Expression and regulation of luteinizing hormone/human chorionic gonadotropin receptors in ovarian cancer and its correlation to human chorionic gonadotropin–doxorubicin sensitivity - 25/08/11

Doi : 10.1016/j.ajog.2004.03.045

Gerhard Gebauer, MD, PhD ^a,^⁎ , Natalia Mueller, MD ^b, Tanja Fehm, MD ^c, Alexander Berkholz, MD ^b, Eberhard P Beck, MD ^d, Wolfram Jaeger, MD, PhD ^e, Peter Licht, MD, PhD ^c
Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany^a; Department of Obstetrics and Gynecology, University of Erlangen-Nuremberg, Erlangen, Germany^b; Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany^c; Department of Obstetrics and Gynecology, Brandenburg Hospital, Brandenburg, Germany^d; Department of Obstetrics and Gynecology, Dusseldorf, Germany^e

Reprint requests: Gerhard Gebauer, MD, PhD, Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany.

Abstract

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.

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Keywords : Ovarian cancer, Gonadotropin, Chemotherapy, Doxorubicin, Drug conjugate