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Title: The mechanisms underlying the anti-cancer activity of substance-P analogues
Author: Waters, Catherine M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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This study explores the range of tumour types, which are sensitive to substance P analogues. It was found that a wider range of tumour types than had been previously demonstrated were sensitive to growth inhibition by the substance P analogue, [Arg6,D-Trp7,9,NmePhe8]- Substance P(6-11) (antagonist G). Sensitive tumour types included SCLC, NSCLC, colo-rectal and ovarian tumour cell lines with a mean IC50 value of 33mM for 11 tumour cell lines of various origin. The mechanism of action of the growth inhibitory effects of substance P analogues is unclear. Using RT-PCR this study shows that sensitivity of tumour cells to antagonist G is dependent upon the expression of neuropeptide receptors, in particular the bombesin/gastrin releasing peptide (GRP) receptor, and not dependent on tumour type. This is confirmed by the demonstration of increased sensitivity of rat-1 fibroblasts transfected with the bombesin receptor when compared to the parent cell line. Substance P analogues have previously been thought to act as neuropeptide receptor antagonists but more recently they have been shown to have some agonist effects including the activation of c-Jun N-terminal kinase (JNK). Further studies using fibroblast cells transfected with the bombesin receptor show that substance P analogues are potent activators of MAPK and that this occurs via activation of the bombesin receptor. It was found that the substance P analogue, [Arg, D-Phe, D-Trp, Leu11]-Substance P (antagonist D), activates MAPK and inhibits bombesin stimulated calcium flux by the activation of Gi stimulated down stream effectors in preference to the bombesin stimulated Gq downstream effectors. It is demonstrated that MAPK activation by antagonist D is integral in the pro-apoptotic effects of this compound. Thus, the combined effects of substance P analogue stimulated, discordant MAPK and JNK activation, together with the inhibition of neuropeptide stimulated calcium flux, results in growth inhibition and apoptosis in cell types which express neuropeptide receptors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available