NEW SHORT-CHAIN ANALOGS OF A SUBSTANCE-P ANTAGONIST INHIBIT PROLIFERATION OF HUMAN SMALL-CELL LUNG-CANCER CELLS IN-VITRO AND IN-VIVO

Human small-cell lung-cancer cells (SCLC) produce and secrete gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BN). There is some evidence to suggest that CRP is an autocrine regulator of SCLC cell growth. In the search for potent BN antagonists, several substance-P (SP) analogs were found to inhibit the growth of SCLC cells. We found that a known short-chain SP antagonist, pHOPA-DTrp-Phe-DTrp-Leu-Leu-NH2 (NY3238), inhibits the binding of I-125-Tyr(4)-BN on Swiss 3T3 cell line expressing BN receptors, as well as the proliferation of NCI-H69 SCLC cells. In this study we tested several analogs of NY3238 and we found that NY3521 and NY3460 ave more effective in inhibition of proliferation of SCLC cells but less potent in inhibition of binding of I-125-Tyr(4)-BN on Swiss 3T3 cells than NY3238. Furthermore, we detected specific binding of radiolabelled NY3238 even below I nM on NCI-H69 cells that could have been inhibited by SP and NY3460 rather than by BN. In addition to these in vitro studies, NY3460 proved to be effective in inhibiting the growth of NCI-H69 SCLC xenografts in nude mice in vivo. These analogs of NY3238 could be promising therapeutic agents in the treatment of SCLC.(C) 1995 Wiley-Liss, Inc.