Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities

Abstract

Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH 2 . The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [ (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH-RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

“…In recent years several series of antagonistic analogs of growth hormone-releasing hormone (GHRH) were synthesized in an endeavour to develop a new class of antineoplastic agents [8][9][10][11]. GHRH antagonists inhibit the growth of various experimental human cancers [12], but their effects on triple-negative breast cancers have not been studied.…”

Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

“…Antagonistic analogs of GHRH have been synthesized in many laboratories (9,(11)(12)(13)(14)(15)(16) because of their expected applications (17)(18)(19)(20)(21). These analogs could be useful for therapy of endocrine disorders such as acromegaly, diabetic retinopathy, or diabetic nephropathy.…”

“…However, the main applications of GHRH antagonists would be in the field of cancer (17,(19)(20)(21). GHRH antagonists synthesized in this laboratory (14)(15)(16) inhibit tumor growth in experimental animals acting: (i) indirectly through pituitary GHRH-R leading to the suppression of GHRH-GHinsulin-like growth factor (IGF)-I axis; or (ii) directly via the reduction of IGF-I and IGF-II production in tumors (21). GHRH antagonists also inhibit the proliferation of various cancers in vitro apparently by a direct action on cancer cells (22,23).…”

Antagonists of growth hormone releasing hormone (GHRH) given before whole body radiation lead to modulation of radiation response and organ-specific changes in the expression of angiogenesis

“…The finding that GHRH can function as a tumor growth factor [5][6][7][8][9][12][13][14][15][16] increased interest in the development of GHRH antagonists. Antagonists of GHRH can exert both direct and indirect effects on tumors and other tissues.…”

“…Peptides were synthesized in our laboratory by solid phase method and purified by reverse-phase HPLC as described previously [12,13]. The structure of JMR-132 are the following: …”