INVITRO EFFECTS OF SUBSTANCE-P ANALOG [D-ARG(1), D-PHE(5), D-TRP(7,9), LEU(11)] SUBSTANCE-P ON HUMAN TUMOR AND NORMAL-CELL GROWTH

Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7.9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50-mu-M. There was dose dependent inhibition of colony forming efficiency (CFE) in 3/3 SCLC and 1/1 N-SCLC CL, IC50s of 0.5-6.5-mu-M in 5% serum. Exposure of SCLC CL HC12 to 100-mu-M D-Phe5SP for 1-4 h caused a progressive fall in viable cell number; surviving cells, grown in the absence of peptide, showed a decreased growth rate. During 1 week's exposure of two SCLC CLs to 20-mu-M D-Ph5SP, growth was slower than control cultures, while 50-100-mu-M completely inhibited growth. These inhibitory effects were partially reversed by increasing serum concentration from 5 to 20%, but not by SP, vasopressin, bombesin or insulin-like growth factor 1. There was some inhibition of CFE by 3/3 normal human bone marrows, IC50s of 30-80-mu-M, compared with 8-mu-M for HC12 in 20% FCS. Therefore D-Phe5SP appears to have more potent antiproliferative effects in tumor cells than normal cells, suggesting a role for this analogue in tumour treatment.