Woll, Penella J.; (1990) Neuropeptide growth factors and small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Quiescent cultures of Swiss 3T3 cells are a useful model system for elucidating the mechanisms of mitogenesis. Here, Swiss 3T3 cells were used to test novel mitogens and characterise bombesin antagonists. Bradykinin was identified as a potent mitogen, acting in synergy with insulin. Two groups of antagonists were characterised: the substance P analogues [DArg1, DPro2, DTrp7,9, Leu11]- substance P (antagonist A), [DArg1, DPhe5, DTrp7,9, Leu11]- substance P (antagonist D) and [Arg6, DTrp7,9, Leu11] substance P(6-11) (antagonist G); and the bombesin-specific antagonists (Leu13-psi(CH2NH)Leu14]bombesin and N- acetyl-GRP(20-26). The substance P antagonists appear to interact with a common domain on the receptors for three mitogenic neuropeptides in Swiss 3T3 cells: bombesin, vasopressin and bradykinin. The bombesin-specific antagonists did not interact with other receptors. Small cell lung cancer (SCLC) is an aggressive form of lung cancer. The bombesin-like peptides, including gastrin- releasing peptide (GRP), have been postulated to act as autocrine growth factors for these tumours. In SCLC cell lines, all the antagonists were shown to block the early effect of bombesin, mobilisation of cytosolic Ca2+. The substance P antagonists also inhibited SCLC growth in liquid and semisolid media, in a reversible, dose-dependent fashion. The bombesin-specific antagonists did not inhibit SCLC growth, suggesting that other growth factors blocked by the substance P antagonists may be more important for regulating SCLC growth. A variety of peptides and hormones were tested for their ability to mobilise cytosolic Ca2+ in SCLG cell lines. Ca2+ signals were induced by GRP, vasopressin, bradykinin, cholecystokinin, galanin and neurotensin, and all were blocked by antagonists D and G. These neuropeptides are suggested as possible growth factors for SCLC.

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