Incidence Of Skin Tumors Research Articles

Acrylamide Carcinogenicity

The induction of cancer by chemicals is a multiple-stage process. Acrylamide is carcinogenic to experimental mice and rats, causing tumors at multiple organ sites in both species when given in drinking water or by other means. In mice, acrylamide increased the incidence and multiplicity of lung tumors and skin tumors. In two bioassays in rats, acrylamide administered in drinking water consistently induced mesotheliomas of the testes, thyroid tumors, and mammary gland tumors. In addition, brain tumors appeared to be increased. In one of the rat bioassays, pituitary tumors, pheochromocytomas, uterine tumors, and pituitary tumors were noted. The conversion of acrylamide metabolically to the reactive, mutagenic, and genotoxic product, glycidamide, can occur in both rodent and humans. Glycidamide and frequently acrylamide have been positive for mutagenicity and DNA reactivity in a number of in vitro and in vivo assays. The effects of chronic exposure of glycidamide to rodents have not been reported. Epidemiologic studies of workers for possible health effects from exposures to acrylamide have not shown a consistent increase in cancer risk. Although an increase in the risk for pancreatic cancer (almost double) was seen in highly exposed workers, no exposure response relationship could be determined. The mode of action remains unclear for acrylamide-induced rodent carcinogenicity, but support for a genotoxic mechanism based on in vitro and in vivo DNA reactivity assays cannot be ruled out. In addition, the pattern of tumor formation in the rat following chronic exposure supports a genotoxic mode of action but also suggests a potential role of endocrine modification.

Myricetin Suppresses UVB-Induced Skin Cancer by Targeting Fyn

Skin cancer is currently the most common type of human cancer in Americans. Myricetin, a naturally occurring phytochemical, has potent anticancer-promoting activity and contributes to the chemopreventive potential of several foods, including red wine. Here, we show that myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-kappaB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis.

Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients.

Photoprotection of bacterial‐derived melanin against ultraviolet A–induced cell death and its potential application as an active sunscreen

The increase in the incidence of non-melanoma skin tumours, photoaging, and immunosuppression demand for more effective sunscreen on ultraviolet A (UVA) irradiation. The aim of the study is to evaluate the photoprotective effects of a bacterial-derived melanin against UVA-induced damages in vitro and in vivo. Methods Human fibroblasts were used to assess the role of the bacterial-derived melanin on cell viability against UVA. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and nuclear morphology were employed to evaluate the photoprotection at the cellular level. Fluorometric assays were performed to detect the formation of reactive oxygen species (ROS) in the cells. Evaluations of the bacterial-derived melanin as a sunscreen were measured by transmission test and persistent pigment darkening on human skin. Bacterial-derived melanin efficiently scavenged ROS in the fibroblasts after UVA irradiation. The cell viability of xeroderma pigmentosum (XP) fibroblast treated with varied doses of melanin increased dramatically in comparison with untreated control and the treated XP fibroblasts became more resistant to UVA-induced apoptosis than normal fibroblasts. Although the relative transmission didn't change too much with different concentration of bacterial-derived melanin, this melanin could keep UVA-irradiated skin from pigment darkening and act as an active sunscreen on skin. The bacterial-derived melanin provided significant protection to fibroblast cell and human skin against the UVA radiation. It has the potential to be developed as an active sunscreen for the patients with photosensitivity skin to sun exposure.

Enhancement of UVB-Induced Apoptosis by Apigenin in Human Keratinocytes and Organotypic Keratinocyte Cultures

Topical application of the bioflavonoid 4',5,7-trihydroxyflavone (apigenin) to mouse skin effectively reduces the incidence and size of skin tumors caused by UVB exposure. The ability to act as a chemopreventive compound indicates that apigenin treatment alters the molecular events initiated by UVB exposure; however, the effects of apigenin treatment on UVB-irradiated keratinocytes are not fully understood. In the present study, we have used three models of human keratinocytes to study the effect of apigenin treatment on UVB-induced apoptosis: HaCaT human keratinocyte cells, primary keratinocyte cultures isolated from human neonatal foreskin, and human organotypic keratinocyte cultures. Each keratinocyte model was exposed to a moderate dose of UVB (300-1,000 J/m(2)), then treated with apigenin (0-50 micromol/L), and harvested to assess apoptosis by Western blot analysis for poly(ADP)ribose polymerase cleavage, annexin-V staining by flow cytometry, and/or the presence of sunburn cells. Apigenin treatment enhanced UVB-induced apoptosis >2-fold in each of the models tested. When keratinocytes were exposed to UVB, apigenin treatment stimulated changes in Bax localization and increased the release of cytochrome c from the mitochondria compared with UVB exposure alone. Overexpression of the antiapoptotic protein Bcl-2 and expression of a dominant-negative form of Fas-associated death domain led to a reduction in the ability of apigenin to enhance UVB-induced apoptosis. These results suggest that enhancement of UVB-induced apoptosis by apigenin treatment involves both the intrinsic and extrinsic apoptotic pathways. The ability of apigenin to enhance UVB-induced apoptosis may explain, in part, the photochemopreventive effects of apigenin.

Inhibition of 7,12-dimethylbenzanthracene-induced skin tumors by a nutrient mixture

The annual incidence of all forms of skin cancer, the most common of all human cancers, is increasing yearly. A unique nutrient mixture (NM) was shown to exhibit anticancer activity in vivo and in vitro. We examined the effect of NM on the development of skin cancer induced by 7,12-dimethylbezanthracene (DMBA) in female SENCAR mice by a complete carcinogenesis protocol. Mice (n=55) were divided into four groups and carefully shaved on dorsum. After 2 days, the mice in Groups 1 (n=10), 3 (n=20), and 4 (n=20) were treated topically with 100 nM DMBA in 0.2 ml of acetone twice a week for 4 weeks; Group 2 (n=5), the control group, was treated with acetone 0.2 ml. Groups 1 and 2 were fed the regular diet. Group 3A (n=10) was fed a diet containing 0.5% NM from the day of DMBA treatment and 3B (n=10) the regular diet and received NM (75 mg in 0.4 ml of 1:1 acetone/water) topically to the shaved area 15 min before DMBA application twice a week for 4 weeks. Group 4 mice were fed a diet containing 0.5% NM for 2 weeks prior to the application of DMBA and then divided into two groups: 4A (n=10) was fed the 0.5% NM diet as in 3A, and 4B (n=10) the regular diet as described for 3B. Body weight and diet consumption of the mice were monitored and the skin tumors (papillomas) were counted and recorded. Ten weeks thereafter the mice were euthanized, skinned, and tumors were processed for histology. NM significantly (P<0.0001) inhibited DMBA-induced skin tumor multiplicity by 59, 62, 69, and 86% in NM-treated Groups 3A, 3B, 4A, and 4B, respectively. These results suggest that NM has strong potential as a useful therapeutic regimen for skin cancer by significantly inhibiting the incidence and tumor multiplicity of DMBA-induced skin tumors.

Tissue Levels of Arsenicals and Skin Tumor Response Following Administration of Monomethylarsonous Acid and Arsenite to K6/ODC Mice

The effects of monomethylarsonous acid (MMA[III]) and arsenite, administered in drinking water on tissue levels of arsenicals, cytogenetics, and mouse skin tumorigenicity were determined. A low-methionine diet modified the pattern of arsenical tissue concentrations and decreased the tissue arsenical concentrations, particularly in kidney and urinary bladder, less so in liver, and had little effect in the lungs. In mice given 75 ppm arsenite and a low-methionine diet, the urinary bladder tissue levels were only 29%, 26%, and 38% of the inorganic arsenic (iAs), MMA, and dimethylarsinic acid (DMA) concentrations found in mice eating the control diet. In K6/ODC transgenic mice that consumed a normal diet (Purina 5002), a 26-week drinking water exposure to 10 ppm arsenite resulted in 5% of the treated animals having squamous skin tumors. Exposure to 10, 50, 75, or 150 ppm MMA(III) caused 5%, 6.7%, 5%, or 0% tumor-bearing animals. A low-methionine diet did not markedly change the incidence of skin tumors--10 ppm arsenite led to 10% tumors. With a low-methionine diet, 10 and 50 ppm, MMA(III) caused 5% and 6.7% tumor-bearing animals. In comparing the frequency of tumors in the concurrent control groups (1/70, 1.4%) with the frequency of tumors in the pooled arsenical-treated responsive groups (8/122, 6.6%), there is an excess of 6 mouse skin tumors observed in the pooled arsenical-responsive treatment groups compared to the expected number of tumors based on frequency of tumors observed in concurrent control mice. In summary, studies with MMA(III) and arsenite-treated K6/ODC transgenic mice showed (1) a low-methionine diet substantially altered mouse tissue arsenical levels and (2) numerically elevated incidence of mouse skin tumors following arsenical exposures.

Supplementing Vitamin B6 to a Low Vitamin B6 Diet Exaggerates UVB-Induced Skin Tumorigenesis in DMBA-Treated Hairless Mice

7,12-Dimethylbenz[a]anthracene (DMBA)-treated hairless mice exposed to UVB radiation were used to examine the effect of graded levels of vitamin B(6) [1, 7 or 35 mg pyridoxine (PN) HCl/kg] on skin tumorigenesis for 18 wk. Compared to the 1 mg PN HCl/kg diet, the 35 mg PN HCl/kg diet significantly elevated the incidence and multiplicity of skin tumors, while there was no difference in skin tumorigenesis between the 7 and 35 mg PN HCl/kg diets. Skin levels of oxidative stress markers (lipid peroxides and protein carbonyls) were unaffected by dietary treatment. Compared to the 1 mg PN HCl/kg diet, the 7 and 35 mg PN HCl/kg diets significantly elevated serum pyridoxal 5'-phosphate (PLP) without affecting the skin level of PLP. The results suggest that dietary supplemental vitamin B(6) exaggerates UVB-induced skin tumorigenesis in hairless mice without affecting oxidative stress in the skin.

犬の腫瘍5, 819例の疫学的分析

The purpose of this study was to document the incidence of canine tumors in Japan. During the period April 1985 to March 2006, 26, 072 dogs were referred to the Azabu University Veterinary Teaching Hospital. Of this number, 5, 819 dogs were diagnosed with a tumor. The 5, 819 canine neoplasm cases were analyzed by age, sex, malignant tumor rate, breed and site-specific tumor incidence. The average age of dogs with tumors was 9.2±3.3 years old.Cases with tumors were significantly older than general clinicalcases (6.1 ± 4.2 years) in dogs. The gender ratio was male 1: female 1.45, with female dogs showing asignificantly higher incidence than male dogs. The odds ratio, which reflects tumor incidence, washigher for Golden Retrievers (1.5) and Shetland Sheep Dogs (1.4), and significantly lowerfor Miniature Pinschers and Cavaliers. From the analysis of tumor incidence, malignancy rate, age, sex and canine breed for each specific site, we were able to confirm the statistical significance for each factor. Japanese canine breeds such as Shiba-inu and Kai-ken showed a significantly higher incidence of skin tumors, which included mast cell tumors. The odds ratio in Collies, Cocker Spaniels and Golden Retrievers for lymphoma was remarkably high in comparison with American reports. It was concluded that these results were useful clinical indicators for the diagnosis and treatment of canine tumors.

Dominant-Negative but not Gain-of-Function Effects of a p53.R270H Mutation in Mouse Epithelium Tissue after DNA Damage

p53 alterations in human tumors often involve missense mutations that may confer dominant-negative or gain-of-function properties. Dominant-negative effects result in inactivation of wild-type p53 protein in heterozygous mutant cells and as such in a p53 null phenotype. Gain-of-function effects can directly promote tumor development or metastasis through antiapoptotic mechanisms or transcriptional activation of (onco)genes. Here, we show, using conditional mouse technology, that epithelium-specific heterozygous expression of mutant p53 (i.e., the p53.R270H mutation that is equivalent to the human hotspot R273H) results in an increased incidence of spontaneous and UVB-induced skin tumors. Expression of p53.R270H exerted dominant-negative effects on latency, multiplicity, and progression status of UVB-induced but not spontaneous tumors. Surprisingly, gain-of-function properties of p53.R270H were not detected in skin epithelium. Apparently, dominant-negative and gain-of-function effects of mutant p53 are highly tissue specific and become most manifest upon stabilization of p53 after DNA damage.

Functions of Rad16 Endonuclease at Telomeres in S. pombe

Telomeres are nucleoprotein structures that protect the ends of linear chromosomes from degradation and end-to-end fusions mediated by DNA-damage response proteins. Interestingly, accumulating evidence in recent years indicates that multiple proteins involved in DNA damage response pathways are localized to telomeres and actively participate in regulating telomeres. The ERCC1/XPF heterodimer is a highly conserved endonuclease complex which functions in multiple DNA repair pathways. Deficiencies in human ERCC1/XPF result in Xeroderma Pigmentosum (XP), a disease that is characterized by sensitivity to UV light and a high incidence of skin tumors. Our work shows that fission yeast rad16+, the homolog to mammalian XPF, is synthetic lethal with pot1+, the gene encoding the protection of telomeres protein which binds to single-stranded telomere DNA. Further study indicates that a portion of Rad16 is physically associated with telomeres and plays various roles when the protecting structure of telomeres is disrupted. Upon loss of telomeres in the pot1+ or telomerase null cells, survivor strains emerge through intra-chromosome fusions of all three chromosomes. Lack of Rad16 blocks the survival mechanisms in the pot1+ or telomerase null cells but does not affect taz1+ null cells. Our data suggests roles for Rad16 in chromosome circularization and in the maintenance of circular chromosomes during mitotic growth.

Skin tumors among employees of a tar refinery: the current data and their implications

Skin tumors and their preliminary stages may be recognized and compensated as an occupational disease only after exposure to soot, raw paraffin, tar, anthracene, pitch or similar substances. The presented study was carried out in one of the world's largest tar refineries and special attention was paid to the dermatological long-term effects and today's relevance of tar-induced skin lesions. The data were generated by means of a standardized questionnaire based on occupational disease records and dermatological reports that have been carried out on a regular basis retrospectively. Among other things, the localization, the number and type of skin tumor, the date of diagnosis and the histological evaluation, where available, were taken into account. In a longitudinal analysis from 1946 to 2002, a total of n = 618 employees were examined. Squamous cell carcinomas n = 393, basal cell carcinomas n = 298, keratoacanthomas n = 194 and melanomas n = 6 were diagnosed. Latency periods for keratoacanthomas (median 29.5 years) and squamous cell carcinomas (median 28.0 years) were almost identical and could possibly imply that the pathomechanisms for both types of skin tumor might be comparable. Of the persons diagnosed, the skin tumors were mainly localized in the head region (n = 1,662). A remarkable divergence in the localization and distribution of the lesions was found when compared to the general population, for example the relative susceptibility of the upper lip (n = 67) compared to the lower lip (n = 31) as well as the less sun-exposed forearms (n = 381) compared to the back of the hand (n = 331), being typically preferred sites of squamous cell carcinomas. Furthermore, a discrepancy between the distribution of premalignant nonmelanoma skin tumors and carcinomas on the back of the nose, which is more exposed to the sun (n = 56) and those in the nostrils (n = 89), which are less exposed to the sun, but are in the act of breathing more exposed to tar, could be found. Tar-induced skin lesions are still of importance nowadays, which is reflected in the incidence of new cases and in the relapses of skin tumors. As a consequence, intensified measures are necessary, in the form of primary and secondary prevention. In view of the high incidence of malignant skin tumors in the general public, it is urgently necessary to take occupational hazards into consideration as well.

Differential Role of Basal Keratinocytes in UV-Induced Immunosuppression and Skin Cancer

Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion- and cell-type-specific manner.

Inhibitory effect of ailanthoidol on 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion in mouse skin

Many components derived from dietary or medicinal plants showing antioxidant and anti-inflammatory potential have been found to possess chemopreventive properties. In our previous study, we achieved the total synthesis of ailanthoidol (AT), a neolignan from Zanthoxylum ailanthoides or Salvia miltiorrhiza Bunge, which are used in Chinese traditional herbal medicine. In the present study, preliminarily, AT exhibited a radical quenching property by DPPH assay. Following this, we assessed the effect of AT on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in female CD-1 mouse skin which was closely linked to tumor promotion. The topical application of AT (0.5-2.5 mM; 200 microl) reduced the formation of hydrogen peroxide and inhibited the myeloperoxidase (MPO) activity in the mouse skin when compared with that of the TPA-treated alone group. In addition, AT presented a suppression effect on the TPA-induced hyperplasia and leukocyte infiltration in the epidermis and edema of mouse ears. Furthermore, it showed that AT inhibited the TPA-induced expression of COX-2 protein and ornithine decarboxylase (ODC) activity in epidermis. Finally, AT was evaluated for its ability to inhibit the TPA-induced promotion in skin tumors of female CD-1 mice. Topical application of AT 5 min prior to TPA (5 nmol) three times weekly for 12 weeks to mice which were initiated with benzo[a]pyrene (B[a]P) inhibited the incidence of skin tumors in mice and the average number of tumors per mice as compared to TPA-treated alone. These results indicate that AT possesses potential as a chemopreventive agent against tumor promotion.

Inhibition of 7,12-Dimethylbenz(a)anthracene-Induced Skin Tumorigenesis in C57BL/6 Mice by Sulforaphane Is Mediated by Nuclear Factor E2–Related Factor 2

Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.

Potent Skin Cancer Chemopreventing Activity of Some Novel Semi-synthetic Cembranoids from Marine Sources

In the course of our continuing research in development and evaluation of novel skin cancer chemopreventive agents from marine sources, five semi-synthetic cembranoids derived from the marine natural product sarcophine, isolated from the soft coral Sarcophyton glaucum, were synthesized and shown to exhibit a remarkable chemopreventive activity in the in-vitro Epstein Barr Virus Early Antigen (EBV-EA) activation assay. These compounds were assayed in vivo using the two-stage carcinogenesis test of mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator, and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter by topical administration. They showed potent inhibition of both percentage incidence of skin tumor as well asthe multiplicity of skin tumors per mouse compared to untreated controls.Semi-synthetic Cembranoids from Marine Sources

Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53

Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53(Val135/wt) mice with TG.AC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced approximately 26% skin tumor incidence, whereas BaP treatment of p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53(wt/wt)Hras(wt/wt)) mice, whereas approximately 1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53(wt/wt)Hras(wt/wt)) in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. Histopathologically, all tumors from p53(wt/wt)Hras(wt/wt) mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53(Val135/wt)Hras(TG.AC/wt) mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val135) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression.

Low Incidence of Malignancy among Sirolimus/Cyclosporine-Treated Renal Transplant Recipients

Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects. We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone. Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes. The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.

Final Report of the Safety Assessment of Methacrylate Ester Monomers Used in Nail Enhancement Products1

Methacrylate ester monomers are used in as artificial nail builders in nail enhancement products. They undergo rapid polymerization to form a hard material on the nail that is then shaped. While Ethyl Methacrylate is the primary monomer used in nail enhancement products, other methacrylate esters are also used. This safety assessment addresses 22 other methacrylate esters reported by industry to be present in small percentages as artificial nail builders in cosmetic products. They function to speed up polymerization and/or form cross-links. Only Tetrahydrofurfuryl Methacrylate was reported to the FDA to be in current use. The polymerization rates of these methacrylate esters are within the same range as Ethyl Methacrylate. While data are not available on all of these methacrylate esters, the available data demonstrated little acute oral, dermal, or i.p. toxicity. In a 28-day inhalation study on rats, Butyl Methacrylate caused upper airway irritation; the NOAEL was 1801 mg/m3. In a 28-day oral toxicity study on rats, t-Butyl Methacrylate had a NOAEL of 20 mg/kg/day. Beagle dogs dosed with 0.2 to 2.0 g/kg/day of C12 to C18 methacrylate monomers for 13 weeks exhibited effects only in the highest dose group: weight loss, emesis, diarrhea, mucoid feces, or salivation were observed. Butyl Methacrylate (0.1 M) and Isobutyl Methacrylate (0.1 M) are mildly irritating to the rabbit eye. HEMA is corrosive when instilled in the rabbit eye, while PEG-4 Dimethacrylate and Trimethylolpropane Trimethacrylate are minimally irritating to the eye. Dermal irritation caused by methacrylates is documented in guinea pigs and rabbits. In guinea pigs, HEMA, Isopropylidenediphenyl Bisglycidyl Methacrylate, Lauryl Methacrylate, and Trimethylolpropane Trimethacrylate are strong sensitizers; Butyl Methacrylate, Cyclohexyl Methacrylate, Hexyl Methacrylate, and Urethane Methacrylate are moderate sensitizers; Hydroxypropyl Methacrylate is a weak sensitizer; and PEG-4 Dimethacrylate and Triethylene Glycol Dimethacrylate are not sensitizers. Ethylene Glycol Dimethacrylate was not a sensitizer in one guinea pig study, but was a strong sensitizer in another. There is cross-reactivity between various methacrylate esters in some sensitization tests. Inhaled Butyl Methacrylate, HEMA, Hydroxypropyl Methacrylate, and Trimethylolpropane Trimethacrylate can be developmental toxicants at high exposure levels (1000 mg/kg/day). None of the methacrylate ester monomers that were tested were shown to have any endocrine disrupting activity. These methacrylate esters are mostly non-mutagenic in bacterial test systems, but weak mutagenic responses were seen in mammalian cell test systems. Chronic dermal exposure of mice to PEG-4 Dimethacrylate (25 mg, 2 x weekly for 80 weeks) or Trimethylolpropane Trimethacrylate (25 mg, 2 x weekly for 80 weeks) did not result in increased incidence of skin or visceral tumors. The carcinogenicity of Triethylene Glycol Dimethacrylate (5, 25, or 50%) was assessed in a mouse skin painting study (50 microl for 5 days/week for 78 weeks), but was not carcinogenic at any dose level tested. The Expert Panel was concerned about the strong sensitization and crossor co-reactivity potential of the methacrylate esters reviewed in this report. However, data demonstrated the rates of polymerization of these Methacrylates were similar to that of Ethyl Methacrylate and there would be little monomer available exposure to the skin. In consideration of the animal toxicity data, the CIR Expert Panel decided that these methacrylate esters should be restricted to the nail and must not be in contact with the skin. Accordingly, these methacrylate esters are safe as used in nail enhancement products when skin contact is avoided.

Marjolin's ulcer on frostbite

Malignant skin tumors are known to occur on various forms of scars, chronic ulcerations, inflammations, fistulas and mainly on burn scars after a long latent period [1,2]. The term ‘‘Marjolin’s ulcer’’ is used for these malignant skin tumors arising on chronic wound and irritation sites [3]. The relation between malignant degeneration and thermal burn scars is known to have been defined by Celsus in the first century A.D., for the first time. This situation is named after the French surgeon Jean-Nicholas Marjolin who demonstrated the cellular changes of the ulcerated lesions in the scarred tissue in 1828, but it is claimed that Dupuytren also reported the malignant degeneration in 1839 [3,4]. The latent period between the initial injury and the diagnosis of the malignancy is quite long. Though various time periods have been reported, it is accepted to be longer than 20 years [2,5]. On the other hand, there is a reported case of Marjolin’s ulcer occurring a few months after the initial injury [2,3,6]. The pathogenesis of Marjolin’s ulcer is controversial [3,5,7–11]. The incidence of malignant skin tumors on scarred tissues is 0.1–2.5% and squamous cell cancers constitute the majority [2]. Though half of the cases (49%) are due to burn scars, physical and chemical frostbites, stasis ulcers, osteomyelitic sinuses, amputation stumps, syphilis, lupus vulgaris, hidradenitis suppurativa, vesicovaginal fistulas and lymphogranuloma venereum are among the reported rare causes of Marjolin’s ulcers [12]. Frostbite of the lower extremity, also known as ‘‘trench foot’’, is one of the etiologic factors of Marjolin’s ulcer, but