Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate.

Application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin results in a large and rapid induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17) activity, a phenotypic change proposed to be essential for skin tumor promotion. Induction of ODC activity by TPA was inhibited by prior treatment of skin with inhibitors of prostaglandin synthesis in the order, indomethacin > naproxen > flufenamic acid > acetylsalicylic acid. In contrast, dexamethasone, a steroidal anti-inflammatory drug, was ineffective at a 280-nmol dose. The inhibitory effect of indomethacin on ODC induction was found to be specific. The 280-nmol dose of indomethacin that inhibited the induction of ODC activity by 80% did not inhibit the induction by TPA of S -adenosylmethionine decarboxylase and cyclic adenosine 3′:5′-monophosphate phosphodiesterase (EC 3.1.4.17) activities. Furthermore, indomethacin treatment affected neither normal epidermal protein nor DNA synthesis. The inhibition by the prostaglandin synthesis inhibitors of the induction of ODC activity by TPA was completely overcome by concurrent application of about 25 to 100 nmol of prostaglandins E1, E2, D2, or the 6,9-thio analog of prostaglandin I2 with TPA. In contrast, prostaglandins F1α and F2α, 6-keto-prostaglandin F1α, or arachidonic acid at doses of as much as 100 nmol were ineffective. Application of 17 nmol of TPA led to about a 3-fold increase in epidermal levels of prostaglandins E and F, and that increase was blocked by pretreatment with 280 nmol of indomethacin. Application of 280 nmol of indomethacin before each TPA treatment significantly inhibited the formation of skin papillomas. Prostaglandin E2 alone could neither induce epidermal ODC activity nor promote skin tumors in an initiation/promotion experiment. However, potentiation of TPA-induced ODC activity by prostaglandin E2 was observed. The findings that the application of indomethacin prior to TPA treatment inhibits the accumulation of prostaglandins, the induction of ODC activity, and the formation of skin papillomas suggest that ( a ) prostaglandins E1, E2, D2, and I2 may play a role in the induction of ODC activity by TPA and that ( b ) TPA-induced ODC activity may be an important component of the mechanism of skin tumor promotion.

[1]  C. Ashendel,et al.  Prostaglandin E and F levels in mouse epidermis are increased by tumor-promoting phorbol esters. , 1979, Biochemical and biophysical research communications.

[2]  F. Marks,et al.  The effect of indomethacin on cell proliferation induced by chemical and mechanical means in mouse epidermis in vivo. , 1979, Research communications in chemical pathology and pharmacology.

[3]  R. A. Mufson,et al.  Increased cyclic adenosine 3':5'-monophosphate phosphodiesterase activity in the epidermis of phorbol ester-treated mouse skin and in papillomas. , 1979, Cancer research.

[4]  A. Verma,et al.  Induction of mouse epidermal ornithine decarboxylase activity and DNA synthesis by ultraviolet light. , 1979, Cancer research.

[5]  A. Verma,et al.  Correlation of the inhibition by retinoids of tumor promoter-induced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion. , 1979, Cancer research.

[6]  M. Caton,et al.  Prostaglandins and thromboxanes. , 1979, Progress in medicinal chemistry.

[7]  F. Marks,et al.  Indomethacin inhibition of cell proliferation induced by the phorbolester TPA is reversed by prostaglandin E2 in mouse epidermis in vivo. , 1978, Biochemical and biophysical research communications.

[8]  J. Hammond,et al.  Prostaglandin stimulation of ovarian ornithine decarboxylase in vitro. , 1978, Biochemical and biophysical research communications.

[9]  A. Lupulescu.  Enhancement of carcinogenesis by prostaglandins in male albino Swiss mice. , 1978, Journal of the National Cancer Institute.

[10]  E. Hecker,et al.  Inflammatory, tumor initiating and promoting activities of polycyclic aromatic hydrocarbons and diterpene esters in mouse skin as compared with their prostaglandin releasing potency in vitro. , 1978, Cancer letters.

[11]  A. Verma,et al.  Prostaglandins and skin tumor promotion: inhibition of tumor promoter-induced ornithine decarboxylase activity in epidermis by inhibitors of prostaglandin synthesis. , 1977, Biochemical and biophysical research communications.

[12]  F. Sun,et al.  Metabolism of prostaglandin endoperoxide in animal tissues. , 1977, Prostaglandins.

[13]  A. Hassid,et al.  Effects of phorbol-12,13-diesters on prostaglandin production and phospholipase activity in canine kidney (MDCK) cells. , 1977, Biochemical and biophysical research communications.

[14]  L. Levine.  Chemical carcinogens stimulate canine kidney (MDCK) cells to produce prostaglandins , 1977, Nature.

[15]  A. Verma,et al.  Vitamin A acid (retinoic acid), a potent inhibitor of 12-O-tetradecanoyl-phorbol-13-acetate-induced ornithine decarboxylase activity in mouse epidermis. , 1977, Cancer research.

[16]  M. Wigler,et al.  Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator. , 1977, Cancer research.

[17]  C. Pace-Asciak.  Oxidative biotransformations of arachidonic acid. , 1977, Prostaglandins.

[18]  J. Walsh,et al.  Prostaglandin biosynthesis in the epidermis and dermis of young mouse skin, and the effects of calcium and cyclic nucleotides. , 1977, The Journal of investigative dermatology.

[19]  R. Boutwell,et al.  Dissociation of increases in levels of 3':5'-cyclic AMP and 3':5'-cyclic GMP from induction of ornithine decarboxylase by the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate in mouse epidermis in vivo. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[20]  L. Levine,et al.  Elevated prostaglandins synthetase activity in methylcholanthrene-transformed mouse BALB/3T3. , 1977, Prostaglandins.

[21]  B. Samuelsson.  Prostaglandins and Thromboxanes , 1977, NATO Advanced Study Institutes Series.

[22]  C. Byus,et al.  Proposed model of major sequential biochemical events of a trophic response. , 1976, Life sciences.

[23]  R. Boutwell,et al.  The effect of colchicine on the induction of ornithine decarboxylase by 12-O-tetradecanoyl-phorbol-13-acetate. , 1976, Cancer research.

[24]  M. Greaves,et al.  Factors affecting prostaglandin synthesis by rat skin microsomes. , 1976, Prostaglandins.

[25]  T G O'Brien,et al.  The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis. , 1976, Cancer research.

[26]  R. Polsky-Cynkin,et al.  Stimulation of prostaglandin biosynthesis by vasoactive substances in methylcholanthrene-transformed mouse BALB/3T3. , 1976, The Journal of biological chemistry.

[27]  J. Heller,et al.  Studies on the regulation of ornithine decarboxylase activity by the microtubules: the effect of colchicine and vinblastine. , 1976, Biochemical and biophysical research communications.

[28]  M. Froscio,et al.  Croton oil- and benzo(a)pyrene-induced changes in cyclic adenosine 3':5'-monophosphate and cyclic guanosine 3':5'-monophosphate phosphodiesterase activities in mouse epidermis. , 1976, Cancer research.

[29]  M. Hamberg,et al.  Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Boutwell,et al.  Induction of the polyamine-biosynthetic enzymes in mouse epidermis and their specificity for tumor promotion. , 1975, Cancer research.

[31]  B. Jaffe,et al.  Prostaglandins and cancer: an update. , 1974, Prostaglandins.

[32]  R. Flower.  Drugs which inhibit prostaglandin biosynthesis. , 1974, Pharmacological reviews.

[33]  R. Boutwell,et al.  The early stimulation of phospholipid metabolism by 12-0-tetradecanoyl-phorbol-13-acetate and its specificity for tumor promotion. , 1973, Cancer research.

[34]  V. Ziboh.  Biosynthesis of prostaglandin E 2 in human skin: subcellular localization and inhibition by unsaturated fatty acids and anti-inflammatory drugs. , 1973, Journal of lipid research.

[35]  H. Behrman,et al.  Ovulation blockade by aspirin or indomethacin--in vivo evidence for a role of prostaglandin in gonadotrophin secretion. , 1972, Prostaglandins.

[36]  J. Vane,et al.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. , 1971, Nature: New biology.

[37]  J. Voorhees,et al.  A method for bioassay of an epidermal chalone-like inhibitor. , 1971, The Journal of investigative dermatology.

[38]  M. Caton.  The prostaglandins. , 1971, Progress in medicinal chemistry.

[39]  T. Kotchen.  Prostaglandins. , 1968, JAMA.

[40]  K. Burton.  A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. , 1956, The Biochemical journal.

[41]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.