Alternative mechanisms of action of anti-oestrogens.
The molecular mechanism of action of anti-oestrogens such as tamoxifen appears to be a complex mixture of antagonism of the mitogenic action of oestradiol at the level of the oestrogen receptor, plus a range of other activities from enzyme inhibition to growth factor modulation. This article will concentrate on two specific areas: 1) the inhibition of protein kinase C and calmodulin-dependent cAMP phosphodiesterase; and 2) the regulation by tamoxifen of peptide regulators of breast cancer epithelial cell growth such as insulin-like growth factor I (IGF I) and transforming growth factor beta (TGF-beta). The elucidation of these mechanisms is potentially important in the treatment and chemoprevention of breast cancer-the quantitative contribution of each individual mechanism of the overall antineoplastic action of anti-oestrogens is central to developing new and possibly more effective anti-oestrogens and optimizing strategies for their use.
Colletta
A A
AA
Section of Academic Surgery, Royal Marsden Hospital, London, UK.
Benson
J R
JR
Baum
M
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004958:Estradiol / Q000502:physiology; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000502:physiology
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1