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 luteinizi ng hormone-releasing hormone (LH-RH), consisting of an intensely poten t derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201) conjugate d to carrier agonist [D-Lys(6)]LH-RH. In this study, we investigated t he effects of cytotoxic analog AN-207, designed for targeted chemother apy and radical AN-201 on pituitary function in rats, A selective dama ge to the pituitary gonadotroph cells was found at 1 week after a sing le i.v. injection of 150 nmol/kg AN-207, as evidenced by a 63% decreas e in the LH-RH-stimulated release of LH in vitro, The release of growt h hormone (GH) and thyrotropin (TSH), stimulated by GH-releasing hormo ne (GH-RW) and TSH-releasing hormone (TRH), respectively, was reduced by only 11-12%. In contrast, even a smaller dose of 75 nmol/kg of AN-2 01 nonselectively damaged pituitary function, reducing the stimulated release of LH, GH, and TSH by 57%, 74%, and 67%, respectively. Two wee ks after administration, the LH-RH-stimulated LH release in vivo entir ely 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 respon ses to receptor-mediated stimuli with GH-RH and TRH were normal at 2 w eeks in both treated groups. Neither cytotoxic compound caused changes in the concentration of pituitary LH, GH, or TSH, as determined by RI A at 1 week and 7 weeks after treatment, This study demonstrates that the cytotoxic LN-RH analog AN-207 exerts highly selective effects on t he gonadotroph cells containing LH-RH receptors and is less toxic for other tells, Conversely, its cytotoxic radical AN-201 nonselectively d amages the pituitary cells, The damaging effect of both cytotoxic comp ounds on pituitary functions is reversible, In view of its high select ivity and reduced toxicity, AN-207 could be a potential therapeutic ag ent for the treatment of tumors that possess receptors for LH-RH such as prostatic, mammary, ovarian, and endometrial cancers.