[D-ARG(1),D-TRP(5,7,9),LEU(11)]SUBSTANCE-P - A NOVEL POTENT INHIBITOROF SIGNAL-TRANSDUCTION AND GROWTH IN-VITRO AND IN-VIVO IN SMALL-CELL LUNG-CANCER CELLS

[D-Arg(1),D-Trp(5,7,9),Leu(11)]Substance P (SP) was identified out of a panel of novel SP analogues as the most potent inhibitor of small ce ll lung cancer (SCLC) cell growth. This analogue inhibited proliferati on of H-510 and H-69 SCLC cells in liquid culture and in semisolid med ia (IC50, 5 mu M). Colony formation stimulated by multiple neuropeptid es, including vasopressin and bradykinin, was also blocked by [D-Arg(1 ),D-Trp(5,7,9),Leu(11)]SP. This new SP analogue inhibited vasopressin- or bradykinin-induced Ca2+ mobilization and mitogen-activated protein kinase activation, Administration of [D-Arg(1),D-Trp(5,7,9),Leu(11)]S P inhibited the growth of an H-69 xenograft in nude mice. Our results support the hypothesis that SP analogue broad-spectrum neuropeptide an tagonists could be of therapeutic value in SCLC.