TY - JOUR
T1 - Effective inhibition of experimental human ovarian cancers with a targeted cytotoxic bombesin analogue AN-215
AU - Engel, Jörg B.
AU - Keller, Gunhild
AU - Schally, Andrew V.
AU - Halmos, Gabor
AU - Hammann, Brian
AU - Nagy, Attila
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/3/15
Y1 - 2005/3/15
N2 - 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 MC-3095 alone had no significant effects. Blockade of bombesin/GMP 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.
AB - 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 MC-3095 alone had no significant effects. Blockade of bombesin/GMP 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.
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U2 - 10.1158/1078-0432.CCR-04-1670
DO - 10.1158/1078-0432.CCR-04-1670
M3 - Article
C2 - 15788692
AN - SCOPUS:16844372709
VL - 11
SP - 2408
EP - 2415
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -