trends: Urologic Gene Therapy","authors":"M. Gong, W. Fair","doi":"10.1089/10915360050138530","DOIUrl":"https://doi.org/10.1089/10915360050138530","url":null,"abstract":"GENE THERAPY, a rapidly growing field of interest in the basic sciences, is a relatively new area of research and clinical application within urology. With increasing technological advances, the number of gene therapy-based clinical trials has increased dramatically. As such, translational research involving gene therapy for a variety of urologic diseases has also increased. In this issue, the contributors present a review of the proceedings from the First Meeting of Japanese Urological Association for Gene Therapy, held on November 20, 1999 in Okayama, Japan. An overview of the meeting was presented by the society’s first president, Dr. Kumon. A guest speaker, Dr. Asano, defined gene therapy translational research objectives and emphasized the importance of applying appropriate basic science concepts in selected preclinical models. He also stressed the careful design of good manufacturing principles and clinical trial indications, patient selection, and logistics. Specific urologic applications of gene therapy were also presented and discussed at the meeting. Gene therapy strategies can essentially be classified into three basic categories: (1) immune augmentation; (2) as a mode of delivery of cytotoxic agents; and (3) specific gene replacement. One of the earliest gene therapy strategies to augment the immune system attempted to deliver high concentrations of cytokines to localize the host immune response. Two basic cytokine delivery strategies are currently utilized: one is to vaccinate patients with tumor cells expressing a particular cytokine, and the other is to directly express cytokines within the tumor. Vaccination with cytokine-expressing tumor cells enhances the efficacy of tumor cell vaccination strategies in rodent models. The most widely utilized cytokine in current clinical trials is granulocyte-macrophage colony-stimulating factor (GM-CSF). Kawai et al., review the data of trials using GM-CSF expressing autologous tumor cells in renal cell carcinoma, malignant melanoma, and prostate cancer. Thus far, despite demonstrating histologic confirmation of host immune response at the sites of immunization, clinically evident tumoricidal responses of the in situ tumor are not yet evident. However, multiple variables need to be addressed before disregarding this approach as a viable gene therapy strategy. These variables include vaccination dosage and frequency as well as the in situ tumor burden at the time of vaccination. An alternative method to augment the host immune response with local cytokines is direct expression of the cytokine with the tumor itself. Nishitani et al. review cytokine gene therapy using naked DNA gene transfer techniques. They presented promising preliminary preclinical data using interleukin-12 (IL12) transfected in situ into subcutaneous renal cell carcinoma tumors in a murine model. One potential limitation of this strategy centers on efforts to ensure delivery of the cytokine gene into the tumor. In particular, ","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 1","pages":"37-38"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/10915360050138530","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60626291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Status and prospects of gene therapy for urologic cancer.","authors":"H. Kumon","doi":"10.1089/10915360050138549","DOIUrl":"https://doi.org/10.1089/10915360050138549","url":null,"abstract":"SINCE THE FIRST APPROVED CLINICAL PROTOCOL for somatic gene therapy in patients with adenosine deaminase deficiency started in 1990, approximately 400 clinical protocols, mainly for malignant diseases, have been approved worldwide. In Japan, however, only two clinical studies on cancer gene therapy—immunotherapy for renal cell carcinoma using granulocyte-monocyte colony stimulating factor (GM-CSF) and gene replacement therapy using an adenovirus-p53 for lung cancer—are currently being conducted. Recently, three new clinical protocols have been approved, and three protocols, including “suicide gene” therapy using an adenovirus-herpes simplex virus thymidine kinase gene (HSV-tk) and ganciclovir (GCV) for prostate cancer, are being reviewed by the Japanese National Committee for Gene Therapy. Although the number of clinical protocols in Japan is still small, fundamental research is reaching high levels of excellence. There is an increasing need for our urologists to have an understanding of the basic concepts of gene therapy, its potential applications, and its shortcomings. Accordingly, we founded the Japanese Society for Urological Gene Therapy in 1999 in order to stimulate communication and collaboration with other physicians and basic scientists. The first meeting was held on November 20th, 1999, in Okayama. Two guest speakers, Prof. Asano, Director of the Research Hospital, Institute of Medical Science, at the University of Tokyo, and Dr. Fujiwara, Department of Surgery, Okayama University Medical School, and seven active urologists outlined the status of and prospects for gene therapy for urologic cancer. As Prof. Asano explains in this issue, current gene therapy is regarded as translational research from the bench to the bedside, which must go back to the bench after the clinical data have been reviewed. The main problems are still the failure of vectors to transduce efficiently in vivo and the incomplete understanding of the molecular pathology of tumor development and progression. In this early stage of the technology, urogenital organs are excellent targets for the application and evaluation of gene therapy. For example, because conventional cytokine therapy and adoptive immunotherapy are clearly effective against renal-cell carcinoma, it is very suitable to incorporate their use for immune gene therapy by means of cytokine gene transfer and tumor cell vaccination. Bladder tumors have shown excellent responses to intravesically administered immune response modifiers such as interferon and bacillus Calmette-Guerin. Intravesical administration is a simple and reliable way to deliver the genetic agent, and cystoscopy and urinary cytology will be helpful in evaluating the response of the tumor to treatment. For prostate cancer, direct intratumoral injection under ultrasonographic guidance is also a simple and effective way to deliver the genetic agent, and prostate-specific antigen (PSA) is an extremely sensitive marker for therapeutic effect","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 2 1","pages":"39-40"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/10915360050138549","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60626430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex vivo gene therapy using granulocyte-macrophage colony-stimulating factor-transduced tumor vaccines.","authors":"K. Kawai, K. Tani, S. Asano, H. Akaza","doi":"10.1089/10915360050138567","DOIUrl":"https://doi.org/10.1089/10915360050138567","url":null,"abstract":"There is no standard effective therapy for metastatic renal-cell carcinoma (RCC) or prostate cancer. Both of these cancers may be immunogenic, so therapy targeted to a tumor-associated antigen may be effective. Transduction of the gene encoding granulocyte-macrophage colony-stimulating factor has shown promise in preclinical studies, and clinical trials are in their early stages. Both autologous cancer cells and partially HLA-matched allogenic cells are being studied. No dose-limiting side effects have been observed, and a few patients have had transient objective tumor regressions. Further trials with more frequent and, probably, longer immunization schedules are needed to define efficacy.","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 2 1","pages":"43-6"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/10915360050138567","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60626603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-specific promoters in gene therapy for the treatment of prostate cancer.","authors":"T. Shirakawa, A. Gotoh, Y. Wada, S. Kamidono, S. Ko, C. Kao, T. Gardner, Leland W.K. Chung","doi":"10.1089/10915360050138620","DOIUrl":"https://doi.org/10.1089/10915360050138620","url":null,"abstract":"Delivery of therapeutic toxic genes to and their expression in tumor cells through the use of tissue-specific promoters could decrease their toxic effect on neighboring normal cells when virus-mediated gene delivery results in their infection. We have demonstrated the utility of two prostate cancer-specific promoters, long PSA and osteocalcin, for tissue-specific toxic gene therapy for prostate cancer. The two promoters were highly active in both androgen-dependent and androgen-independent prostate cancer cells. We also introduce the Phase I trial of osteocalcin promoter-based toxic gene therapy for bone metastases of prostate cancer, which is in progress at the University of Virginia.","PeriodicalId":80296,"journal":{"name":"Molecular urology","volume":"4 2 1","pages":"73-82"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/10915360050138620","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60626784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}