The Tumor-Enhancing and Irritant Principles from Croton tiglium L.

Bl, Vanduuren; Arroyo, E.; Orris, Leo

doi:10.1021/jm00341a041

Cited by 27 publications

(18 citation statements)

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“…1) (Hecker et al 1964;Hecker 1967 and1968) or phorbol myristate acetate (PMA, Fig. 1) (van Duuren and Orris 1965;van Duuren 1979) on mouse skin con®rmed the signi®cant stage of tumor promotion in chemical carcinogenesis (Berenblum and Shubik 1947), and revealed that croton oil contains various active principles of the phorbol ester structural type that act as tumor promoters. The study on TPA revealed that it binds to and activates protein kinase C (PKC), as the teleocidin and aplysiatoxin classes (Fujiki and Sugimura 1987) do, and acts on the signal transduction pathway (Nishizuka 1984;Fujiki et al 1984b;Hecker 1985;Kazanictz et al 1995;Krauter et al 1996): this results in clonal growth of initiated cells containing the mutation of CAA to CTA in codon 61 of mouse c-H-ras gene, induced by a single topical application of 7,12-dimethylbenz(a)anthracene (DMBA) (Balmain and Pragnell 1983;Kloz et al 1989;K.…”

Section: Introductionmentioning

confidence: 99%

Unique features of the okadaic acid activity class of tumor promoters

Fujiki¹,

Suganuma²

1999

Journal of Cancer Research and Clinical Oncology

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Following the first report of tumor promotion by okadaic acid in 1988, we further identified additional tumor promoters of the okadaic acid activity class, such as calyculin A and microcystin-LR. However, tautomycin, which is also an inhibitor of protein phosphatases-1 and -2A (PP-1 and PP-2A), as are okadaic acid, calyculin A and microcystin-LR, is not a tumor promoter on mouse skin or in rat glandular stomach. This paper presents unique features of the okadaic acid activity class of tumor promoters with regards to three significant findings: 1) the okadaic acid pathway, mediated through inhibition of PP-1 and PP-2A, is a general tumor promotion pathway in various organs; 2) simultaneous treatment of okadaic acid with teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA) activity type of tumor promoters, did not show any synergistic effects on tumor promotion; and 3) two different types of tumor promoters, okadaic acid and TPA, commonly induced tumor necrosis factor-alpha (TNF-alpha) gene expression on mouse skin. The results also strongly suggest that TNF-alpha, now known to be an endogenous tumor promoter and a mediator of cancer development, plays an important role in tumor promotion and progression in humans. In the light of this, we discuss a practical method of screening for chemical tumor promoters based on their induction of TNF-alpha release from HL-60 cells.

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Section: Introductionmentioning

confidence: 99%

Unique features of the okadaic acid activity class of tumor promoters

Fujiki¹,

Suganuma²

1999

Journal of Cancer Research and Clinical Oncology

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“…In the chemical and biological work that resulted in the isolation and structure elucidation of the phorbol esters from croton oil, random-bred ICR/Ha mice were used (10). These mice were also used in our subsequent work on the promoter phorbol myristate acetate [PMA, also referred to as (12-O-tetradecanoylphorbol-13-acetate TPA)], including dose-response studies, the effect of aging in two-stage carcinogenesis studies, and other studies (4).…”

Section: Introductionmentioning

confidence: 99%

Phorbol myristate acetate and catechol as skin cocarcinogens in SENCAR mice.

Duuren¹,

Melchionne²,

Seidman³

1986

Environ Health Perspect

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The enhancement of the carcinogenicity of benzo(a)pyrene (B[a]P) and 3-propiolactone (BPL) by the mouse skin cocarcinogens phorbol myristate acetate (PMA) and catechol were examined in female SEN-CAR mice, 30 per group. The carcinogen and cocarcinogen were applied simultaneously, three times weekly for 490-560 days. B(a)P and BPL were used at constant doses of5 and 50 jig, respectively, in all experiments.PMA was used at three doses, 2.5, 1.0, and 0.5 p.g per application, and catechol was used at one dose, 2 mg per application. Control groups included animals that received carcinogen only, cocarcinogen only, acetone only, and no treatment. The carcinogenicity of B(a)P and BPL were enhanced by the cocarcinogens, particularly in terms of tumor multiplicity. For both carcinogens, the most marked cocarcinogenic effects were observed at the lowest dose of PMA used (0.5 ,ug per application). This observation applied for days to first tumor, animals with tumors, tumor multiplicity, and incidence of malignant skin tumors. Catechol applied alone did not induce any tumors; with PMA alone there were significant incidences of benign and malignant tumors, e.g., at a dose of only 0.5 ,ug per application, 15 of 30 animals had 28 tumors, 5 of which were squamous carcinomas. In two-stage carcinogenesis experiments with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and PMA as promoter, SENCAR mice showed a greater susceptibility to tumor induction when compared to ICR/Ha mice used in earlier work. This susceptibility was most notable in terms of rate of tumor appearance and tumor multiplicity. The two-stage model for chemical carcinogenesis was first described in the classic work of Berenblum (1,2), who used mouse skin as the route of exposure. At the same time, Berenblum showed that remarkable enhancement of the carcinogenic activity of benzo(a)-pyrene [B(a)P] occurs when croton oil or its concentrate, croton resin, and B(a)P are applied simultaneously and repeatedly to mouse skin. The latter type of experimental protocol was referred to by Berenblum as cocarcinogenesis (1). Since that time, the mouse skin test system has been used in many laboratories for studies on two-stage carcinogenesis and, to a lesser extent, cocarcinogenesis, and these endeavors have been reviewed (3,4). The two protocols as used by Berenblum are summarized in Table 1 opment of sensitive mice was first accomplished in the pioneering work of Boutwell (5), who explored the development of skin tumor-susceptible (STS) mice by careful inbreeding experiments using two-stage carcinogenesis for selection of STS mice. The necessary requirements of inbreeding and the small sizes of colonies used for the development of STS mice resulted in the decline of reproductive performance in these mice. This poor breeding performance was alleviated by crossbreeding male STS mice with female Charles River CD-1 mice. The details and history of the susceptible mice thus developed were recently described (6). These mice, originally maintained at the Oak Ridge National Labor...

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“…Stimulation of epithelial cell proliferation (54,107,144,154) and changes in immunological status (102,103,114) have been implicated in the promotion process and have in turn been questioned (134,136,145,183). A large number of chemicals promote skin tumorigenesis, notably croton oil (7,8) and its purified, active constituents, certain phorbol esters (75,179). The importance of the cellular environment for the carcinogenic response is illustrated by experiments in which subcutaneous implantation of chemically inert plastic films causes the formation of cutaneous tumors (16).…”

Section: Later Stages Of Promotionmentioning

confidence: 99%