The biochemistry of peptides and growth factors in lung cancer was investigated. Bombesin/gastrin releasing peptide (BB/GRP) is a positive autocrine growth factor for small cell lung cancer (SCLC) and the growth of SCLC is inhibited by synthetic receptor antagonists. In our studies, GRP gene expression was increased by phorbol-12-myristate-13 acetate (PMA), which activates protein kinase C (PKC). The increase in GRP mRNA caused by PMA was reversed by (5-isoquinolinesulfonyl)-2-methylpiperazine (H7). We also found that PMA increased SCLC growth and H7 significantly inhibited proliferation. These data suggest that PKC may be an important enzyme mediating SCLC growth. Also, SCLC growth was inhibited by the chemopreventive protease inhibitor Bowman-Birk inhibitor (BBI). BBI decreased levels of bioactive GRP levels but increased levels of inactive proGRP. BBI may inhibit enzymes which process GRP. Transforming growth factor alpha/epidermal growth factor (TGFalpha/EGF) is a positive autocrine growth factor for non-SCLC (NSCLC). Here a TGFalpha- pseudomonas exotoxin (TGFalpha-PE40) chimera bound with high affinity to the EGF receptor. TGFalpha-PE40 was internalized by NSCLC cells and the PE40 metabolites were released into the cytosol inhibiting protein synthesis. As a result, TGFalpha-PE40 killed NSCLC cells in vitro and in vivo. TGFalpha-PE40 was cytotoxic for NSCLC cells. In contrast, thymosin alpha1 (THNalpha1) was cytostatic for NSCLC cells. THNalpha1 inhibited colony formation using cell biology techniques and xenograft formation in nude mice in a reversible manner. THN`1 also stimulated arachidonic acid (AA) release from NSCLC cells. THNalpha1 may activate phospholipase A2 stimulating AA releases from endogenous phospholipids. These data suggest that THNalpha1 may be a negative autocrine growth factor for NSCLC cells.
