Recently, new potent antagonistic analogs of growth hormone-releasing hormone (GH-RH) have been synthesized. These GH-RH antagonists bind to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. This suggests that they could be clinically useful in conditions such as acromegaly. The main applications of GH-RH antagonists would be in the field of insulin-like growth factor I (IGF-I)- and IGF-II-dependent cancers. GH-RH antagonists inhibit the growth of various human cancer cell lines xenografted into nude mice, including mammary cancers, androgen-independent prostate cancers, small-cell lung carcinomas, non-small-cell lung carcinomas, renal adenocarcinomas, pancreatic cancers, colorectal carcinomas and malignant gliomas. These effects could, in part, be exerted indirectly through inhibition of the secretion of GH and the resulting reduction in levels of hepatic IGF-I. However, the principal action of GH-RH antagonists in vivo appears to be the direct suppression of the autocrine and/or paracrine production and expression of the genes encoding IGF-I (IGF1) and IGF-II (IGF2) in tumors. In vitro, antagonists of GH-RH inhibit the proliferation of mammary, prostatic, pancreatic and colorectal cancer cell lines, reducing the expression of IGF2 mRNA in the cells and the secretion of IGF-II. The presence of the GH-RH ligand has been demonstrated in human ovarian, endometrial, mammary and lung cancers, suggesting that GH-RH could be a growth factor. Further development of GH-RH antagonists should lead to potential therapeutic agents for IGF-dependent cancers.
Because hGH-RH(1–29) (Fig. 1) is the shortest fully active fragment of human GH-RH (hGH-RH), this sequence has been used for the development of agonistic and antagonistic GH-RH analogs (reviewed in 3, 10). Although shorter GH-RH antagonists were prepared, there was a major loss of potency (M. Zarandi and A.V. Schally, unpublished). Synthetic work was aimed at developing GH-RH antagonists with increased receptor-binding affinity, enhanced enzymatic stability and protracted biological activity.
The investigation of GH-RH antagonists in nude mice bearing transplanted human cancer lines and in various animal tumor models was initiated mainly on the assumption that blocking the pituitary GH–hepatic IGF-I axis might inhibit the growth of IGF-I-dependent cancers7, 8, 9, 10. Subsequently, it was discovered that GH-RH antagonists can also suppress the proliferation of diverse tumors that are influenced by autocrine and/or paracrine production of IGF-I and IGF-II. Hence, a much wider range of
The presence of GH-RH and its receptors in several extrahypothalamic tissues, including ovary, testis and the digestive tract suggests that GH-RH might have a regulatory role in these tissues1, 2, 37. Frohman et al. first demonstrated ectopic production of GH-RH by carcinoid and pancreatic tumors in 1981 (Ref. 38). Recently, biologically or immunologically active GH-RH and mRNA encoding GH-RH were found in several human malignant tumors, including cancers of the breast, endometrium and ovary,
Only the earliest GH-RH antagonist [Ac-Tyr 1, D-Arg 2]hGH-RH(1–29)NH 2 has been evaluated clinically 44. Large doses of this antagonist (400 μg kg−1) eliminated nocturnal GH secretion in normal subjects and inhibited the response to GH-RH. This GH-RH antagonist also reduced GH levels in a patient with acromegaly 45.
The GH-RH antagonists could be used for the treatment of conditions caused by excess GH, such as acromegaly 36. In addition, diabetic retinopathy and diabetic nephropathy
Both IGF-I and IGF-II have been implicated in the malignant transformation of cells, tumor progression and the metastasis of various cancers7, 8, 9, 10, 27, 28, 29, 30, 31, 36, 46, 47, 48, 49, 50, 51, 52. The involvement of IGF-I or IGF-II in breast, prostatic, pancreatic, and colon cancer, brain tumors, SCLCs, non-SCLCs, renal cancers, osteosarcomas and other malignancies is established or suspected3, 7, 8, 9, 10, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 46, 47, 48, 49,
GH-RH antagonists appear to inhibit the growth of IGF-I- and IGF-II-dependent cancers through indirect and direct pathways10, 26 (Fig. 5). The indirect mechanism operates through suppression of the GH release from the pituitary and the resulting inhibition of IGF-I production in the liver (Fig. 5A). Thus, GH-RH antagonists decrease the level of IGF-I in the serum of nude mice bearing xenografts of prostatic, breast and renal cancers, osteosarcomas, and SCLCs and non-SCLCs (10, 20, 21, 24, 25, 26
The authors’ work was supported by the Medical Research Service of the Veterans Affairs Department, an award from CaP CURE (Association for the Cure of Prostate Cancer) and grants from ASTA Medica to Tulane University School of Medicine.
