Thesis (doctoral)--Freie Universität Berlin, 1979.

Zugl.: Marburg, Univ., Diss., 2005.

The advent of prostate-specific antigen (PSA) testing and increased patient awareness has led to patients being diagnosed with prostate cancer at an earlier stage and a younger age than previously. Adjuvant hormonal therapy to radiotherapy or prostatectomy has been shown to reduce the risk of tumour progression, and in some studies survival benefits have been demonstrated. The non-steroidal antiandrogen bicalutamide (‘Casodex’) has undergone extensive evaluation and is currently undergoing clinical trials as immediate therapy, either alone or as adjuvant to treatment of curative intent in patients with localized or locally advanced disease. Data from the first analysis of one of the studies in the Early Prostate Cancer (EPC) programme involving 3,603 patients have shown that, after a median follow-up of 2.6 years, the risk of prostate cancer progression was significantly reduced (by 43%) in patients receiving bicalutamide 150 mg compared with those receiving standard care alone (HR 0.57; 95% CI 0.48, 0.69; p ≪ 0.0001). The risk of PSA progression was also significantly reduced (by 63%). At this stage the survival data are still immature. Side effects of bicalutamide were mostly gynaecomastia and breast pain, which is consistent with its pharmacology. Overall withdrawal rates were similar in the bicalutamide 150 mg and standard care alone groups. In the bicalutamide 150 mg group, withdrawals were mainly due to side effects, whereas in the group receiving standard care alone, withdrawals were mainly due to disease progression. The programme is ongoing, and survival data are awaited. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The advent of prostate-specific antigen (PSA) testing and increased patient awareness has led to patients being diagnosed with prostate cancer at an earlier stage and a younger age than previously. Adjuvant hormonal therapy to radiotherapy or prostatectomy has been shown to reduce the risk of tumour progression, and in some studies survival benefits have been demonstrated. The non-steroidal antiandrogen bicalutamide (‘Casodex’) has undergone extensive evaluation and is currently undergoing clinical trials as immediate therapy, either alone or as adjuvant to treatment of curative intent in patients with localized or locally advanced disease. Data from the first analysis of one of the studies in the Early Prostate Cancer (EPC) programme involving 3,603 patients have shown that, after a median follow-up of 2.6 years, the risk of prostate cancer progression was significantly reduced (by 43%) in patients receiving bicalutamide 150 mg compared with those receiving standard care alone (HR 0.57; 95% CI 0.48, 0.69; p ≪ 0.0001). The risk of PSA progression was also significantly reduced (by 63%). At this stage the survival data are still immature. Side effects of bicalutamide were mostly gynaecomastia and breast pain, which is consistent with its pharmacology. Overall withdrawal rates were similar in the bicalutamide 150 mg and standard care alone groups. In the bicalutamide 150 mg group, withdrawals were mainly due to side effects, whereas in the group receiving standard care alone, withdrawals were mainly due to disease progression. The programme is ongoing, and survival data are awaited. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Hormonell wirksame Chemikalien, wie Pflanzenschutzmittel oder Pharmaka gelangen durch Abwässer in die Umwelt und akkumulieren vor allem in Oberflächengewässern. Ein erhöhtes Augenmerk liegt auf Substanzen, die durch (anti)androgene und (anti)östrogene Wirkungsweise die Reproduktion von Tieren und Menschen beeinträchtigen. Bei den bisherigen Nachweismethoden für diese Stoffe handelt es sich um invasive Methoden, die das Töten der Tiere beinhalten. Diesen Methoden mangelt es jedoch an der nötigen Sensitivität, um umweltrelevante Konzentrationen der endokrinen Disruptoren (EDs) nach Kurzzeitexposition nachweisen zu können, sowie am Vermögen, alle vier Wirkmechanismen (androgen, antiandrogen, östrogen und antiöstrogen) mit einer einzelnen Testmethode feststellen und unterscheiden zu können. In dieser Studie wurde deshalb mit Hilfe männlicher Afrikanischer Krallenfrösche (Xenopus laevis) eine Testmethode entwickelt, bei der die Frösche verschiedenen (anti)androgenen und (anti)östrogenen EDs ausgesetzt wurden und ihr Rufverhalten untersucht wurde. Diese nicht-invasive Methode erwies sich als schnell und höchst sensitiv. Zudem war es erstmals möglich, die vier verschiedenen Wirkmechanismen allein anhand veränderter Ruftypen und Rufparameter zu bestimmen und zu unterscheiden. Darüber hinaus konnte gezeigt werden, dass bei Anwendung dieser Methode die Möglichkeit besteht, die Versuchstiere in weiteren Tests wiederzuverwenden, da die Rufparameter nach einer expositionsfreien Zeit von sechs Wochen wieder Kontrollwerte erreichten. Zusammengefasst kann die hier vorgestellte verhaltensphysiologische und damit nicht-invasive Methode als Biomarker für den Nachweis von (anti)androgenen und (anti)östrogenen EDs verwendet werden. Ferner zeigt die hohe Sensitivität des Tests, sowie die Möglichkeit der vollautomatischen Analyse enormer Datenmengen, dass dieser schnelle Verhaltenstest ein großes Potential hat, ein sensitiver, standardisierter und nicht-invasiver Biomarker zu werden. / Endocrine disrupting compounds (EDCs), such as herbicides, pesticides or pharmaceuticals enter the environment via sewage effluents and especially accumulate in surface waters. Research efforts so far mainly focused on EDCs with (anti)androgenic and (anti)estrogenic modes of action (MOAs), which can interfere with reproductive biology of vertebrates. To date, biomarkers for the assessment of such compounds are invasive techniques, which are not sensitive enough to detect EDCs after short-term exposures and which cannot distinguish between the four MOAs. Hence, in this study a non-invasive method for the assessment of EDCs was developed using male African clawed frogs (Xenopus laevis) as model species. Frogs were exposed to individual (anti)androgenic and (anti)estrogenic EDCs in the surrounding water and their calling behavior was analyzed. This non-invasive method turned out to be a fast and highly sensitive biomarker for the detection of (anti)androgenic and (anti)estrogenic EDCs. Moreover, this method was able to differentiate between the four different MOAs solely by determining affected parameters of the calling behavior. It was also shown that by using this method, it might be possible to reuse already tested experimental animals, because the measured affected parameters were reversed after a period of six weeks under control conditions. Taken together the here established non-invasive behavioral method can be used as biomarker for the detection of (anti)androgenic and (anti)estrogenic EDCs. Furthermore, the high sensitivity of this testing method, as well as the possibility of analyzing vast datasets rapidly in a completely automated fashion indicate the huge potential for this rapid behavior test to become a sensitive, standardized, non-invasive biomarker.

There is increasing interest in the use of adjuvant hormonal therapies, which are given after the resection or destruction of all gross disease, in early-stage prostate cancer, as a significant proportion of patients experience progression and/or die from the disease despite undergoing therapy with curative intent. Several retrospective studies suggest that adjuvant hormonal therapy may improve long-term outcome after radical surgery in men with positive lymph nodes, although this approach has yet to be studied in a prospective setting. No studies of adjuvant therapy for patients with extracapsular extension at surgery have been completed, but in an interim analysis of an open controlled trial, adjuvant flutamide significantly improved progression-free survival at 4 years. Three prospective studies in the radiotherapy setting have shown that adjuvant luteinizing hormone-releasing hormone (LH-RH) agonist therapy significantly improves progression-free and/or overall survival. Future studies need to define patient subgroups who will benefit most from adjuvant therapy. The side effects of the different therapeutic options also need to be compared. It is hoped that many of the outstanding questions concerning adjuvant hormonal therapy will be answered by the ongoing Bicalutamide Early Prostate Cancer Programme. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

There is increasing interest in the use of adjuvant hormonal therapies, which are given after the resection or destruction of all gross disease, in early-stage prostate cancer, as a significant proportion of patients experience progression and/or die from the disease despite undergoing therapy with curative intent. Several retrospective studies suggest that adjuvant hormonal therapy may improve long-term outcome after radical surgery in men with positive lymph nodes, although this approach has yet to be studied in a prospective setting. No studies of adjuvant therapy for patients with extracapsular extension at surgery have been completed, but in an interim analysis of an open controlled trial, adjuvant flutamide significantly improved progression-free survival at 4 years. Three prospective studies in the radiotherapy setting have shown that adjuvant luteinizing hormone-releasing hormone (LH-RH) agonist therapy significantly improves progression-free and/or overall survival. Future studies need to define patient subgroups who will benefit most from adjuvant therapy. The side effects of the different therapeutic options also need to be compared. It is hoped that many of the outstanding questions concerning adjuvant hormonal therapy will be answered by the ongoing Bicalutamide Early Prostate Cancer Programme. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.