Skin tumors can be effectively induced in mice by the repetitive application of a carcinogen. The relative order of sensitivity to complete carcinogenesis is Sencar > CD-1 > C57BL/6 2 BALB/c 2 ICR/Ha Swiss > C3H. Skin tumors in mice can also be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a weak or noncarcinogenic tumor promoter (promotion phase). The relative order of sensitivity to initiation-promotion is Sencar> > CD-1 > ICR/Ha Swiss L Balb/c > C57BL/6 r C 3 H rDBA/2. The initiation phase requires only a single application of a carcinogen and is essentially an irreversible step, which probably involves a somatic cell mutation as is evidenced by a good correlation between the carcinogenicity of many chemical carcinogens and their mutagenic activities; the promotion stage, however, is initially reversible, later becoming irreversible. For strains and stocks of mice which respond to initiation-promotion, there is a good correlation between the tumor-initiating activities of polycyclic aromatic hydrocarbons (PAH) and their abilities to bind covalently to DNA. Potent inhibitors and stimulators of PAH tumor initiation appear to effect the level of the PAH diol epoxide bound to specific DNA adducts. However, when the binding of a given PAH to DNA is compared in various stocks and strains of mice, there is no correlation, since in those mice which are able to metabolize PAH, the amounts of carcinogen bound to DNA are similar.The phorbol ester tumor promoters have been shown to have several cellular and biochemical effects on the skin. Of all the observed phorbol ester related effects on the skin, the induction of epidermal cell proliferation, polyamines, prostagladins, and dark basal keratinocytes as well as other embryonic conditions appear to correlate the best with promotion. Mezerein, a Abbreviations used: PAH, polycyclic aromatic hydrocarbon; BA, benz(a)anthracene; DB(a,c)A, dibenz(a,c)anthracene; BP-diolepoxide; benzo(a)pyrene 7,8-dihydrodiol-9,10-epoxide; BA-diolepoxide, BA-3,4-dihydrodiol-l,2-epoxide; DMBA, 7,12-dimethylbenz(a)anthracene; BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PCB, polychlorobiphenyls; Poly I:C, po1yinosinic:polycytidylic acid; TPA, 12-O-tetradecanoylphorbol-l3-acetate; ODC, ornithine decarboxylase; FA, fluocinolone acetonide; DMSO, dimethyl sulfoxide; BCG, Bacillus Calmette-Guerin; DFMO, ol-difluoromethylornithine; IBMX, isobutylmethylxanthine; olMO, a-methylornithine; ETYA, 5,8,11-14-eicosatetraynoic acid; EPP, ethylphenylpropiolate; TPCK, tosyl phenylalanine chloromethylketone; RA, retinoic acid.
1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.
Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.
The low-molecular-weight immunomodulator drug candidate, imiquimod (R-837), and its hydroxylated metabolite R-842, induce interferon-alpha (IFN-alpha) in human blood cells in vitro when tested in concentrations of 0.5 microgram/ml or more. The amounts of IFN-alpha found increased with time from 2-6 h of incubation up to 24-48 h, and were dependent on cell number and drug concentration. These two chemicals yielded more IFN-alpha in human peripheral blood mononuclear cell (PBMC) cultures than other known inducers tested in parallel. They also induced detectable amounts of interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha in human PBMC cultures in vitro.
The role ofornithine decarboxylase (OrnDCase, EC 4.1.1.17) and of the polyamines [putrescine (Put), spermidine (Spd), and spermine (Spm)] in mouse skin tumor promotion was investigated by the use ofa-difluoromethylornithine (CHF2-Orn), an enzyme-activated irreversible inhibitor of OrnDCase. 12-0-Tetradecanoylphorbol 13-acetate (TPA), mezerein, and ethyl phenylpropiolate (EPP) were employed as complete, stage II specific, and nonpromoting agents, respectively. TPA and mezerein, but not EPP, provided for a dose-dependent increase in tissue Put accumulation. The Put level in papillomas developed by TPA (2 ,ig) treatment was =15-fold higher than that of the surrounding skin tissue; Spd accumulation was 2-to 3-fold greater in the papillomas. Put administered (intraperitoneally) with TPA greatly enhanced papilloma yield. CHF2-Orn, given orally or intraperi- USA 77, 2251-2254] reduced tumor size, inhibited by 65-70% the number of papillomas per mouse, and decreased by 40% the percentage of mice with tumors when given with the stage II agent mezerein. CHF2-Orn provided considerably less effect on tumorigenesis when administered with the TPA portion of the protocol, and CHF2-Orn did not inhibit the induction of dark basal keratinocytes by TPA. Based on our results with CHF2-Orn, we suggest that regulation of polyamine biosynthesis, particularly Put, is a critical factor in stage El promotion.Carcinogenesis in mouse skin can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of a carcinogen and is essentially irreversible. The promotion phase is initially reversible but later becomes irreversible (1). Recent data from our laboratory suggest that the tumor promotion stage can be divided into two stages (2)(3)(4)(5)
The effects of fluocinolone acetonide (FA), retinoic acid (RA), and tosylphenylalanine chloromethyl ketone (TPCK) on two-stage promotion after 7,12-dimethylbenzfaJ anthracene (DMBA) initiation in female Sencar mice were investigated. The two-stage promotion protocol was achieved by twice weekly applications of 2 sg of 12Otetradecanoylphorbol 13-acetate (TPA) for 2 weeks (stage I) followed by twice Carcinogenesis in the skin can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct-acting carcinogen or a procarcinogen (which has to be metabolized before being active) and is essentially irreversible; the promotion phase is initially reversible but later becomes irreversible. This system not only has provided an important model for studying carcinogenesis and for bioassaying carcinogenic agents, but it is also one of the best systems for investigating the effects of inhibitors of chemical carcinogenesis (1). Recent data from our laboratory suggest that the tumor promotion stage can be divided into two stages (2, 3). The first stage can be effectively brought about by limited applications of 12-0-tetradecanoylphorbol 13-acetate (TPA), or, to a lesser degree, of 4-0-methyl-TPA. Mezerein, a diterpene similar to TPA in its biochemical and morphological effects but a weak promoter, is a-potent stage II promoter when given repetitively after stage I promotion (2-4). The combined treatment after tumor initiation will give a tumor response similar to single-stage or complete promotion by TPA (3, 4).We have recently reported (3) that the only major biochemical and morphological difference between the effects of TPA and mezerein on the skin is the ability of TPA to induce a large number of dark basal keratinocytes, which suggests that these dark cells are important in stage I of promotion. The importance of these dark basal keratinocytes in tumor promotion was originally reported by Raick and coworkers (5-8). They found that TPA induced the appearance of these cells in the epidermis whereas ethylphenylpropiolate did not (5-8).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 2251Inhibitors of tumor promotion have been useful in the identification of important events in tumor promotion. This has been especially true for anti-inflammatory steroids, retinoids, and protease inhibitors (1,(9)(10)(11)(12)(13)(14). These agents all are potent inhibitors of tumor promotion and chemical carcinogenesis in general (9-18). The purpose of this study was to determine the effects of some inhibitors of tumor promotion on the first and second stages of promotion and their effect on TPA-induced dark, basal keratinocytes. Tosylphenylalanyl chloromethyl ketone (TPCK) was found to inhibi...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.