Rezeptorvermittelte Chemotherapie gynäkologischer Tumoren und des Mammakarzinoms

Zusammenfassung

Der folgende Artikel behandelt die medikamentöse Tumortherapie, basierend auf dem Einsatz von Hormonanaloga des GnRH, des Bombesins/GRP und des Somatostatins als Trägersubstanzen für Chemotherapeutika. Durch diese Therapieform soll eine höhere Wirkstoffkonzentration des Chemotherapeutikums im Tumor erreicht werden. So sollen die antitumorale Wirkung gesteigert und gleichzeitig die Nebenwirkungen minimiert werden. Die rezeptorvermittelte Therapie („Targeted Therapy“) mit zytotoxischen Analoga des GnRH, des Bombesins/GRP und des Somatostatins ist in präklinischen Tumormodellen des Mamma-, Endometrium- und Ovarialkarzinoms bei geringer Hämatotoxizität hochwirksam. In den hier vorgestellten Studien waren diese Hybridmoleküle deutlich potenter als das reine Chemotherapeutikum. Die Expression des jeweiligen Targetrezeptors auf Tumorzellen ist allerdings notwendige Bedingung für eine effektive Therapie, denn eine Blockade der tumoralen Rezeptoren führte im Tiermodell immer zu einer deutlichen Wirkungsabschwächung der zytotoxischen Peptidanaloga. Die Hämatotoxizität nach rezeptorvermittelter Chemotherapie war in allen Tierexperimenten geringer als nach ungerichteter Therapie mit dem zytotoxischen Radikal. Mit der schnellen Entwicklung einer Chemoresistenz nach rezeptorvermittelter Therapie ist wahrscheinlich nicht zu rechnen, denn in keinem Experiment wurde eine vermehrte Expression von MDR-Proteinen nach Behandlung beobachtet. Mit AN-152 ist jetzt eines der hier untersuchten Therapeutika in die klinische Prüfung eingetreten. In einer Phase-I-Studie an Patientinnen mit GnRH-rezeptorpositiven Mamma-, Ovarial-und Endometriumkarzinomen war AN-152 gut verträglich und wird jetzt in Phase-II-Studien weiter auf seine Wirksamkeit überprüft.

Abstract

The current article reviews a novel approach in tumor therapy based on peptide hormon analogs of GnRH, Bombesin/GRP and Somatostatin as carrier substances for cytotoxic agents, thus aiming to achieve a higher concentration of the active compound in the vicinity of the tumor. This therapeutic concept should lead to an increased antitumoral efficacy and minimized side effects. Targeted therapy with cytotoxic analogs of GnRH, Bombesin/GRP and Somatostatin has been highly effective in preclinical tumor models of breast-, endometrial, and ovarian cancer, although associated with only a low haematological toxicity. In the current studies cytotoxic hybrid molecules were significantly more potent than the chemotherapeutic agent alone. However, the expression of the respective target receptor on the tumor cells is a necessary requirement for an effective therapy, as blockade of tumoral receptors significantly decreased the efficacy of the cytotoxic hybrid molecules in vivo. The haematological toxicity of targeted chemotherapy was significantly less pronounced than the corresponding nondirected therapy with a cytotoxic radical alone in all animal experiments. The rapid development of a resistance to targeted chemotherapy is unlikely, as the expression of MDR proteins after targeted therapy was not increased as compared to a corresponding non-targeted approach in all experiments. AN-152, one of the compounds investigated in this article has already entered clinical testing. Thus, AN-152 showed a good tolerability in a clinical phase I study for patients with GnRH-positive breast-, ovarian-, and endometrial cancer and is now tested for efficacy in a clinical phase II study.

Schlüsselwörter

Chemotherapie - rezeptorvermittelte Therapie - gynäkologische Tumoren - Mammakarzinom - Peptidhormonanaloga als Trägersubstanzen - zytotoxische Hybridmoleküle

Key words

chemotherapy - targeted therapy - gynaecological tumors - breast cancer - peptide hormone analogs as carrier substances - cytotoxic hybrid molecules

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