Synergistic stimulation of histamine release from rat peritoneal mast cells by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters.

Thapsigargin, a non-TPA (12-O-tetradecanoylphorbol 13-acetate)-type tumor promoter, provoked histamine release from rat peritoneal mast cells at concentrations above 30 ng/ml, but not at 10 ng/ml. TPA-type tumor promoters such as TPA, teleocidin and aplysiatoxin released very little, if any, histamine even at 100 ng/ml. When mast cells were incubated in medium containing thapsigargin at 10 ng/ml and varying concentrations of TPA-type tumor promoters, histamine release was increased synergistically.

Modulation of phorbol ester receptors in mouse skin by application of quercetin.

The topical application of quercetin, an anti-tumor promoter, to mouse skin reduced the number of phorbol ester receptors, although quercetin did not inhibit specific 3H-12-O-tetradecanoylphorbol-13-acetate binding to a mouse skin particulate fraction. Quercetin, morin, kaempferol and luteolin inhibited activation of protein kinase C by teleocidin, and caused half-maximal activation at 25 microM. (+)-Catechin, which has been reported not to inhibit tumor-promoting activity, did not have any effect on these reactions.

Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis.

Palytoxon, which is a toxin with a molecular weight of 2681 daltons isolated from a marine coelenterate, is a potent skin irritant. However, it did not induce ornithine decarboxylase in mouse skin, or adhesion of human promyelocytic leukemia cells (HL-60). Moreover, it did not inhibit the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to a mouse skin particulate fraction or activate protein kinase C isolated from mouse brain in vitro.

Binding studies of [3H]lyngbyatoxin A and [3H]debromoaplysiatoxin to the phorbol ester receptor in a mouse epidermal particulate fraction.

The preparation of [3H]lyngbyatoxin A by catalytic triton-proton exchange of lyngbyatoxin A and [3H]debromoaplysiatoxin by tritiation-debromination of aplysiatoxin is described. The dose-response curves for the binding of [3H]lyngbyatoxin A and [3H]debromoaplysiatoxin to a mouse epidermal particulate fraction are virtually the same as the one previously described for [3H]12-O-tetradecanoylphorbol-13-acetate ([3H]TPA). The specific binding of [3H]TPA, [3H]-lyngbyatoxin A and [3H]debromoaplysiatoxin to the mouse epidermal particulate fraction is inhibited to the same degree by unlabeled TPA, teleocidin, lyngbyatoxin A, aplysiatoxin and debromoaplysiatoxin.

Des-O-methylolivoretin C is a new member of the teleocidin class of tumor promoters.

Des-O-methylolivoretin C, a demethylated form of olivoretin C, is a naturally occurring compound in Streptomyces mediocidicus and Streptoverticillium olivoreticuli. Des-O-methylolivoretin C is a regioisomer of teleocidin B, which has the same activity as teleocidin. The tumor-promoting activity of des-O-methylolivoretin C was studied in a two-stage carcinogenesis experiment on mouse skin in comparison with that of teleocidin.

Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis.

Thapsigargin, a hexaoxygenated tetraacylated sesquiterpene lactone, induced irritation of mouse ear and histidine decarboxylase (HDC) activity in mouse skin, but it did not induce ornithine decarboxylase in mouse skin or adhesion of human promyelocytic leukemia (HL-60) cells. Although thapsigargin did not give consistent positive results in a short-term screening system for tumor promoters, it was tested in a two-stage carcinogenesis experiment on mouse skin. The potency of thapsigargin to induce HDC in mouse skin was used to determine the dose in this experiment.

A blue-green alga from Okinawa contains aplysiatoxins, the third class of tumor promoters.

The causative agents of swimmer's itch were isolated from the marine blue-green alga, Lyngbya majuscula, which grows off the coast of the Okinawa islands, Japan. Nuclear magnetic resonance and mass spectral studies revealed that these agents were identical with aplysiatoxin and debromoaplysiatoxin, which were previously shown to be the causative agents of swimmer's itch in Hawaii. Aplysiatoxin and debromoaplysiatoxin were recently found to be potent tumor promoters in two-stage carcinogenesis in mouse skin.

Studies on olivoretins indicate a requirement for a free hydroxyl group for teleocidin B activity.

Three olivoretins, A, B and C (isolated from Streptoverticillium olivoreticuli), which are O-methylated teleocidin B isomers, were found to be biologically inactive. A fourth olivoretin, D, which has a free hydroxyl group and is identical to one of the four teleocidin B isomers, teleocidin B-4 (teleocidin B of Hirata) was biologically active. These findings indicate that the free primary hydroxyl group of teleocidin B isomers is necessary for activity.

A two-stage mouse skin carcinogenesis study of lyngbyatoxin A.

A strong skin irritant, lyngbyatoxin A, isolated from the marine blue-green alga Lyngbya majuscula is structurally related to teleocidin. Since lyngbyatoxin A satisfied our short-term screening tests for possible tumor promoters, viz. irritation of mouse ear, induction of ornithine decarboxylase (ODC) in mouse skin, and adhesion of human promyelocytic leukemia cells (HL-60), a two-stage carcinogenesis experiment was carried out.