Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone

Magdolna Kovacs, Andrew V. Schally, Attila Nagy, Miklos Koppan, Kate Groot

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Recently, we developed a targeted cytotoxic analog AN-2117 of luteinizing hormone-releasing hormone (LH-RH), consisting of an intensely potent derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201) conjugated to carrier agonist [D-Lys6]LH-RH. In this study, we investigated the effects of cytotoxic analog AN-207, designed for targeted chemotherapy and radical AN-201 on pituitary function in rats. A selective damage to the pituitary gonadotroph cells was found at 1 week after a single i.v. injection of 150 nmol/kg AN-207, as evidenced by a 63% decrease in the LH-RH-stimulated release of LH in vitro. The release of growth hormone (GH) and thyrotropin (TSH), stimulated by GH-releasing hormone (GH-RH) and TSH-releasing hormone (TRH), respectively, was reduced by only 11-12%. In contrast, even a smaller dose of 75 nmol/kg of AN-201 nonselectively damaged pituitary function, reducing the stimulated release of LH, GH, and TSH by 57%, 74%, and 67%, respectively. Two weeks after administration, the LH-RH-stimulated LH release in vivo entirely normalized in the AN-207-treated rats, and only a 13% decrease in the LH response was found in the group given AN-201. GH and TSH responses to receptor-mediated stimuli with GH-RH and TRH were normal at 2 weeks in both treated groups. Neither cytotoxic compound caused changes in the concentration of pituitary LH, GH, or TSH, as determined by RIA at 1 week and 7 weeks after treatment. This study demonstrates that the cytotoxic LH- RH analog AN-207 exerts highly selective effects on the gonadotroph cells containing LH-RH receptors and is less toxic for other cells. Conversely, its cytotoxic radical AN-201 nonselectively damages the pituitary cells. The damaging effect of both cytotoxic compounds on pituitary functions is reversible. In view of its high selectivity and reduced toxicity, AN-207 could be a potential therapeutic agent for the treatment of tumors that possess receptors for LH-RH such as prostatic, mammary, ovarian, and endometrial cancers.

Original languageEnglish (US)
Pages (from-to)1420-1425
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number4
DOIs
StatePublished - Feb 18 1997
Externally publishedYes

Keywords

  • growth hormone
  • pituitary hormones
  • selective damage
  • targeted chemotherapy
  • thyrotropin

ASJC Scopus subject areas

  • Genetics
  • General

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