ABSTRACT

Dinophysistoxin‐1, 35‐methylokadaic acid, is a causative agent of diarrhetic shellfish poisoning. The biological activities and tumor‐promoting activity of dinophysistoxin‐1 were studied together with those of okadaic acid and 7‐O‐palmitoyl okadaic acid. Dinophysistoxin‐1 is a skin irritant and induces ornithine decarboxylase in mouse skin with the same potency as okadaic acid. 7‐O‐Palmitoyl okadaic acid induced a lower activity than the other compounds. Dinophysistoxin‐1 inhibited the specific [3H]okadaic acid binding to a participate fraction of mouse epidermis. The binding affinities of dinophysistoxin‐1 and okadaic acid to a particulate fraction were almost the same. Dinophysistoxin‐1 showed a tumor‐promoting activity as strong as that of okadaic acid in a two‐stage carcinogenesis experiment on mouse skin. The percentages of tumor‐bearing mice in the groups treated with 100 μg of 7,12‐dimethylbenz[α]anthracene (DMBA) followed by 5 μg of dinophysistoxin‐1, twice a week, and with DMBA followed by 5 μg of okadaic acid twice a week were 86.7% and 80.0% in week 30, respectively. The average number of tumors per mouse was 4.6 in the former group and 3.9 in the latter. Dinophysistoxin‐1 and okadaic acid act on cells through different pathways from the 12‐O‐tetradecanoylphorbol‐13‐acetate‐type tumor promoters.

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The tumor promoter okadaic acid binds specifically to a particulate as well as a cytosolic fraction of various mouse tissues, e.g., skin, brain, lung and colon. The Ko value was 21.7 nM for receptors in the particulate fraction and 1 .O nM for those in the cytosolic fraction of mouse skin. The specific binding of PH]okadaic acid to the particulate fraction of mouse skin was inhibited dosedependently by okadaic acid, but not okaidaic acid tetramethyl ether, an inactive compound, or by other tumor promoters, such as 12-0-tetradecanoylphorbol-13-acetate and teleocidin. The results suggest a new pathway of tumor promotion mediated through the okadaic acid receptor(s).

Sarcophytols A and B, isolated from a soft coral, Sarcophyton glaucum, are cembrane-type diterpenes with different numbers of hydroxyl groups. Sarcophytols A and B inhibited tumor promotion by teleocidin in two-stage carcinogenesis experiments on mouse skin. The inhibitory effect of sarcophytol A was demonstrated with two different initiating doses of 7,12-dimethylbenz[a]anthracene (DMBA): 50 micrograms (experiment 1) and 100 micrograms (experiment 2). In experiment 1, three groups of mice were treated with DMBA, and then twice a week with doses (1.6 micrograms, 16 micrograms, and 82 micrograms) of sarcophytol A followed by 2.5 micrograms teleocidin. In week 25, the incidences of tumors in these groups were only 7.1%, 20.0%, and 13.3%, respectively, whereas that in the control group treated with DMBA plus teleocidin was 53.3%. Moreover, at this time, the average numbers of tumors per mouse in these groups were 0.1, 0.3, and 0.3, respectively, while that in the control group was 2.1. In experiment 2 an amount of sarcophytol A (1.6 micrograms) or B (1.7 micrograms) equimolar to 2.5 micrograms teleocidin was applied twice a week, as in experiment 1, and results showed that sarcophytol B also inhibited tumor promotion by teleocidin. Both sarcophytols A and B caused delay in onset of tumor formation, and reduced the percentage of tumor-bearing mice and the average number of tumors per mouse. The effective concentrations of sarcophytols A and B were in the microgram range with an equimolar amount of teleocidin.

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Tumor promoters induce tumor formation from initiated cells. We have found new tumor promoters that are structurally different from 12-O-tetradecanoylphorbol-13-acetate (TPA).These new tumor promoters include lyngbyatoxin A debromoaplysiatoxin, aplysiatoxin, bromoaplysiatoxin, oscillatoxin A and anhydrodebromoaplysiatoxin isolated from marine blue-green algae, and dibromoaplysiatoxin synthesized chemically; palytoxin isolated from a marine coelenterate; and okadaic acid isolated from a black sponge. These new tumor promoters are classified as TPA-type and non-TPA type tumor promoters on the basis of their abilities to bind to the phorbol ester receptor.Lyngbyatoxin A and aplysiatoxins belong to the TPA-type, and palytoxin and okadaic acid are non-TPA type tumor promoters.TPA-type tumor promoters activate protein kinase C, which serves as the phorbol ester receptor, while non-TPA type tumor promoters do not activate protein kinase C in vitro.Therefore, these two types of tumor promoters provide direct evidence for divergent mechanisms of action in two-stage carcinogenesis experiments on mouse skin.The process of chemical carcinogenesis consists of two stages, initiation and promotion (i). Initiation is caused by a single application of a small amount of a carcinogen, which induces irreversible genetic damage to DNA Application of the carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA), for example, to the skin of the back of a mouse was reported to induce mutation of an oncogene, so-called activation of the ras gene (2). Agents that then promote carcinogenesis from initiated cells are called tumor promoters (5). Treatment with DMBA followed by repeated applications of a tumor promoter, results in a high percentage of tumor-bearing mice, whereas treatment with an initiator alone or tumor promoter alone does not produce any tumors in mouse skin. TPA or phorbol-myristate-acetate (PMA) is

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