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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.
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.
Online only?
(1998)
Modular process nets are a graphical and formal notation for the representation of technical and business process models containing concurrent activities. Originally this class of Petri nets was developed for the modeling, analysis, simulation and control of workflows and computer-based process control systems, but it is also suitable for use in all other areas where a formal but comprehensible description of complex processes is needed. After a description of the basic aims and design decisions for modular process nets, the report gives a brief introduction to low-level Petri nets including different types of transition rules and aspects of the descriptive and prescriptive use of process models. The main and most innovative points which are explained in more detail are the introduction of a hierarchical module concept for nets and the definition of elementare process nets. The module concept is part of a more general ("object-based") approach to Petri nets allowing severaltypes of ab straction, whereas the main points of elementary process nets are synchronous and asynchronous communication between separately interpreted net instances via events and token passing. Modular process nets are low-level Petri nets equipped with these module and communication concepts and optionally enhanced by die use of a task concept, a method known from the areas of computer-supported cooperative work (CSCW) and work-flow management. Because the report is aimed at a systematic and easy-to-understand introduction to modular process nets, it provides a precise explanation of this net class which is kept as informal as possible and enhanced by some typical application examples
An innovative net-based methodology to integrate qualitative and quantitative analysis of distributed software systems is outlined, and an on-going prototype implementation of a related graphic-oriented tool kit is sketched. The proposed method combines qualitative analysis, monitoring and testing as well as quantitative analysis on the basis of a net-based intermediate representation of the distributed software system under consideration. All transformations (from the distributed software system into a first Petri net model, and between the different kinds of net models) can be made formally, and therefore automated to a high degree. The evaluation of quantitative properties is based on so-called object nets which are obtained by a property-preserving structural compression and quantitative expansion of the qualitative model. In this way, the frequency and delay attributes necessary to generate quantitative models are provided by the monitoring and testing component.
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