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Title: Mechanism of growth inhibition of cAMP analogues on cultured cancer cells
Author: Gilbert, Robin Leon
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1991
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Adenosine 3',5'-cyclic monophosphate (cAMP) analogues have antiproliferative effects on a range of cancer cells including breast, colon and lung. The most potent analogue, described to date, is 8-chloro cAMP but its mechanism of inhibition is poorly understood. The aim of this thesis was to investigate the mechanism of action of cAMP analogues on human cancer cell lines, in particular the hormone-responsive breast cancer cell line MCF-7. Growth inhibitory effects of 8-chloro cAMP was confirmed on MCF-7 cells. However, this effect was not present in serum-free conditions and the degree of inhibition was dependent on the concentration of foetal calf serum in the medium. This effect could also be demonstrated in the presence and absence of added oestradiol suggesting that 8-chloro cAMP does not antagonise the oestradiol stimulation of MCF-7 cells. Effects of 8-chloro cAMP were also tested on other cancer cell lines derived from breast, ovary and colon. Inhibition of cellular proliferation was again dependent on the addition of serum in the culture medium. Partial characterisation and purification of serum was attempted in order to identify the component(s) responsible for this serum-dependent 8-chloro cAMP inhibition. The component(s) was heat labile and fractions separated by gel filtration chromatography containing inhibitory activity were eluted before the major albumin peak. When medium containing 8-chloro cAMP and serum was pre-incubated, antiproliferative activity remained after removal of most of the serum components by ultrafiltration. In serum-free conditions, phosphodiesterases conferred the ability to 8-chloro cAMP to inhibit growth of MCF-7 cells; addition of a phosphodiesterase inhibitor appeared to protect the cells from the antiproliferative effect in serum containing medium. High pressure liquid chromatography of cAMP analogues incubated with serum or with gel filtration fractions detected a peak that had identical UV spectrum and a column retention time as an 8-chloro adenosine standard.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available