Tumour-promoting and hyperplastic effects of phorbol and daphnane esters in CD-1 mouse skin and a synergistic effect of calcium ionophore with the non-promoting activator of protein kinase C, sapintoxin A.
Using an 18 week two-stage protocol we have compared the tumour-promoting properties of a range of phorbol and daphnane esters on female CD-1 mice. The induction of epidermal hyperplasia in this mouse strain by these compounds has also been assessed by comparison with the standard phorbol ester, 12-O-tetradecanoylphorbol-13-O-acetate (TPA). Two compounds, sapintoxin D (SAP D) and thymeleatoxin A (TA) (a daphnane structurally related to the second-stage promoter mezerein) were shown to be second-stage promoters using 5 nmol TPA as a first-stage promoter and 0.2 mumol 7,12-dimethylbenz[a]anthracene (DMBA) as initiator. Both compounds at a dose of 17 nmol were hyperplasiogenic. Two further derivatives, sapintoxin C (SAP C) and 4 alpha-sapinine (alpha-SAP) were inactive as promoters and hyperplastic agents. 4 alpha-sapinine, which prevents in vitro stimulation of protein kinase C (PKC), by 12-O-tetradecanoylphorbol-13-O-acetate (TPA) failed to inhibit significantly TPA-induced promotion and hyperplasia at a dose of 20 nmol and 100 nmol respectively. Sapintoxin A (SAP A), a potent activator of PKC, was neither a complete nor second-stage promoter at doses of up to 20 nmol. A series of in vivo and in vitro experiments which were carried out to determine the metabolic fate of this compound under experimental conditions showed that SAP A was not metabolized to any significant extent up to 48 h. When SAP A was co-administered with sub-hyperplastic doses of the calcium ionophore A23187 (5 micrograms and 10 micrograms) tumours appeared in a dose-dependent manner. This combination was also hyperplasiogenic in mouse skin. SAP A may be a useful probe for studying the involvement of PKC isozymes in tumour promotion and cell proliferation.
Brooks
G
G
Department of Pharmacognosy, School of Pharmacy, University of London, UK.
Evans
A T
AT
Aitken
A
A
Evans
F J
FJ
D000818:Animals; D002273:Carcinogens; D055598:Chemical Phenomena; D002621:Chemistry; D004224:Diterpenes; D005260:Female; D006965:Hyperplasia / Q000209:etiology*; D010703:Phorbol Esters / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013729:Terpenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002273:Carcinogens; D004224:Diterpenes; D010703:Phorbol Esters; D013729:Terpenes; C011309:mezerein; D013755:Tetradecanoylphorbol Acetate