Wolfgang E. Berdel
Free University of Berlin
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International Journal of Cancer | 1997
Elisabeth Oelmann; Annette Kraemer; Hubert Serve; Birgit Reufi; Dorothea Oberberg; Stephan Patt; Hermann Herbst; Harald Stein; Eckhard Thiel; Wolfgang E. Berdel
In situ hybridization (ISH) of human glioblastoma tissue sections revealed expression of interleukin‐1 (IL‐1)α and/or β and IL‐1 receptor types I and II (IL‐1R I and II) in the majority of cases evaluable. To understand the function of IL‐1‐family members in human glioblastomas, we have studied 6 glioblastoma cell lines. RT‐PCR, ISH, ELISA and 125I‐IL‐1‐binding assays revealed expression of IL‐1 and high‐affinity receptors for human (h)IL‐1 in all but 1 cell line. Using a colony growth assay in semi‐solid media for testing serial plating efficacy (PE, number of colonies per number of cells seeded in %), only the IL‐1R‐negative cell line was not influenced by recombinant human (rh)IL‐1α or ‐β, whereas IL‐1 down‐regulated the self‐renewal of clonogenic cells of the other glioblastomas. Tritiated thymidine uptake was down‐regulated by rhIL‐1 in all cell lines studied. Cell viability remained unchanged by rhIL‐1. Wherever growth modulation by rhIL‐1 was detected, it could be reversed by either soluble IL‐1R I or II or by rhIL‐1 receptor antagonist (ra). IL‐1ra not only was able to reverse rhIL‐1‐induced growth modulation but alone could modulate glioblastoma growth in comparison with control in cell lines producing IL‐1. Our results show the presence of public autocrine loops for IL‐1 leading to growth inhibition in some glioblastomas. To understand these loops, we have studied expression and function of IL‐1ra in glioblastomas. ISH of human glioblastoma tissue sections revealed expression of hIL‐1ra in all 8 cases evaluable. In 4 of 6 cell lines, IL‐1ra was found in the supernatant under constitutive conditions, the IL‐1R‐negative line being among the 2 non‐producers. The other non‐producing cell line, HTB 17, showed expression of hIL‐1R II. Most interestingly, a neutralizing antibody against IL‐1ra down‐regulated growth of IL‐1‐ and IL‐1ra‐producing glioblastoma cells to approx. 30% of the controls. Thus, public autocrine loops for IL‐1 in human glioblastomas exist and result in growth inhibition. An autocrine production of IL‐1‐antagonizing molecules such as IL‐1ra by these tumors can counteract this IL‐1 function and represent a basic escape mechanism supporting malignant growth in some glioblastomas. Int. J. Cancer 71: 1066‐1076, 1997.
Lipids | 1991
Chung Il Hong; Charles R. West; Ralph J. Bernacki; Cameron K. Tebbi; Wolfgang E. Berdel
The 1-β-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemiain vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octadecyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01–0.04 μ).. Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.
Cancer Letters | 1992
Michael Koenigsmann; Monica Zafferani; Susanne Danhauser-Riedl; Birgit Reufi; William J. Houlihan; Eckhard Thiel; Wolfgang E. Berdel
Four new antagonists of platelet activating factor (PAF) from two different chemical classes (imidazoisoquinolines: SDZ 62-434, SDZ 63-135, SDZ 62-759; imidazopiperidines: SDZ 62-293) were tested for in vivo therapeutic activity in various tumor models including the murine myelomonocytic leukemia WEHl-3B, xenografts of human colon (HTB 38) and lung (HTB 119) cancer cell lines and the murine Lewis-lung tumor. After intraperitoneal (i.p.) injection of 1 x 10(3), 5 x 10(3) and 1 x 10(4) WEHl-3B cells into Balb/c mice, the drugs were given per os (p.o.) or i.p. over 6-14 days. Drug doses were pushed to exceed the lethal dose for 10% of the animals (LD10) and ranged from 1 to 100 mg/kg daily for p.o. treatment and from 1 to 75 mg/kg daily for i.p. treatment. In the xenotransplants and the Lewis-lung tumor experiments, PAF antagonists were given i.p. to nude Balb/c and C57 Black mice after intracutaneous (i.c.) tumor cell inoculation. None of the four compounds induced reproducible prolongation of life span, significant numbers of long term survivors, reduction of tumor size, or delay of tumor growth in any of the therapeutic models. Oral SDZ 62-759 had some activity in experiments in which there was slow WEHl-38 tumor growth in the controls. Toxicity of equivalent drugs doses was higher in the i.p. than in the p.o. schedules.
Onkologie | 1998
Carsten Bokemeyer; A. Harstrick; J. Beyer; Bernd Metzner; Ulrich Rüther; J. Hartmann; K. Holstein; H.G. Derigs; R. de Wit; J. Casper; Patrick Schöffski; I. Kührer; Illiger Hj; B. Kempf; A. Reichle; A. Föller; Dieter K. Hossfeld; J.Th. Fischer; Wolfgang E. Berdel; H. H. Gerhartz; Hartmut Kirchner; K. Pflüger; H. Ostermann; L. Kanz; H.-J. Schmoll
Background: With the use of cisplatin-based chemotherapy metastatic testicular cancer has become a model for a highly curable malignant disease. Today 70–80% of patients will achieve long-term survival following PEB therapy (cisplatin, etoposide, bleomycin). The role of high-dose chemotherapy with autologous stem cell support is being investigated in patients with metastatic germ cell cancer in order to improve the outcome of patients with relapse after previous standard-dose chemotherapy and of patients presenting initially with advanced metastatic disease. Patients and methods: The application of upfront high-dose therapy may not only be better tolerated compared to its use in the salvage situation but may also achieve a rapid initial cell kill prior to the development of cytostatic drug resistance. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin, etoposide and ifosfamide (HD-PEI) given with G-CSF and PBSC support for 4 cycles every three weeks. Within this ongoing study patients with ‘advanced disease’ testicular germ cell tumors have received dose intensive PEI therapy at 8 consecutive dose levels. Starting from a nearly standard dose PEI therapy (125 mg/m2 cisplatin, 600 mg/m2 etoposide and 6 g/m2 ifosfamide, given in total from days 1–5) the doses of etoposide and ifosfamide were escalated. Dose escalations were only performed when the previous dose level was considered safe. The first 73 patients were treated on dose levels 1–3 without PBSC support, receiving GM-CSF 10 mg/kg s.c. per day. The next 68 patients at levels 3–5 received PBSC retransfusion on the second day after each PEI cycle plus G-CSF 5 mg/kg. From dose level 6 on patients received one initial cycle of standard dose PEI therapy followed by PBSC-separation and 3–4 high-dose PEI cycles. The dose-limiting toxicity is reached at dose level 8 with cisplatin 100 mg/m2, etoposide 1.75 g/m2 and ifosfamide 12 g/m2 per cycle given for 3–4 consecutive courses at 3-week intervals. Results: 82 (58%) of the fully evaluable 141 patients at dose levels 1–5 have achieved CR/NED and 32 patients (22%) PR with marker normalization. The early death rate was 8%. The achieved overall and event-free survival rates at two years are 78 and 73% with a projected 5-year overall survival of 74%. Despite preliminary favorable results, this approach can not be considered standard treatment. A randomized US Intergroup study comparing 2 cycles of PEB plus 2 cycles of high-dose chemotherapy to 4 cycles of standard PEB was initiated in early 1996. Conclusion: The application of high-dose chemotherapy with peripheral stem cell transplantation for patients with testicular cancer should only be performed within controlled clinical trials in order to allow both the evaluation of long-term cure rates and of treatment-related late side effects. Schlüsselwörter Hodentumor · Keimzelltumoren · Hochdosis-Chemotherapie · Periphere Blutstammzellen · IGCCCG-Klassifikation Zusammenfassung Hintergrund: Mit dem Einsatz einer cisplatinhaltigen Kombinations-Chemotherapie sind metastasierte Keimzelltumoren des Hodens zu einem Modell für eine kurativ behandelbare maligne Erkrankung geworden. Heute können 70–80% aller Patienten mittels PEB-Chemotherapie (Cisplatin, Etoposid, Bleomycin) langfristig geheilt werden. Der Einsatz einer Hochdosis-Chemotherapie mit autologer Stammzelltransplantation wird gegenwärtig bei Patienten mit metastasiertem Hodentumor untersucht, um die Therapieergebnisse im Rezidiv nach vorheriger Standardchemotherapie und bei primär weit fortgeschrittener Erkrankung («poor prognosis») zu verbessern. Patienten und Methoden: Der Einsatz einer Hochdosis-Chemotherapie in der Primärtherapie wird in der Regel nicht nur besser toleriert als in der Rezidivsituation, sondern kann auch zu einer raschen Tumorzellzerstörung führen, noch bevor eine Zytostatikaresistenz auftritt. Die deutsche Hodentumorstudiengruppe hat daher ein sequentielles Hochdosisregime mit Cisplatin, Etoposid und Ifosfamid (HD-PEI) mit G-CSFund PBSC-Unterstützung entworfen. Die Therapie wird über vier Zyklen alle drei Wochen appliziert. Im Rahmen dieser Studie erhalten Patienten mit «poor prognosis» oder «advanced disease» Keimzelltumoren das HDPEI-Schema auf acht konsekutiven Dosisstufen. Nachdem zunächst mit einem nahezu standarddosierten PEI-Regime begonnen wurde (125 mg/m2 Cisplatin, 600 mg/m2 Etoposid und 600 mg/m2 Ifosfamid, verteilt auf Tag 1–5), wurde insbesondere die Dosis von Etoposid und Ifosfamid eskaliert. Es wurden keine intraindividuellen Dosiseskalationen durchgeführt, und die nächste Dosisstufe wurde erst gestartet, wenn die vorherige Dosisstufe als sicher erkannt wurde. Die ersten 73 Patienten wurden auf den Dosisstufen 1–3 ohne PBSC-Unterstützung, nur mit G-CSF 10 mg/kg s.c. pro Tag behandelt. Die nächsten 68 Patienten auf den Dosisstufen 3–5 erhielten eine PBSC-Transplantation nach jedem HD-PEI-Zyklus plus GM-CSF 5 mg/kg. Ab Dosisstufe 6 erhielten alle Patienten einen initialen Zyklus Standard PEI-Chemotherapie gefolgt von PBSC-Separation und anschließend 3–4 HD-PEI-Zyklen. Die dosislimitierende Toxizität wird auf Dosisstufe 8 mit Cisplatin 100 mg/m2, Etoposid 1,75 g/m2 und Ifosfamid 12 g/m2 pro Zyklus erreicht. Ergebnisse: 82 (58%) der 141 vollständig auswertbaren Patienten der Dosisstufen 1–5 haben eine CR/NED erreicht und 32 Patienten (22%) eine PR mit Markernormalisierung. Die frühe Todesfallrate betrug 8%. Das erzielte gesamtund rezidivfreie Überleben lab nach zwei Jahren bei 78 und 73% mit einem projiziertem 5-JahresÜberleben von 74%. Trotz dieser sehr ermutigenden Ergebnisse kann diese Form der Hochdosis-Chemotherapie noch nicht als Standardbehandlung gesehen werden. Eine randomisierte US-Intergroup-Studie, die zwei Zyklen PEB gefolgt von zwei Zyklen Hochdosis-Chemotherapie gegen vier Zyklen PEB vergleicht, wurde bereits 1996 gestartet. Schlußfolgerung: Der Einsatz einer Hochdosis-Chemotherapie mit Transplantation autologer Stammzellen bei Patienten mit weit fortgeschrittenen Hodentumoren sollte nur innerhalb kontrollierter klinischer Studien durchgeführt werden, um eine adäquate Evaluation der Langzeitheilungsraten und der potentiellen therapie-assoziierten Nebenwirkungen zu erlauben.
Oncology | 1997
A.-R. Hanauske; Agnieszka Korfel; Michael Perker; Bernhard Heinrich; Gisela Schwab; Martina Graf; Henrik Depenbrock; G. Höffken; E.D. Kreuser; Eckhard Thiel; Thomas Zwingers; Wolfgang E. Berdel
BACKGROUND The purpose of the study was to evaluate the feasibility of increasing dose intensity by a stepwise reduction of the time intervals between chemotherapy cycles in separate patient cohorts with small-cell lung cancer. Patients received up to 6 courses of combination chemotherapy with carboplatin, etoposide, ifosfamide and vincristine followed by support with filgrastim. Dose intensity, incidence, duration and severity of neutropenic fever and infections, objective response to chemotherapy, and safety of filgrastim were determined. PATIENTS AND METHODS 29 patients with small-cell lung cancer (limited disease: 2, extensive disease: 27) were treated with a combination of carboplatin 250 mg/m2 i.v. day 1, ifosfamide 2 g/m2 and etoposide 120 mg/m2 i.v. days 1 and 2, etoposide 120 mg/m2 orally day 3, and vincristine 1.4 mg/m2 day 14. Initially, filgrastim (5 micrograms/kg) was administered subcutaneously from day 7 to 16. With shorter treatment intervals, filgrastim was administered on days 4-16 or 4-14. RESULTS An overall increase in dose intensity by a factor of 1.44 was achieved after reducing the treatment interval from 27 to 17 days. Further reduction to 14 days was not feasible due to persistent thrombocytopenia. Six patients (21%) developed a total of 9 febrile episodes, and 14 patients (48%) had to be withdrawn from the study before the completion of six cycles of chemotherapy. The median duration of infectious episodes was 6 days. Overall, a total of 22 of 27 evaluable patients had an objective response. Longer treatment intervals resulted in a lower probability for objective response (> or = 23 days: 10/14 patients vs. < or = 17 days: 7/7 patients). CONCLUSION Filgrastim allows for the reduction of treatment intervals in patients with small-cell lung cancer and increased dose intensity with acceptable hematologic and nonhematologic toxicities.
Onkologie | 1998
B. Gleissner; A. Hellmann; Wolfgang E. Berdel; L. Edler; M. Koldehoff; A. Rost; F. Opri; D. Fritze; S. Öhl
Breast cancer ist the most common malignancy among women of Western industrialized countries and still 80% of patients with newly diagnosed breast cancer will develop metastases. Breast cancer metastatic to sites beyond regional axillary lymph nodes represents an incurable condition. While Phase I/II Study of Paclitaxel and 5-Fluorouracil as Second-Line Therapy in Patients with Metastatic Breast Cancer B. Gleissnera, A. Hellmannb W.E. Berdelc, L. Edlerd M. Koldehoff b, A. Roste F. Opri f, D. Fritzee, S. Öhlb for the Phase I/II Study Group of the Association for Medical Oncology (AIO) in the German Cancer Society
Clinical Cancer Research | 1998
Agnieszka Korfel; M E Scheulen; Hans-Joachim Schmoll; O Gründel; A. Harstrick; M Knoche; L M Fels; M Skorzec; F Bach; J Baumgart; G Sass; Siegfried Seeber; Eckhard Thiel; Wolfgang E. Berdel
Biochemical Journal | 1996
Roland Brinckmann; Max S. Topp; Ildikó Zalán; Dagmar Heydeck; Peter Ludwig; Hartmut Kühn; Wolfgang E. Berdel; Andreas J. R. Habenicht
Cancer Research | 1995
Elisabeth Oelmann; Lydia Sreter; Irmela Schuller; Hubert Serve; Michael Koenigsmann; Bertram Wiedenmann; Dorothea Oberberg; Birgit Reufi; Eckhard Thiel; Wolfgang E. Berdel
Journal of Medicinal Chemistry | 1986
Chung Il Hong; Seung Ho An; David J. Buchheit; Alexander Nechaev; Alan J. Kirisits; Charles R. West; Wolfgang E. Berdel