Effective treatment of metastatic MDA-MB-435 human estrogen-independent breast carcinomas with a targeted cytotoxic analogue of luteinizing hormone-releasing hormone AN-207

I. Chatzistamou, A. V. Schally, A. Nagy, P. Armatis, K. Szepeshazi, G. Halmos

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

A highly potent derivative of doxorubicin, 2-pyrrolin-odoxorubicin (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 tile 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.

Original languageEnglish (US)
Pages (from-to)4158-4165
Number of pages8
JournalClinical Cancer Research
Volume6
Issue number10
StatePublished - Nov 13 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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