Induction of short-term markers of tumor promotion by organic peroxides

Gimenez-Conti, Irma; Viaje, Aurora; Chesner, J.; Conti, C; Slaga, Thomas J.

doi:10.1093/carcin/12.4.563

Cited by 21 publications

(14 citation statements)

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“…In this regard, it may be speculated that the affected allelic form either carried a recessive germ-line mutation or sustained a somatic alteration selectively due to differences in allelic mutability (32). Consistent with our findings is the fact that SSIN, an inbred mouse strain derived from SENCAR and characterized for its high incidence of papilloma formation but very low frequency of malignant conversion to carcinoma (33), exhibits the HbbS genotype, suggesting again a possible linkage between the latter allelic form and the wild-type allele of a putative suppressor gene hypothetically involved in the acquisition of the malignant phenotype. Although the small number of informative cases analyzed for the int-2 locus prevents us from assessing a similar association, tumorbearing SENCAR mice were found to be predominantly homozygous for the int-2 A2 allele as opposed to the int-2 Al genotype characteristic of SS1N, providing circumstantial evidence for a possible linkage between int-2 A2 and the presumably inactive allele of a suppressor locus.…”

Section: Resultssupporting

confidence: 88%

Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis.

Bianchi

Navone

Aldaz

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiationpromotion protocol, we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci.In a previous study, these tumors had been analyzed for their allelic composition at the Harvey ras-) (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study, by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses, we detected complete loss ofheterozygosity at the f-globin (Hbb) locus, distal to Ha-ras-i, in 15 of 20 (75%) skin carcinomas. In addition, 5 of 5 informative cases attained homozygosity at the int-2 locus, 27 centimorgans distal to Hb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus, demonstrating that this event occurs during premalignant stages of tumor development. Interestingly, loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric s of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-I indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative tumor suppressor gene linked to the Hbb locus in the 7FM-ter region of mouse chromosome 7, the functional inactivation of which may constitute a critical event in skin tumor progression, possibly during the malignant conversion stage.Chromosomal deletions, nondisjunction, and mitotic recombination are among the mechanisms that may account for loss of heterozygosity (LOH), resulting in the unmasking of recessive mutations (1, 2). In this regard, the tumor-specific LOH at particular chromosomal loci has signaled the presence of putative suppressor genes in various human neoplasias (3, 4) and, in some instances, led to the cloning and identification of genes that were shown to be involved at defined stages of the tumorigenesis process (5). One region that has been shown to be affected by allelic losses in several human malignancies (3) is the short arm of chromosome 11 (lip), which shares a large syntenic group with mouse chromosome 7 that includes, among others, the Harvey ras-) (Ha-ras-1) and the f3-globin (Hbb) genes (6). At least two putative suppressor lo...

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Section: Resultssupporting

confidence: 88%

Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis.

Bianchi

Navone

Aldaz

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…If BzPO also acts to promote tumors through activation of PKC, it is reasonable to assume that BzPO would also induce a variety of short-term responses characteristic of compounds that activate PKC. This hypothesis has been dis cussed and examined in a number of studies using mouse skin [5], human bronchial epi thelial cells [16], and human epidermal kérati nocytes [6]. Typical parameters studied have been mitogenic activity, ornithine decarbox ylase activity, induction of differentiation, and intracellular metabolic cooperation.…”

Section: Discussionmentioning

confidence: 99%

“…For example, both TPA and BzPO cause inflammation and epidermal hy perplasia when applied to the backs of mice [1], BzPO has also been shown to be active to varying degrees in inducing other short-term markers which are characteristic of known tumor-promoting compounds, such as hyperkeratinization, induction of ornithine decar boxylase activity, and the induction of dark basal kératinocytes [5]. BzPO has also been shown to inhibit intracellular metabolic coop eration in cultured human epidermal kérati nocytes [6], The potential tumor-promoting properties of BzPO are of interest with particular regard to nonmelanoma skin cancers, and we there fore wished to examine the effects of BzPO in normal human epidermal kératinocytes (NHEK).…”

Section: Introductionmentioning

confidence: 99%

Effect of Benzoyl Peroxide on Protein Kinase C in Cultured Human Epidermal Keratinocytes

Matsui¹,

Mintz²,

DeLeo³

1995

Skin Pharmacol Physiol

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Benzoyl peroxide (BzPO) has been the most widely used topical agent for acne since the 1960s. This is true despite numerous reports that BzPO can enhance the development of carcinomas from murine epidermal papillo-mas. Because activation of protein kinase C (PKC) is considered to mediate cellular responses to other epidermal tumor promotors, we wished to investigate the relationship between BzPO and PKC in cultured human epidermal keratinocytes (NHEK). We assayed (a) direct effects of BzPO on PKC activity in a cell-free system using semipurified human keratinocyte PKC, (b) BzPO effects on the subcellular distribution of PKC, and (c) BzPO modulation of NHEK proliferation and phorbol ester-induced differentiation. NHEK maintained in serum-free media (0.15 mMCa²⁺) were treated with concentrations of BzPO in acetone from 100 nM to 500 µM, with concentrations of acetone not exceeding 0.1%. No short-term translocation of PKC from cytosol to membrane was observed at any BzPO concentration. BzPO did not downregulate subcellular levels of PKC activity after 24 h of exposure. BzPO did not significantly antagonize phorbol ester-induced inhibition of proliferation or differentiation but did weakly antagonize Ca²⁺-induced differentiation. Consistent with a PKC-mediated mechanism for Ca²⁺-induced differentiation, BzPO inhibited both human and murine PKC in a cell-free system. These results suggest that BzPO does not promote malignant conversion through a PKC-dependent mechanism, and in fact, inhibits PKC activity in vitro.

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“…EVA cross-linking agents such as dicumyl peroxide, are possible respiratory toxicants and carcinogens [8,9]. The coupling agent gamma-methacryloxy-propyltrimethoxysilane is produced from a highly flammable silane, and is a dermal and respiratory irritant when in liquid form [10].…”

Section: Module Encapsulationmentioning

confidence: 99%

“…Specifically, from cradle to grave (or cradle again), this system is defined by (1) Solar grade feedstock, (2) used to make a single crystalline cell (3) using the float zone process, (4) phosphorous diffusion by rapid thermal processing, (5) an unframed and functionally integrated module, (6) without heat recovery, (7) installed in new construction to (8) an optimally inclined building surface as a (9) fixed array; the array is (10) grid-connected with (11) no energy storage and (12) recycled after functional life.…”

Section: Description Of the Best-case Systemmentioning

confidence: 99%