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Retrospective analysis of GnRH analogue administration in patients with advanced ovarian cancer
(1992)
Zusammenfassung
Intrauterin wachstumsretardierte Neugeborene konnten ihr genetisches Wachstumspotential aufgrund einer intrauterinen Mangelversorgung nicht realisieren und werden deshalb zu klein oder zu leicht geboren. Das Merkmal „zu leicht” wird mit Hilfe von Gewichtsperzentilen quantifiziert. Kinder mit einem Gewicht< 10. Perzentile werden als „small for gestational age” (SGA) bezeichnet. Diese Einteilung berücksichtigt jedoch nicht die Proportionen eines Neugeborenen, so daß vor allem asymmetrisch retardierte Neugeborene, deren Gewicht zwar die 10. Perzentile noch überschreitet, die jedoch für ihre Körpergröße untergewichtig sind, nicht erfaßt werden. Der Ponderal Index (PI) dagegen berücksichtigt sowohl Gewicht als auch Länge des Neugeborenen. Kinder mit einem PI < 10. Perzentile werden als „low Ponderal Index” (LPI) klassifiziert. Aus pädiatrischen Studien ist bekannt, daß LPI-Kinder vermehrt durch Hypoglykämien, Hypothermien, Hypokalzämien und Mekoniumaspirationen/Aspirationspneumonien gefährdet sind. Langzeiterhebungen zeigten eine verzögerte körperliche Entwicklung und gehäuft motorische oder neurologische Verhaltensauffälligkeiten sowie schulische Probleme.
Fragestellung: Ziel der vorliegenden Arbeit war die Frage, ob Mangelgeborene, insbesondere LPI-Neugeborene, auch intrapartum einer erhöhten Gefährdung ausgesetzt sind.
Methoden: Hierzu wurden 3687 Neugeborene retrospektiv erfaßt, die anhand von Perzentilenkurven des betrachteten Kollektivs als SGA, LPI, SGA/LPI oder Vergleichskollektiv klassifiziert wurden.
Ergebnisse: Unterschiede im Geburtsmodus zwischen SGA- bzw. LPI-Mangelgeborenen und eutrophen Neugeborenen waren schwach ausgeprägt. Demgegenüber unterschied sich die Indikation, aufgrund deren ein geburtshilflicher Eingriff vorgenommen werden mußte deutlich. Bei 31 % aller operativ entbundenen LPI-Neugeborenen, 47 % der SGA-Neugeborenen und 52 % der SGA/LPI-Kinder erfolgte die operative Entbindung aus fetaler Indikation, im Vergleich zu 16 % des Normalkollektivs. Bezüglich des „fetal outcome”, das die Merkmale neonataler Säure-Basen-Status, Apgar-Wert, Verlegung in die Kinderklinik und perinatale Mortalität einbezog, verhielten sich die Gruppen SGA, LPI und SGA/LPI in gleicher Weise schlechter gegenüber dem Vergleichskollektiv. Die Unterschiede zwischen proportionierten (SGA) und dysproportionierten (LPI) Mangelgeborenen waren weniger deutlich.
Schlußfolgerungen: Es zeigte sich, daß das gegenwärtige engmaschige, geburtshilfliche Management mit nahezu permanenter CTG-Überwachung sub partu Probleme rechtzeitig erkennen und beherrschen ließ. Die Erfassung des niedrigen Ponderal Index war zur Erkennung und Vermeidung subpartaler geburtshilflicher Risikofaktoren nicht entscheidend.
Cis-diammine dichloro platinum (II) (CDDP), is a highly potent antineoplastic agent that is used in the treatment of ovarian cancer. However, the clinical use of CDDP is restricted by its severe side effects. In order to reduce these side effects and to enhance its therapeutic efficacy, we developed specific immunoconjugates consisting of the murine monoclonal antibody OC125 and CDDP, using diethylene triamine pentaacetic acid (DTPA) as a linker.
The coupling efficiencies of the different preparations synthesized, varied between 1.10±0.42 and 2.65±1.60 mol of CDDP per mol of antibody protein. Despite the chemical modification of the antibody molecule, specific binding activity of the OC125-CDDP conjugates toward the CA125 antigen was maintained as was demonstrated by means of immunohisto-/cytochemical staining of frozen sections of ovarian cancer tissue, amniotic epithelium, and the CA125 positive ovarian cancer cell line NIH:OVCAR 3.
The antiproliferative activity of the immunoconjugates was tested against the human ovarian cancer cell lines NIH:OVCAR3 and SKOV 3, applying a kinetic crystal violet microassay.
Despite the promising results obtained with the specific immuno-staining of the target cells, no significant antiproliferative activity of our immunoconjugates against the cell lines tested was observed.
One possible explanation for the lack of antitumor activity could be the fact that CA125 is released in large amounts by the NIH:OVCAR 3 cells. This may have prevented an efficient immunotargeting of the cancer cells by the formation of soluble immune complexes.
Untersuchungen zur Amenorrhoe unter adjuvanter CMF-Chemotherapie bei Mammakarzinom-Patientinnen
(1993)
Summary
Background: Combination chemotherapies of platinum compounds with alkylating agents have been the standard treatment for patients with advanced ovarian carcinoma over the last decades. The recent development of taxans has added a group of new promising agents; however, long-term results are not yet available. Platin derivates have proven to be an indispensable part in combination chemotherapies for ovarian carcinoma. The dose intensity of cisplatin is, however, still a matter of debate. We report on the long-term results of a prospective randomized trial comparing two dosages of cisplatin combined with treosulfan in patients with advanced epithelial ovarian cancer. Patients and Methods: Between 1988 and 1995, 125 patients with ovarian cancer (FIGO stage II–IV) were randomized to receive 4 cycles (28-day intervals) of either cisplatin 100 mg/m2 (high dose, HD) or 50 mg/m2 (low dose, LD) in combination with 5 g/m2 treosulfan after primary cytoreductive surgery. Postoperative residual tumor was absent in 39 patients (HD: 16; LD: 23), < 2 cm in 61 patients (HD: 36; LD: 25) and > 2 cm in 25 patients (HD: 13; LD: 12). 65 and 60 patients received HD and LD cisplatin, respectively. Second-look surgery was optional. Results:The overall response rate was 70.0% (HD: 70.9%; LD: 68.9%). Pathological complete response (CR) was seen in 45 patients (37.5%), clinical CR in 23 patients (19.2%), partial response (PR) in 16 patients (13.3%), stable disease (SD) in 2 patients, and progression of disease (PD) in 34 patients (28.3%). 5 patients were not assessable for response. Overall median survival was 25.6 (HD: 26.9, LD: 25.2) months. The overall disease-free survival for responders was 19.6 and 24.7 months (HD and LD, respectively). HD chemotherapy did not result in any significant survival benefit in completely resected patients: HD: 39.8 months versus LD: 49.5 months. In suboptimally debulked patients (residual tumor < 2 cm), median survival was 24.1 months (HD) versus 22.6 months (LD). In patients with residual tumors > 2 cm median survival was 14.6 months (HD) versus 15.5 months (LD). Significantly less side effects were seen in the LD group: anemia (p = 0.008); nephrotoxicity (p = 0.014); alopecia (p = 0.017). Conclusions: Our data suggest that LD cisplatin-based chemotherapy is as effective as HD chemotherapy in patients with advanced epithelial ovarian cancer, but is far less toxic.
Copyright © 2000 S. Karger GmbH, Freiburg
BACKGROUND
Despite radical surgery and the introduction of novel chemotherapeutic agents, the prognosis of ovarian cancer remains poor. Since in the past the potential role of gonadotropins in the induction and progression of ovarian cancer has been discussed, we conjugated doxorubicin to human chorionic gonadotropin (hCG) in order to specifically target ovarian cancer cells.
MATERIALS AND METHODS
Doxorubicin was conjugated to hCG via glutaraldehyde. 48 hours post seeding, NIH:OVCAR 3 cells were treated with various concentrations of hCG-conjugated and non-conjugated doxorubicin for 2 hours. Cells were cultured for a total of 168 hours. Cell growth was monitored by a crystal violet assay.
RESULTS
Conjugating doxorubicin to hCG resulted in an average specific uptake of 22 mol doxorubicin per mol protein (range 3.0-43.3 mol). Incubating NIH:OVCAR 3 cells for 2 hours with the conjugate led to a more than 8 fold increase of the IC50 values compared to non-conjugated doxorubicin (0.55 microM versus 4.43 microM). The antiproliferative activity of both conjugated and free doxorubicin was detectable up to 168 hours post treatment.
CONCLUSIONS
The present experiments clearly demonstrate a more than 8-fold increase in cytotoxicity of the conjugates compared to free doxorubicin. It was also shown that this effect was not restricted to an acute toxic event but that it resulted in a prolonged antiproliferative activity.