Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the appearance of single strand breaks (SSB) in DNA of mouse keratinocytes exposed in vitro to various tumor promoters. Mouse basal keratinocytes were selectively cultured in low calcium medium, prelabeled with [14C]thymidine, exposed to test agents, and SSB quantified by alkaline elution. 12-O-Tetradecanoylphorbol-13-acetate (TPA) caused a dose-dependent (10(-9)-10(-7) M) increase in SSB after 24 h but not after shorter exposures. DNA containing TPA-induced SSB was found only in cells which had detached from the culture plate as a consequence of TPA-induced terminal differentiation. Attached cells, resistant to the differentiation-inducing effects of TPA, had the low level of SSB found in DNA from vehicle-treated control cells. Attached cells were resistant to the formation of SSB and to induced differentiation when reexposed to TPA. Other tumor-promoting phorbol esters, mezerein and retinyl phorbol acetate, also produced SSB in detached cells, whereas phorbol or resiniferatoxin caused neither SSB or cell detachment. Retinoic acid, which blocks the induction of differentiation by TPA, inhibited the production of SSB by TPA; however, fluocinolone acetonide, chymostatin, catalase, or superoxide dismutase blocked neither TPA-induced SSB nor terminal differentiation. Epidermal cell lines resistant to TPA-induced differentiation were also resistant to SSB production by TPA. Benzoyl peroxide (BP) (10(-4) M) induced SSB in basal keratinocytes within 1 h, and attached cells showed extensive SSB by 12 h. Retinoic acid had only a slight effect on BP-induced SSB, and 1 of 3 TPA-resistant cell lines developed SSB when exposed to BP. These results suggest that TPA-induced SSB in epidermal cells are an indirect consequence of the induction of terminal differentiation, whereas BP produces SSB by a more direct mechanism of DNA damage.
 ...
PMID:Association of DNA strand breaks with accelerated terminal differentiation in mouse epidermal cells exposed to tumor promoters. 402 73

A number of characteristics of phorbol ester-mediated mouse skin tumor promotion indicate that cell selection is the underlying biological process. Studies in vivo and in cultured mouse epidermal cells suggest that selection is based on heterogeneous responses of subpopulations of basal cells which can be induced to proliferate or differentiate in response to promoter exposure. Retinoids are effective inhibitors of tumor promotion in mouse skin but do not influence the proliferative response to phorbol esters. Since both retinoids and phorbol esters modify epidermal differentiation, the antipromoter action of retinoids could be related to differentiation responses. Retinoic acid induces transglutaminase activity in cultured mouse epidermal basal cells grown in less than 0.1 mM Ca2+. While this enzyme is associated with terminal differentiation in skin, retinoic acid paradoxically blocks the terminal differentiation of cultured cells. In contrast, phorbol esters and extracellular calcium greater than 0.1 mM induce both transglutaminase activity and terminal differentiation. Enzyme kinetic analyses indicate that the transglutaminases induced by all three inducers are the same enzyme. The increase in activity of transglutaminase by all three inducers requires RNA and protein synthesis. However, the time course of increase and decay of each activity differs for each inducer. A variety of biologically active retinoids induce transglutaminase activity, and their effectiveness correlates with their reported antipromoter activity. Exposures to both retinoic acid and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate are antagonistic resulting in less than additive induction. Induction kinetics with both inducers are more like those of retinoic acid than those of the phorbol ester. Simultaneous exposure to retinoic acid and 12-O-tetradecanoylphorbol-13-acetate protects the epidermal cell population from induced terminal differentiation and cell loss which is observed in response to the promoter alone. These results suggest that the antipromoting action of retinoids could be mediated by modification of phorbol ester-accelerated terminal differentiation through an effect on transglutaminase and cornification. This action of retinoids would block a critical aspect of cell selection involving loss of cells and subsequent regenerative hyperplasia, although simple hyperplasia may still occur.
 ...
PMID:Regulation of epidermal transglutaminase activity and terminal differentiation by retinoids and phorbol esters. 613 62

Retinoic acid (RA) suppressed the production of interferon (IFN) alpha and IFN gamma of human peripheral blood leukocytes in response to stimulation with lectin mitogens, bacterial products, synthetic polynucleotides, viruses, and tumor cell lines in vitro. Virus-induced secretion of IFN alpha of human lymphoblastoid cells was also inhibited. RA-mediated suppression was dose-dependent and required the near-concurrent addition of RA and inducers to human leukocyte cultures, thus suggesting that RA affects an early cellular function in the generation of IFN. Implications of these findings for the use of retinoids in the treatment of human malignancies are discussed.
 ...
PMID:Retinoic acid suppression of human leukocyte interferon production. 618 Oct 13

In order to investigate the role that hyperplasia plays in the induction of the keratin modifications by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the effects of several inhibitors of tumor promotion and cycloheximide on the TPA-induced protein changes were studied. The antiinflammatory steroid fluocinolone acetonide and cycloheximide, which prevent the induction of hyperplasia, were found to prevent the appearance of the TPA-induced keratin modifications. Retinoic acid and tosylphenylalanylchloromethyl ketone, which have minor influence on hyperplasia, were found to have essentially no effect on these protein changes. These results provided further evidence that the TPA-induced epidermal keratin changes were associated with the induction of hyperplasia by TPA and not necessarily related to promoting ability.
 ...
PMID:Effects of inhibitors of tumor promotion on 12-O-tetradecanoylphorbol-13-acetate-induced keratin modification in mouse epidermis. 618 46

A series of conformationally restricted retinoids was synthesized and screened in two assays used to measure the ability of retinoids to control cell differentiation, namely, the reversal of keratinization in tracheal organ culture from vitamin A deficient hamsters and the inhibition of the induction of mouse epidermal ornithine decarboxylase by a tumor promoter. These compounds had bonds corresponding to selected bonds of the E-tetraene chain of retinoic acid (1) held in a planar cisoid conformation by inclusion in an aromatic ring. The meta-substituted analogue 3 of 4-[(E)-2-methyl-4-(2,6,6-trimethylcyclohexenyl)-1,3-butadienyl+ ++]benzoic acid (2) was far less active than 2 in both assays. In contrast, the vinyl homologue of 2 (4) and the 7,8-dihydro and 7,8-methano analogues (5 and 6) had activity comparable to that of 2. Analogues of 4-[(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-naphthyl)propenyl] benzoic acid (7) were also screened. Replacement of the tetrahydronaphthalene ring of 7 by a benzonorbornenyl group (9) significantly reduced activity, as did removal of the vinylic methyl group from 9 (10). Replacement of the propenyl group of 9 by a cyclopropane ring (12) also reduced activity. Replacement of the tetrahydronaphthalene ring of 7 by 4,4-dimethyl-3,4-dihydro-2H-1-benzopyran and -benzothiopyran rings (13 and 14) also decreased activity. Inclusion of the 7,9 double bond system of 1 in an aromatic ring (15 and 16) reduced activity, whereas inclusion of the 5,7 double bond system in an aromatic ring enhanced activity (7 and 19). Inclusion of the 11,13 and 9,11,13 double bond systems in aromatic rings (2 and 18) also reduced activity below that of 1. Retinoic acid, 7, 13, 14, and 19 inhibited papilloma tumor formation in mice. Toxicity testing indicated that 7 was more toxic than 1, 13, 14, and 19, 19 was more toxic than 1, and 13 and 14 were less toxic than 1.
 ...
PMID:Conformationally restricted retinoids. 620 61

The tumor promotor, 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits DNA synthesis in allogenic, mixed cultures of bovine lymphocytes. Retinoic acid, an antagonist of TPA in in vivo skin promotion, was tested for its ability to counteract the effect of TPA on lymphocyte proliferation. Retinoic acid or related compounds, retinol or retinol acetate, did not reverse or prevent the inhibitory effect of TPA. Instead retinoic acid also inhibited DNA synthesis in mixed lymphocyte cultures. On the average, about 8 microM retinoic acid inhibited the mixed lymphocyte response by 50%. The mitogenic response of lymphocytes to phytohemagglutinin (PHA) was also inhibited by retinoic acid. The degree of inhibition depended both on the concentration of PHA and of retinoic acid. Therefore, in regard to bovine lymphocytes, retinoic acid depresses DNA synthesis in both allogenic and lectin stimulated responses. Such suppression should be taken into account in the use of retinoic acid in chemotherapy.
 ...
PMID:The effects of retinoic acid and a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, on lymphocyte proliferation. 621 57

Retinoic acid was found to be a potent stimulant of pigmentation in human Hs939 melanoma cells. Exposure to 1 microM retinoic acid for longer than four days caused both a decrease in the rate of cell proliferation and a concomitant increase in melanogenesis. These effects of retinoic acid progressed lin-early in a time-dependent and a dose-dependent fashion such that at the end of a seven-day treatment cell growth was inhibited by approximately 65%, and both melanin content and tyrosinase activity increased more than three-fold over the control. Interpolation of the dose-response curves indicated that 3 nM retinoic acid would cause half-maximal melanogenesis stimulation. No elevation in the level of cyclic adenosine 3':5'-monophosphate could be detected in the melanoma cells following various periods of exposure to retinoic acid, and the cells were unresponsive to alpha-melanocyte-stimulating hormone. In the presence of the tyrosinase inhibitor phenylthiocarbamate, retinoic acid was capable of inhibiting cell proliferation without enhancing melanin synthesis. The tumor promoter phorbol myristate acetate did not affect either the proliferation or the differentiation of the Hs939 melanoma cells. However, the enhancement of melanogenesis by 1 microM retinoic acid was inhibited by 66% in the presence of 0.1 microM phorbol myristate acetate. The tumor promoter did not reverse the growth-inhibitory effect of retinoic acid. Phorbol, a non-tumor promoter, was effective. Other retinoids, such as 13-cis-retinoic acid, retinyl acetate, nd the trimethylmethoxyphenyl analog of retinoic acid, also inhibited the proliferation and enhanced melanin production in the Hs939 cells. In contrast, retinyl palmitate, the phenyl analog of retinoic acid, and the pyridyl analog of retinoic acid were ineffective.
 ...
PMID:Stimulation of melanogenesis in a human melanoma cell line by retinoids. 625 61

Retinoic acid (RA), which reduces the rate of cell proliferation in S91 mouse melanoma clone C2 cells, was found to stimulate the expression of their melanotic phenotype. RA treatment also induced the extension of long cellular processes. The RA effects on melanogenesis included stimulation of tyrosinase activity and augmentation of cellular melanin content to levels 3- to 4-fold higher than in untreated cultures at similar cell densities. These effects became apparent after 48 hours of exposure to 10(-5) M RA and increased thereafter. Half-maximal stimulation in cells treated for 6 days occurred at 5 X 10(-7) M RA. Although the degrees of melanogenesis enhancement by RA (10(-5) M) and by alpha-melanocyte stimulatory hormone (2 X 10(-7) M) were similar, the former did not alter the intracellular cAMP level, whereas the latter induced a transient 4-fold increase. In high-passage (p28) cells, as well as in low-passage cells (less than p10) treated with tyrosinase inhibitor phenylthiocarbamate, melanin synthesis was suppressed in the absence and presence of RA, yet the ability of RA to inhibit cell proliferation was not compromised. In the presence of the tumor promotor phorbol myristate acetate (greater than 5 X 10(-9) M) melanin synthesis in control as well as in cells exposed to RA was dramatically inhibited. Phorbol which is not active in tumor promotion had no effect on melanogenesis. In addition to RA, other retinoids, such as 13-cis-retinoic acid, retinyl acetate, the TMMP analog of RA and the phenyl analog of RA, but not the pyridyl analog of RA or retinyl palmitate, also inhibited cell growth and enhanced melanin synthesis.
 ...
PMID:Enhancement of melanotic expression in cultured mouse melanoma cells by retinoids. 626 Aug 17

In this study the effects of retinoic acid on the binding and mitogenic activity of epidermal growth factor (EGF) in mouse fibroblast Balb/c 3T6 cells are further examined. Retinoic acid treatment of 3T6 cells results in a sixfold enhancement of 125I-labeled mouse EGF binding when assayed at 37 degrees C. In both retinoic acid-treated and control cells, cell-associated 125I-EGF is rapidly internalized, degraded, and secreted. Retinoic acid treatment does not seem to have a significant effect on the rate of internalization and degradation of EGF. At 0 degrees C, internalization of EGF is strongly inhibited in both retinoic acid-treated and control cells. Under these conditions retinoic acid-treated cells still exhibit a tenfold higher level of EGF binding compared to control cells. When exposed to high concentrations of EGF both retinoic acid-treated and control cells "down-regulate" their EGF receptors. And although the growth rate of retinoic acid-treated cells is about half that of control cells, the rate at which EGF binding capacity is restored after down-regulation is about three times as fast as in control cells. No direct antagonism on EGF binding was observed between the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and retinoic acid. EGF is a potent mitogen for 3T6 cells in serum-free medium; retinoic acid inhibits the mitogenic activity of EGF even though it increases EGF binding. Retinoic acid also inhibits cell proliferation induced by sarcoma growth factor (SGF) and insulin.
 ...
PMID:Effects of retinoic acid on the binding and mitogenic activity of epidermal growth factor. 628 98

Retinoic acid, a potent inhibitor of mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate, fails to inhibit tumor formation by the complete carcinogen, 7, 12-dimethylbenz[a]anthracene (DMBA). To obtain further clues about the nature of the mechanism of the carcinogenic process as well as the mechanism of the effect of retinoic acid on tumor promotion, the effect of retinoic acid and two other modifiers (dexamethasone and 7,8-benzoflavone) of tumor formation on tumor promotion by 7-bromomethylbenz[a]anthracene (BrMBA) was determined. BrMBA, a structural analogue of DMBA, is a weak mouse skin tumor-initiating agent but is a good skin tumor promoter. Application of 10, 100, and 200 nmol of BrMBA twice weekly to DMBA-initiated skin resulted in 0, 1.6, and 2.5 papillomas per mouse, and 0, 44, and 60% of mice had papillomas at the 25th week of promotion treatment, respectively. Application of 17 nmol of retinoic acid or 76 nmol of dexamethasone 30 min prior to each twice weekly application of 100 nmol of BrMBA to DMBA-initiated skin inhibited the formation of skin papillomas by 73 and 100%, respectively. 7,8-Benzoflavone, at a 367-nmol dose, did not inhibit tumor promotion by BrMBA. Application of 200 nmol of BrMBA to mouse skin induced epidermal ornithine decarboxylase activity; a peak activity was observed between 8 and 18 hr following BrMBA treatment. Application of 17 nmol of retinoic acid or 76 nmol of dexamethasone inhibited the induction of ornithine decarboxylase activity by BrMBA. 7,8-Benzoflavone did not inhibit the induction of ornithine decarboxylase activity by BrMBA. Retinoic acid and dexamethasone, which inhibit tumor promotion by 12-O-tetradecanoylphorbol-13-acetate, also inhibited tumor promotion by BrMBA, but the nature of the mechanism of tumor promotion by BrMBA is unclear; BrMBA did not inhibit specific binding of 12-O-[3H]tetradecanoylphorbol-13-acetate to the cellular membrane fraction of mouse epidermis.
 ...
PMID:Inhibition of 7-bromomethylbenz[a]anthracene-promoted mouse skin tumor formation by retinoic acid and dexamethasone. 640 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>