Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207.
The receptors for luteinizing hormone-releasing hormone (LHRH) are found in 80% of human ovarian carcinomas. These receptors can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to [D-Lys ]LHRH. We investigated the effects of AN-207 and AN-201 on the growth of LHRH receptor-positive ES-2 human ovarian cancers. The effects of the treatment on mRNA and protein levels of human epidermal growth factor (EGF) receptors (EGFR and HER-2) in ovarian tumors were determined by RT-PCR and immunoblotting. In Experiment 1, nude mice bearing ES-2 ovarian tumors were injected i.v. with 250 nmol/kg doses of AN-207, AN-201, the carrier [D-Lys ]LHRH, an unconjugated mixture of AN-201 and [D-Lys ]LHRH or vehicle. AN-207 caused a significant ( <0.01) 59.5% inhibition in tumor growth while its components were ineffective. In Experiment 2, mice with large ES-2 tumors were treated with AN-207 or AN-201 at 250 nmol/kg. Again, AN-207, but not AN-201, inhibited tumor growth. In Experiment 3, the site of action of AN-207 was investigated. The blockade of LHRH receptors with Cetrorelix partially suppressed the antitumor effect of AN-207. Treatment with AN-207 significantly ( <0.01) decreased the expression of mRNA for EGFR, and HER-2 by 27 and 34%, respectively, as compared to controls and reduced the receptor protein levels of EGFR and HER-2 by 35 and 36%, respectively ( <0.05). The results indicate that cytotoxic LHRH analog AN-207 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.
Arencibia
Jose M
JM
Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
Bajo
Ana M
AM
Schally
Andrew V
AV
Krupa
Magdalena
M
Chatzistamou
Ioulia
I
Nagy
Attila
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin; D066246:ErbB Receptors; D007987:Gonadotropin-Releasing Hormone; D011758:Pyrroles; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011966:Receptors, LHRH; C098751:AN 204; C104648:AN 207