7 november 2012: onderaan hebben we twee interessante studies, waaronder een review studie toegevoegd van gerichte chemo therapie met specifiek op zogeheten luteinizing hormone-releasing hormone [LHRH, ook bekend als gonadotropin-releasing hormone (GnRH receptoren gerichte aanpak van hormoon bepaalde vormen van kanker waaronder eierstokkanker, kanker ontstaan vanuit endometriose - baarmoederkanker, borstkanker maar ook voor mannen met prostaatkanker. De toegevoegde studies zijn een vervolg op onderstaande studie uit 2005.
4 juli 2005: Bron; Clin Cancer Res. 2005 Mar 15;11(6):2408-15.
Onderzoekers werkzaam aan het Veterans Affairs Medical Center in Amerika, een medisch centrum waar vooral oorlogsveteranen worden opgenomen, doen al jaren onderzoek naar het effect van sterk op de individele kankercel gerichte chemobehandelingen via bepaalde aanwezige receptoren op de kankercellen. En met succes. Hieronder twee recente publicaties van dierstudies bij respectievelijk eierstokkankercellen en endometriose kankercellen. Beiden met significant goede resultaten en conclusies van de auteurs dat deze aanpak zeer zeker een beloftevolle aanpak voor in dit geval uitgezaaide eierstokkanker en endometrialcancer - baarmoederkanker en kanker ontstaan vanuit endometriose kan betekenen. Overigens zijn al veel proeven gedaan met allerlei soorten kanker , waaronder ook borstkanker en longkanker. Wij hebben nogal wat publicaties over deze aanpak beschikbaar, ook met patiënten, maar willen dat eerst bundelen en voorleggen aan deskundige artsen/onderzoekers voordat we dit op de website publiceren.
Dieren ingespoten met eierstokkankercellen met bepaalde receptoren en daarna behandeld met 2-pyrrolinodoxorubicin onder de naam AN-215 = een direct op de tumorcellen gerichte chemotherapie - geeft sterk en significant remmend effect op de groei van eierstokkankercellen. De conclusie van de onderzoekers is zeer optimistisch:
CONCLUSIES: Onze bevindingen indiceert dat gerichte chemotherapie met cytotoxische bombesin/GRP analoog AN-215 de groei van eierstoktumoren welke bombesin/GRF receptoren hebben kan verhinderen. AN-215 zou een nieuwe behandelingsmogeljikheid kunnen betekenen voor vrouwen met een al uitgezaaide vorm van eierstokkanker of baarmoederkanker - endometrial cancer
CONCLUSIES: Gerichte chemotherapie met AN-152 en AN-207 remt sterk de groei van menselijke endometriosekankercellen, welke LHRH receptoren bevatten, en kan een nieuwe behandelingsmogelijkheid betekenen voor uitgezaaide endometriosekanker.
Clin Cancer Res. 2005 Mar 15;11(6):2408-15.
Effective inhibition of experimental human ovarian cancers with a targeted cytotoxic bombesin analogue AN-215.
Engel JB, Keller G, Schally AV, Halmos G, Hammann B, Nagy A.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
PURPOSE: To determine whether the cytotoxic analogue of bombesin/gastrin-releasing peptide (GRP) AN-215 can inhibit the in vivo growth of four human ovarian cancer cell lines. AN-215 consists of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin linked to a bombesin antagonist carrier des-D-Tpi-RC-3095. This conjugate binds strongly to receptors for bombesin/GRP and can be targeted to tumors that express these receptors. Bombesin/GRP receptors are found in 77% of human ovarian cancer specimens.
EXPERIMENTAL DESIGN: Nude mice bearing xenografts of ES-2, SKOV-3, OV-1063, and UCI-107 human ovarian carcinomas were treated with AN-215. The antitumor effects and the toxicity were determined. The expression of bombesin receptor subtypes was measured by reverse-transcriptase PCR analysis, and the presence of bombesin/GRP receptors was determined by radioligand binding assays.
RESULTS: AN-215 significantly (P < 0.05) inhibited growth of ES-2, OV-1063, and UCI-107 tumors, prevented the metastatic spread of ES-2 cancers, and prolonged the survival of nude mice bearing i.p. ES-2 xenografts. Cytotoxic radical AN-201, the unconjugated mixture of bombesin antagonist RC-3095 and AN-201 or RC-3095 alone had no significant effects. Blockade of bombesin/GRP receptors abolished the effect of AN-215. The expression of bombesin/GRP receptors was not changed after repeated treatment with AN-215.
CONCLUSIONS: Our findings indicate that targeted chemotherapy with cytotoxic bombesin/GRP analogue AN-215 can inhibit ovarian tumors, which express bombesin/GRP receptors. AN-215 might provide a new treatment modality for women with advanced ovarian carcinoma.
PMID: 15788692 [PubMed - indexed for MEDLINE]
Fertil Steril. 2005 Apr;83 Suppl 1:1125-33.
Effective treatment of experimental human endometrial cancers with targeted cytotoxic luteinizing hormone-releasing hormone analogues AN-152 and AN-207.
Engel JB, Keller G, Schally AV, Nagy A, Chism DD, Halmos G.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262, USA.
OBJECTIVE: To treat experimental human endometrial cancers based on targeted chemotherapy with the cytotoxic luteinizing hormone-releasing hormone (LHRH) analogues AN-152 and AN-207.
DESIGN: Experimental study using athymic nude mice bearing xenografts of HEC-1A and RL-95-2 human endometrial cancers to assess the efficacy and toxicity of AN-152 and AN-207. The expression of LHRH receptors in HEC-1A and RL-95-2 cancers was determined by reverse transcription-polymerase chain reaction, Western blot analysis, and radioligand binding assays.
SETTING: Experimental laboratory research. ANIMAL(S): Female athymic nude mice (Ncr, nu/nu).
INTERVENTION(S): Animals were treated with IV injections of the cytotoxic LHRH analogues AN-152 and AN-207 and their respective cytotoxic radicals doxorubicin (DOX) and AN-201 (2-pyrrolinodoxorubicin) on a control vehicle solution.
MAIN OUTCOME MEASURE(S): Tumor volume, final tumor weight, tumor doubling time, body weight, white blood cell count, and LHRH receptor expression. RESULT(S): AN-152 significantly inhibited the growth of HEC-1A tumors. AN-207 also significantly suppressed the proliferation in vivo of HEC-1A and RL-95-2 cancers. The cytotoxic radicals DOX and AN-201 had no effect. Furthermore, mRNA for LHRH receptors, LHRH receptor protein, and high-affinity binding sites for LHRH were demonstrated on tumors.
CONCLUSION(S): Targeted chemotherapy with AN-152 and AN-207 strongly inhibits the growth of human endometrial cancers, which express LHRH receptors, and could provide a new treatment modality for women with advanced endometrial carcinoma.
PMID: 15831285 [PubMed - indexed for MEDLINE]
AEZS-108 : a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors.
AEZS-108 : a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors.
Source
Medical University of Regensburg, Department of Obstetrics and Gynecology, Landshuter Strasse 65, 93059 Regensburg, Germany.
Abstract
INTRODUCTION:
Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys(6)]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy.
AREAS COVERED:
This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed.
EXPERT OPINION:
AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.
- PMID:
- 22577891
- [PubMed - indexed for MEDLINE]
Targeting of Cytotoxic Luteinizing Hormone-Releasing Hormone Analogs to Breast, Ovarian, Endometrial, and Prostate Cancers1
Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers.
Source
Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Abstract
Targeted chemotherapy is a modern approach aimed at increasing the efficacy of systemic chemotherapy and reducing its side effects. The peptide receptors expressed primarily on cancerous cells can serve as targets for a selective destruction of malignant tumors. Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens. Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule. To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys6]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX). In addition, we designed and synthesized a highly active derivative of DOX, 2-pyrrolino-DOX (AN-201), which is 500-1000 times more potent than DOX in vitro. AN-201 is active against tumors resistant to DOX, and noncardiotoxic. As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys6]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207. Both AN-152 and AN-207 can effectively inhibit the growth of LHRH receptor-positive human breast, ovarian, endometrial, and prostate cancers xenografted into nude mice. DOX-containing cytotoxic LHRH analog AN-152 is scheduled for clinical phase I/IIa trials in patients with advanced ovarian and breast cancers in 2005.
- PMID:
- 16033997
- [PubMed - indexed for MEDLINE]
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