Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone.
Recently, we developed a targeted cytotoxic analog AN-207 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.
Kovacs
M
M
Endocrine, Polypeptide, and Cancer Institute, Veterans Administration Medical Center, Tulane University School of Medicine, New Orleans, LA 70146, USA.
Schally
A V
AV
Nagy
A
A
Koppan
M
M
Groot
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013006:Growth Hormone / Q000032:analysis; D007986:Luteinizing Hormone / Q000032:analysis; D008597:Menstrual Cycle / Q000187:drug effects; D010901:Pituitary Function Tests; D010903:Pituitary Gland, Anterior / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000032:analysis
D000970:Antineoplastic Agents; D003603:Cytotoxins; D011758:Pyrroles; C098751:AN 204; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin; D007986:Luteinizing Hormone; D013972:Thyrotropin; D013006:Growth Hormone