New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs

Abstract

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.

Development of a polyclonal antiserum for the detection of the isoforms of the receptors for human growth hormone-releasing hormone on tumors

“…These and other findings (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) suggested the involvement of specific receptors for GHRH antagonists on human cancers. We then reported the expression of four splice variants (SVs) of the full-length human GHRH-R in normal tissues and certain cancer cell lines on the basis of sequence analyses of cDNA encoding these receptors (16,17).…”

“…A ntagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of experimental human cancer cell lines xenografted into nude mice or cultured in vitro and are being developed for cancer therapy (1)(2)(3)(4). To design still more potent antagonists, we have to fully understand their mechanism of action.…”

“…The indirect mechanism operates through a suppression of the growth hormone release from the pituitary and the resulting inhibition of the production of insulin-like growth factor I in the liver (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). However, the principal action of GHRH antagonists is probably exerted directly on tumors and appears to be mediated by specific receptors for GHRH antagonists on cancer cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(11)(12)(13). Although the mRNA for GHRH and immunologically active GHRH were demonstrated in various human tumor cells, the mRNA for human pituitary GHRH receptor (GHRH-R) has not been detected on these tumor cells or any of the other cancer models (11,14,15).…”

Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca 2+ -dependent pathway

“…GH, in turn, induces the production of hepatic insulin-like growth factor I (IGF-I) (1)(2)(3)(4)(5)(6), which is a known mitogen for various cell types and has been linked with malignant transformation, tumor progression, and metastasis of various cancers (reviewed in ref. 7).…”

The Immunohistochemical Expression of Growth Hormone-Releasing Hormone Receptor Splice Variant 1 Is a Favorable Prognostic Marker in Colorectal Cancer

“…Colorectal cancer (CRC) is globally the third most common malignancy among adults, and the fourth leading cause of cancer-related deaths after lung cancer (1,2). Recent studies indicate the involvement of growth factors in the tumorigenesis of various human tumors, including breast, uterine, endometrium, ovary, prostate, and lung as well as gastroenteropancreatic cancers (2)(3)(4).…”