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Institute
Prototypical Implementation of a Decision-supporting System for Operative Breast Cancer Therapy
(2020)
Prototypische Umsetzung eines entscheidungsunterstützenden Systems zur operativen Brustkrebstherapie
(2019)
Informationssuche im Internet – Suchverhalten von an Brustkrebs erkrankten und Nicht-Betroffenen
(2016)
Modellierung medizinischer Prozesse als Grundlage für die systematische klinische Risikoanalyse
(2015)
Conceptual ontology of prospective risk analysis in medical environments - the OPT-Model-Ontology
(2015)
Retrospective analysis of GnRH analogue administration in patients with advanced ovarian cancer
(1992)
Untersuchungen zur Amenorrhoe unter adjuvanter CMF-Chemotherapie bei Mammakarzinom-Patientinnen
(1993)
Identification of insulin and insulin-like growth factor I (IGF I) receptors in ovarian cancer
(1994)
Abstract
The objective of this study was to test if specific insulin and insulin-like growth factor I (IGF I) receptors are expressed in ovarian cancer tissue. Thirteen tissue specimens from primary ovarian cancers, 1 specimen from a primary peritoneal carcinoma, 10 specimens from metastatic lesions of ovarian carcinomas, and 4 specimens from recurrent ovarian cancers together with 13 normal ovaries were tested for their content of insulin and IGF-I receptors, by the application of specific insulin and IGF-I receptor radioimmunoassays. The insulin receptor (IR) and IGF-I receptor (IGF R) content in the primary tumors varied between 23.8-321.4 and 16.4-554.2 ng/0.1 mg DNA, respectively. Metastatic lesions contained between 12.3 and 226.7 ng IR/0.1 mg DNA and between 7.5 and 459.4 ng IGF R/0.1 mg DNA. In recurrent tumors the receptor concentrations were in the range of 41.5-79.8 and 48.9-160.9 ng/0.1 mg DNA for insulin and IGF-I receptors, respectively. Normal ovarian tissue contained between 12.2 and 150.1 ng IR and between 21.4 and 420.1 ng IGF R per 0.1 mg DNA, respectively. As both insulin and IGF-I receptors are present in ovarian cancer tissue, the effects of insulin and IGF-I as potential growth factors in ovarian cancer should be further investigated.
Copyright © 1994 Academic Press. All rights reserved.
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.
The single most common cause leading to the diagnosis of endometrial cancer is postmenopausal bleeding. Although most patients with early-stage disease (FIGO stage I and II) can be cured, prognosis worsens considerably with increasing stage. While serum CA 125 levels are elevated only in a significant proportion of patients with advanced disease, recently a new serum marker (OVX1) for the detection of early-stage endometrial cancer was reported. Serum OVX1 levels were measured using an OVX1 radioimmunoassay (RIA) or enzyme immunoassay (EIA) in 192 patients with endometrial cancer. CA 125 levels were measured in 112 patients using the CIS ELSA CA 125 kit. Apparently healthy females had mean serum OVX1 levels measured with the OVX1–EIA of 1.34 ± 0.74 U/ml, while patients with endometriosis had mean OVX1 serum levels of 3.15 ± 2.45 U/ml. The mean OVX1 serum level for endometrial cancer patients was 2.00 ± 1.32 U/ml. These values were 2.76 ± 1.62, 6.10 ± 4.66, and 5.37 ± 3.49, respectively, using the OVX1–RIA assay. Applying a cutoff value of 2.8 U/ml, serum OVX1–EIA levels in endometrial cancer patients were increased in 25 of 127 patients (19.7%) with stage I disease, 5 of 17 patients with stage II (29.4%), 5 of 22 patients (22.7%) with stage III, and 4 of 11 patients (36.4%) with stage IV disease. Using the OVX1–RIA and a cutoff of 7.2 U/ml, serum levels were increased in 22 of 127 (17.3%) stage I, 6 of 17 (35.3%) stage II, 5 of 22 (22.7%) stage III, and 6 of 11 (54.5%) stage IV patients. Serum CA 125 levels, determined in a total of 112 patients, were elevated above 35 U/ml in 12 of 79 patients (15.2%) with stage I, 4 of 12 patients (33.3%) with stage II, 8 of 13 patients (61.5%) with stage III, and all of 8 patients (100%) with stage IV disease. While a good correlation between serum CA 125 levels and the clinical stage of the disease was found, no correlation could be detected for OVX1 and stage.
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.
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.
The IGF-1 receptor (IGF-1-R) belongs to the tyrosine kinase growth factor receptor family. It is structurally similar to, but distinct from, the insulin receptor, with which it shares a 70% homology. As expected, it crossreacts with insulin and, vice versa, insulin receptor crossreacts with IGF-1. Numerous studies suggest that IGF-1-R is very important for mitogenesis and is essential for phenotype transformation, at least in rodents (1). In particular, the IGF-1-R has been described in human breast cancer (2-4) and ovarian cancer (5) tissues and in cultured human breast cancer cell lines (6,7).
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
PURPOSE: To evaluate the detection of epithelial cells in bone marrow of breast cancer patients as an indicator of metastatic disease.
PATIENTS AND METHODS: Between 1989 and 1994, bone marrow biopsies were performed on 393 breast cancer patients during primary surgery. Specimens were stained immunocytochemically for epithelial cells expressing cytokeratins or the epithelial membrane antigen. The long-term outcomes of these patients were analyzed in this study.
RESULTS: In 166 of 393 patients, epithelial cells were found in bone marrow (BM) aspirates. These patients were designated BM+. The rate of tumor recurrence or cancer-related death was significantly higher in BM+ patients than in BM− patients. Multivariate analysis using the Cox regression model revealed BM status as a prognostic parameter independent of tumor size and axillary lymph node status. However, tumor size and axillary lymph node status were clearly superior prognostic parameters.
CONCLUSION: Disseminated epithelial cells in BM are associated with poor clinical outcome in breast cancer patients. However, the presence of these cells is not a sufficient parameter to predict growing metastases in the majority of patients, suggesting that epithelial cells in the BM of breast cancer patients at the time of surgery have limited metastatic potential. The role of these cells needs to be further evaluated.
Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and doxorubicin alone was investigated compared to doxorubicin in breast cancer cells with and without expression of hCG receptors. Expression of hCG receptor was determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt-PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected in MCF-7 but not in MB231 breast cancer cell line. Cytostatic effect of doxorubicin–hCG conjugates was investigated in these cell lines in comparison to unconjugated doxorubicin. The number of viable cells was determined after 24, 48, 72, 96, and 120 h. To exclude non-specific uptake of the carrier hCG from the culture media, a similar experiment was performed with albumin–doxorubicin conjugates. The number of viable cells decreased in a concentration depending manner after doxorubicin and hCG–doxorubicin conjugate treatment. However, the cytotoxic effect of hCG–doxorubicin conjugate was 10-fold increased compared to unconjugated doxorubin in hCG-receptor positive MCF-7 but not in hCG-receptor negative MB231 cells. Albumin–doxorubicin conjugates showed no increased toxicity compared to doxorubicin. We conclude that the cytotoxic effect of hCG–doxorubicin conjugates is mediated specifically via the hCG receptor. By using hCG conjugates, the development of more selective cytostatics can be achieved.
Objective
Ovarian cancer cell lines and tissues express gonadotropin receptors. Conjugation of cytostatics to ligands of these receptors may increase the specificity of cytotoxic drugs.
Study design
Toxicity of doxorubicin–human chorionic gonadotropin conjugates was determined in 4 ovarian cancer cell lines. Expression and regulation of luteinizing hormone/human chorionic gonadotropin receptors were analyzed before and after treatment with human chorionic gonadotropin, epidermal growth factor, and 8-bromo-cyclic adenosine monophosphate with a nested reverse transcriptase–polymerase chain reaction approach.
Results
Toxicity of human chorionic gonadotropin–doxorubicin conjugates was increased compared with unconjugated doxorubicin in OVCAR-3 cells. However, drug conjugates failed to demonstrate increased toxicity in other cell lines, especially after preincubation with human chorionic gonadotropin. All cell lines expressed luteinizing hormone/human chorionic gonadotropin receptors. Receptor expression in OVCAR-3 cells was not effected by human chorionic gonadotropin, endothelial growth factor, or 8-bromo-cyclic adenosine monophosphate treatment. In other cell lines, receptor expression was down-regulated by these agents.
Conclusion
Cytotoxic activity of doxorubicin was increased specifically by conjugation to human chorionic gonadotropin. However, the regulation of luteinizing hormone/human chorionic gonadotropin receptor expression and other compounds may reduce the drug-uptake of the conjugates.