Effective treatment of metastatic MDA-MB-435 human estrogen-independent breast carcinomas with a targeted cytotoxic analogue of luteinizing hormone-releasing hormone AN-207.
A highly potent derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201), was linked to [D-Lys6]luteinizing hormone-releasing hormone (LH-RH) to form a cytotoxic analogue, AN-207, that can be targeted to LH-RH receptors. The effects of AN-207 were investigated in MDA-MB-435 human estrogen-independent breast carcinomas, which express LH-RH receptors. In experiment 1, nude mice bearing orthotopically implanted tumors received a single i.v. injection of AN-207, AN-201, or the carrier at 250 nmol/kg. Five weeks after administration of AN-207, tumor volume was significantly decreased by 66% (P < 0.001) and tumor burden by 71% (P < 0.05) as compared with controls, but no significant effects occurred in other groups. Six of eight (75%) control animals and 37.5% of mice treated with AN-201 developed metastases in the lymph nodes, whereas no lymphatic spread was found in any of the mice that received injections of AN-207. The antitumor effect of AN-207 could be partially blocked by pretreatment of the tumor-bearing mice with high doses of agonist [D-Trp6]LH-RH, which suggests that AN-207 acts on LH-RH receptors on tumors. The mortality due to toxicity was 25% in the group receiving AN-201 and 12.5% in the AN-207-treated group. Radioligand binding assays revealed the presence of high-affinity binding sites for LH-RH on tumor membranes, and mRNA for LH-RH receptors was demonstrated by reverse transcription-PCR. In experiment 2, two i.v. injections of AN-207 or AN-201 at 150 nmol/kg were given on days 0 and 28 to mice bearing orthotopic xenografts of MDA-MB-435. The outcome of the treatment was similar to that observed in experiment 1, but without any toxicity-related deaths. Tumor growth inhibition and prevention of metastatic disease suggest that cytotoxic LH-RH analogue AN-207 could be considered for the treatment of human estrogen-independent breast cancers expressing receptors for LH-RH.
Chatzistamou
L
L
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Schally
A V
AV
Nagy
A
A
Armatis
P
P
Szepeshazi
K
K
Halmos
G
G
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012313:RNA / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004967:Estrogens; D011966:Receptors, LHRH; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D012313:RNA; D004317:Doxorubicin; D007986:Luteinizing Hormone