Inhibitory Effects of Antagonists of Bombesin/Gastrin Releasing Peptide (GRP) and Somatostatin Analog (RC-160) on Growth of HT-29 Human Colon Cancers in Nude Mice

Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin

“…Accordingly, receptors for BN-like peptides are present on normal, nonmalignant cells in the digestive tract, the central nervous system and other target organs such as the lung (1, 2, 10). Investigation of the role of BN-like peptides in the mitogenesis of various cancers revealed that high-affinity binding sites for these peptide hormones are also expressed on a wide variety of human and experimental animal tumors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). A recent study also indicates that on certain cancers, such as azaserine-induced pancreatic carcinoma in the rat, highaffinity GRP receptors are present in significantly higher numbers than on the normal pancreas (38).…”

“…Antitumoral effects of BN͞GRP antagonists in vivo have been demonstrated on CFPAC-1 and SW-1990 human pancreatic cancers (17,18), nitrosamine-induced pancreatic cancers in hamsters (19), H69 human SCLC (20), MKN45 and Hs746T human gastric cancers (21,22), HT-29 human colon cancers (23,24), PC-82, PC-3, and DU-145 human prostate cancers (25,26), androgen independent Dunning R-3327-AT-1 rat prostate cancers (27), estrogen dependent and independent MXT mouse mammary cancers (28), MCF-7 MIII human breast cancer (29), and U-87MG and U-373MG human glioblastomas (30). Receptor analyses of these tumors showed the presence of high-affinity binding sites for 125 I[Tyr 4 ]BN (1,2,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Recently, we described the synthesis and evaluation of cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin (DOX) or 2-pyrrolino-DOX, a derivative 500-1000 times more potent (34,35).…”

“…These cytotoxic analogs were developed for therapy of cancers that contain receptors for luteinizing hormone-releasing hormone (35). The presence of receptors for BN-like peptides on a wide variety of tumors (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), prompted us to use some of our powerful BN͞GRP antagonists as carrier molecules for targeting cytotoxic agents to tumor cells.…”

Constitutive activation of the gastrin-releasing peptide receptor expressed by the nonmalignant human colon epithelial cell line NCM460.

“…Furthermore, this receptor is associated with the proliferation of all human colon cancer cell lines in which it is expressed (14)(15)(16)(17). Yet little is known about the mechanism(s) whereby this receptor can cause the proliferation of human colon cancers.…”

Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers

“…7,12,13 Subsequent modification of the C-and N-terminal amino acids has led to further improved antagonists such as RC-3940-II [Hca, 14 Binding studies showed that the binding affinity of RC-3940-II to the GRP receptors on CFPAC-1 human pancreatic cancer cells was 50 times higher than that of RC-3095. 15 RC-3940-II showed promising anti-proliferative activity against human experimental carcinomas of the brain, breast, kidney, lung and prostate.…”