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T J Slaga

Publications and source records attributed to T J Slaga.

At least 55 records · Page 3Linked to original sources
PubMed1994

Intermittent 50 Hz magnetic field and skin tumor promotion in SENCAR mice.

A number of epidemiological studies have indicated association between exposure to extremely low frequency electromagnetic fields and a variety of cancers, including leukaemia and brain tumours among residentially exposed children and among occupationally exposed adults. In order to test if intermittent magnetic fields (MF) act as a tumour promoter, a long-term skin carcinogenicity study of 50 Hz sinusoidal MF with flux densities of 50 muT and 0.5 mT, continuous as well as with an intermittence of 15 s on/off, was performed. Female SENCAR mice were divided into eight groups of 50 animals in each and treated according to an initiation- promotion scheme. 7,12-dimethylbenz[a] anthracene (DMBA) in acetone was applied to the dorsal skin at a subcarcinogenic dose, as an initiator and exposure to MF was performed for 19-21 h/day during 104 weeks starting 1 week after the initiator treatment. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as a positive control for skin tumour promoting activity. Two animals from each group were assigned for skin hyperplasia analysis at 2, 6, 12, 18 and 21 months. The animals were observed daily. The appearance of skin lesions and neoplasms were carefully followed and histopathological diagnosis was made for all neoplasms present at death. The experiment was terminated after 105 weeks. DMBA-treatment alone yielded altogether two skin tumours in two tumour-bearing animals and the animals exposed to acetone alone had one skin tumour. The animals exposed to continuous fields showed no skin tumour. Five animals exposed to 0.5 mT on/off had a total of 13 skin tumours and in the group exposed to 50 microT on/off four animals had a total of four skin tumours. The on/off exposed groups differed significantly from the continuously exposed groups (P = 0.014) but the difference between the on/off exposure groups and the DMBA group was not statistically significant when tumour-bearing animals and cumulated skin tumours were compared. There was a statistically significant dose trend (P = 0.045) with flux density and Tesla-h for intermittent MF exposure for cumulated skin tumours per tumour-bearing animals. The epithelial thickness of DMBA + MF-treated animals was of the same magnitude as for DMBA-treated animals indicating that, in the case of a promoting effect being present, another mechanism than one involving sustained hyperplasia may be involved.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Mouse skin tumor-initiating activity of benz[j]aceanthrylene in SENCAR mice.

Benz[j]aceanthrylene (B[j]A), a cyclopenta-fused derivative of benz[a]anthracene, has been reported to be an active bacterial cell and mammalian cell gene mutagen, a morphological transforming agent in C3H10T1/2CL8 mouse embryo fibroblasts and a mouse lung tumorigen in strain A/J mice. B[j]A was evaluated as a skin tumor initiator in female SENCAR mice and was found to induce papilloma formation in the range of 40-400 micrograms/mouse. B[j]A was found to be extremely active, inducing 8.7 papillomas/mouse after an initiating dose of 40 micrograms/mouse. At this dose, 100% of the mice bore tumors. Comparison with four other cyclopenta-fused polycyclic aromatic hydrocarbons suggests that B[j]A is extremely potent.

Animals↗
PubMed1993

The hamster cheek pouch carcinogenesis model.

The Syrian golden hamster cheek pouch carcinogenesis model is probably the best-known animal system that closely compares to events involved in the development of premalignant and malignant human oral cancers. Furthermore, it is one of the most well-characterized models for squamous cell carcinomas (SCCs). However, stages of carcinogenesis (initiation, promotion, and progression) have not been well-defined in this system. Basic understanding of the mechanism(s) of carcinogenesis in this organ is instrumental for the development of new strategies for chemoprevention and early chemointervention. To understand the important early events that occur in the hamster cheek pouch carcinogenesis model, we compared it to the mouse skin model, where a number of critical events have been well characterized. We determined that approximately 60% of the hamster cheek pouch SCCs have a mutation in codon 61 of the Ha-ras gene. We also established a two-stage carcinogenesis protocol in this model using a single dose of dimethylbenz(alpha)anthracene (DMBA) and multiple doses of benzoyl peroxide for 45 weeks. Twenty-five percent of tumors developed with this protocol had the same mutation in codon 61 of the Ha-ras gene, confirming that this mutation, as in the mouse skin model, is initiation-related. We examined the sequential expression of hyperplasia, micronucleated cells, ornithine decarboxylase (ODC) activity, polyamine levels, transglutaminase I activity, epidermal growth factor receptor (EGF-R) levels, keratins, gamma-glutamyltranspeptidase (GGT), transforming growth factor-beta 1 (TGF-beta 1), leukoplakia, and carcinomas induced during carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Low frequency of codon 61 Ha-ras mutations and lack of keratin 13 expression in 7,12-dimethylbenz[a]-anthracene-induced hamster skin tumors.

Alterations in the pattern of keratin expression are a common feature of skin-tumor development. In this study, we investigated whether the loss of epidermal keratin 1 (K1) and its replacement by mucosal keratin 13 (K13) is unique to mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), since it has been reported that human epidermal tumors do not exhibit aberrant expression of K13. With that purpose, we analyzed the keratin profiles of 16 DMBA-induced hamster skin tumors using monospecific antibodies against K1 and K13. Although all the tumors expressed K1, they also showed an overall tendency towards loss of this keratin; furthermore, none of the tumors expressed K13. Previous studies have suggested that the induction of K13 in mouse skin is related to the mutation of the Ha-ras gene by the initiating agent DMBA, a mutation consistently found in murine DMBA/TPA-induced tumors and rarely found in human skin tumors. Therefore, we also evaluated the tumors for the presence of codon-61 mutations by direct sequencing of DNA extracted from paraffin-embedded tissue sections. Only three tumors showed an A-->T transversion in the second nucleotide of Ha-ras codon 61. However, presence of the mutation did not correlate with K1 staining. Although hamster skin tumors were induced by the same initiator as were mouse skin tumors, hamster skin tumors did not show the same keratin profile. Moreover, their immunohistochemical expression of K1 and K13 and their codon 61 sequences resembled that of their human counterparts. These results suggest that the aberrant expression of K13 may be unique to murine skin. Furthermore, although codon 61 Ha-ras mutation appears to be related to keratin alterations in the mouse model, this mutation is not sufficient to produce the same biochemical changes in other species.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

A study on skin tumour formation in mice with 50 Hz magnetic field exposure.

In order to test the possibility that magnetic fields (MF) act as a tumour promoter, a long-term skin carcinogenicity study of 50 Hz sinusoidal MF with flux densities of 50 microT and 0.5 mT was performed in female NMRI mice. 7,12-dimethylbenz[a]anthracene (DMBA) in acetone was applied to the dorsal skin, as an initiator, and exposure to MF was performed for 19 (weekdays) or 21 h/day (weekends and holidays) for 103 weeks starting one week after the initiator treatment. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as a positive control for skin tumour promoting activity. MF was also evaluated for complete carcinogenic action in groups of mice that were treated with acetone only. Six animals from each group were taken for skin hyperplasia analysis and were killed after 9, 26 and 52 weeks. The appearance of skin lesions were carefully followed and histopathological diagnosis was made for all neoplasms present at death. The statistical analyses on occurrence of skin tumour bearing animals and cumulated skin tumours, with corrections for survival did not reveal a difference between the controls and the MF exposed groups. The epithelial thickness of DMBA + MF-treated animals was of the same magnitude as for DMBA-treated animals. Leukaemia was a little more frequent among animals exposed to 0.5 mT MF compared to the control animals. However this difference was not statistically significant.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Further studies on the influence of initiation dose on papilloma growth and progression during two-stage carcinogenesis in SENCAR mice.

The present study was designed to further evaluate the growth and progression of papillomas to squamous cell carcinomas (SCCs) in groups of animals receiving initiating doses of 7,12-dimethylbenz[a]anthracene (DMBA) producing relatively low papilloma yields following long term promotion (60 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA). For comparison, groups of animals were initiated with various doses of DMBA and then promoted with mezerein (MEZ), benzoyl peroxide (BzPo) and chrysarobin (CHRY). Following initiation, groups of female SENCAR mice received the following promoter doses: TPA (1.0 or 2.0 micrograms per mouse); MEZ (2.0 micrograms per mouse); BzPo (20.0 mg per mouse); and CHRY (52.8 micrograms per mouse). The maximum papilloma to SCC conversion ratio obtained with TPA in the current study was 0.32. This value was in the range of maximum conversion ratios obtained with the other compounds: MEZ, 0.40; CHRY, 0.32 and BzPo, 0.19. In general, the highest papilloma to SCC conversion ratios observed with TPA as the promoter were obtained in groups that received the lowest doses of DMBA and had relatively low papilloma burdens. A comparison of papilloma to SCC conversion in groups of mice promoted with TPA, MEZ or CHRY and having similar papilloma yields, revealed very similar conversion ratios. Comparison of the BzPo group with a similar papilloma yield indicated that the conversion ratio was slightly lower with this promoter. The present results indicate that in mice promoted with TPA and having relatively low papilloma numbers, a larger proportion of these papillomas progress to SCCs during continued promoter treatment. Furthermore, the results suggest that papillomas behave similarly in their ability to progress to SCCs regardless of the promoter used when comparing groups of mice with similar tumor numbers. The data are discussed in terms of possible mechanisms for the observed results.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Morphological changes of the nucleolar organizer regions induced by 7,12-dimethylbenz[a]anthracene in the hamster cheek pouch.

The staining of nucleolar organizer regions (NORs), which equate to rDNA transcription, was applied to chemically induced-lesions of the hamster cheek pouch. The cheek pouches of 16 male golden Syrian hamsters were treated three times a week with 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) in mineral oil for 16 weeks. The percentage of gathered-type NORs with high activity nucleoli increased in the pouch epithelium during DMBA treatment and reached the highest values in malignant tumors. The percentage of dispersed-type NORs also increased in the malignant lesions. However, the absolute number of NORs was not affected by DMBA treatment. These results suggest that DMBA induces modification of NOR activity at the early stages of carcinogenesis and shows the potential of this model for studying NOR alterations in neoplasia.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Dissociation of sensitivities to tumor promotion and progression in outbred and inbred SENCAR mice.

The sensitivity of outbred SENCAR mice and inbred SENCAR (SSIN) mice to multistage carcinogenesis was studied. Tumors were induced using either 7,12-dimethylbenz[a]anthracene or N-methyl-N'-nitro-N-nitrosoguanidine as initiators and 12-O-tetradecanoylphorbol-13-acetate or benzoyl peroxide as promoting agents. Although the number of papillomas per mouse was higher in SSIN than in outbred SENCAR mice, the number of carcinomas observed in the SSIN strain was significantly lower regardless of the initiator or promoter used. It was also observed that the expression of markers of premalignant progression (i.e., dysplasia, expression of keratin K13, and loss of keratin K1 expression) was markedly suppressed in SSIN papillomas. After 50 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate, the pattern of expression of K13 and K1 in SSIN mice was comparable to the pattern observed in outbred SENCAR mice after 10 to 20 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate. It was also observed that 67% of the tumors induced in SSIN mice by initiation with 7,12-dimethylbenz[a]anthracene exhibited a mutation in codon 61 of the Ha-ras-1 gene. This latter finding suggests that the differences observed in tumor progression between the inbred strain and the outbred stock are not related to a genetic alteration in the Ha-ras-1 gene but rather to an independent event that we have postulated to involve a putative suppressor gene. The data reported here suggest that the putative gene(s) that confers susceptibility to tumor promotion was segregated from the gene(s) involved in tumor progression during selection and inbreeding of the SENCAR mouse stock.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Differential effects of dietary linoleic acid on mouse skin-tumor promotion and mammary carcinogenesis.

On the basis of reports of rat mammary- and pancreas-tumor models, we hypothesized that an increase in consumption of linoleic acid (LA) would also cause an enhancement in mouse skin-tumor promotion. SEN-CAR mice were placed on diets containing 0.8%, 2.2%, 3.5%, 4.5%, 5.6%, 7.0%, or 8.4% LA, 1 week after initiation with 7,12-dimethylbenz(a)anthracene and 3 weeks before starting promotion with 12-O-tetradecanoylphorbol-13-acetate. An inverse correlation (r = -0.92) was observed between papilloma number and level of LA; however, there was little difference in tumor incidence. A relationship between diet and carcinoma incidence was also found. The fatty acid composition of epidermal phospholipids reflected the dietary LA levels. 12-O-Tetradecanoylphorbol-13-acetate-induced epidermal prostaglandin E2 levels generally decreased with increasing dietary LA. To determine whether this inverse correlation between dietary LA and tumor yield was due to species differences or organ-model differences, a mammary carcinogenesis experiment was performed. SENCAR mice were fed the 0.8%, 4.5%, and 8.4% LA diets. All mice received 6 mg 7,12-dimethylbenz(a)anthracene, administered intragastrically at 1 mg/week. Tumor appearance was delayed in the 0.8% LA diet group, and a positive dose-response relationship between dietary LA and mammary-tumor incidence was observed. These studies suggest that the effect of dietary LA on tumor development is target tissue specific rather than species specific.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

The effect of dietary fat on the rapid development of mammary tumors induced by 7,12-dimethylbenz(a)anthracene in SENCAR mice.

We recently reported (J. Leyton et al., Cancer Res., 51: 907-915, 1991) an inverse correlation between skin tumor number and level of dietary linoleic acid (LA) in SENCAR mice following an initiation-promotion protocol. These results differed from the reported (C. Ip et al., Cancer Res., 45: 1997-2001, 1985) positive correlation between dietary LA and tumor incidence for the rat mammary gland. The goal of the study reported here was to determine whether this dissimilarity was due to organ site or species differences. Female SENCAR mice were fed 1 of 3 15% fat diets containing LA at levels of 0.8, 4.5, and 8.4% before, during, and after intragastric administration of 6 mg (1 mg/week) 7,12-dimethylbenz(a)anthracene. A positive correlation between level of dietary LA and mammary tumor incidence was observed such that for the first 15 weeks, the incidence was greatest in the 8.4% LA diet group, followed by the 4.5% and then the 0.8% LA groups. Distinct dietary effects on latency were also noted in that 15, 12, and 8 weeks after cessation of 7,12-dimethylbenz(a)anthracene were required for a 40% carcinoma incidence in the 0.8, 4.5, and 8.4% LA diet groups, respectively. A histopathological analysis of all tumors revealed that the predominant type was the adenosquamous carcinoma, which comprised 46.6, 54.1, and 77.7% of all mammary tumors for diets containing 0.8, 4.5, and 8.4% LA, respectively. The second most common tumor was the adenocarcinoma type B, which was found with a frequency of 33% in the 0.8% and 4.5% LA diet groups and 22% in the 8.4% LA diet group. These results indicate that SENCAR mice have a short latency period for 7,12-dimethylbenz(a)anthracene-induced mammary tumor development and that rat and mouse mammary tumor development is modified by dietary LA in a similar manner, although in the SENCAR mouse dietary LA did not have a saturating effect. In addition, high dietary LA was found to be associated specifically with an increased incidence of adenosquamous carcinomas but not of other types of mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Activating mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch.

The presence of an activating mutation in the Ha-ras gene in hamster cheek pouch tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) complete carcinogenesis was investigated. The normal sequence of a fragment of genomic DNA encompassing codon 61 of the Ha-ras gene was amplified by the polymerase chain reaction using primers designed for a highly conserved region of the mouse Ha-ras-1 gene. The sequence of the amplified fragment was determined by a direct sequencing technique and exhibited 83.3% and 87.5% homology with the corresponding human and mouse sequences, respectively. At the amino acid level, the sequence was identical among the three species. Paraffin sections of 11 squamous cell carcinomas of the cheek pouch were used to detect mutated Ha-ras alleles. DNA sequencing of the tumors showed that six of 11 tumors presented an A----T transversion in the second position of codon 61, resulting in an amino acid change from glycine to leucine. As has been demonstrated in other systems, we have shown a specific mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch, further supporting the role of this oncogene in chemical carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

O6-alkylguanine-DNA alkyltransferase activity in epidermal tumor and normal epidermal cells of mice of various stocks and strains.

The level of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (MGMT) was examined in benign and malignant skin tumors induced with different initiating and promoting agents and from both SENCAR and Sensitive SENCAR Inbred (SSIN) mice. The MGMT levels in the tumors were approximately one-half the level observed in normal surrounding epidermis and in keratinocytes from untreated controls. In addition, a carcinoma-producing cell line, VT 17DT, derived from papillomas in SENCAR mice had no detectable MGMT activity (Mer- phenotype), whereas in the non-tumor forming line, 3PC, MGMT activity was comparable to that in papillomas. The comparatively low level of MGMT in papillomas may contribute to their ease of conversion to squamous cell carcinomas by N-ethyl-N-nitrosourea or n-methyl-N'-nitro-N-nitrosoguanidine. MGMT activity was also determined in the epidermis of non-exposed mice of various stocks and strains. Epidermal MGMT activity was similar to levels in the corresponding livers and was, in general, parallel with stock/strain susceptibility to tumor formation. This is the first report that examined MGMT activity in skin tumors and normal keratinocytes in the mice of several stocks and strains.

Animals↗
PubMed1992

Alterations in the expression of uvomorulin and Na+,K(+)-adenosine triphosphatase during mouse skin tumor progression.

Uvomorulin (E-cadherin), a cell adhesion molecule, and Na+,K(+)-adenosine triphosphatase (ATPase), a marker protein of the basal-lateral cell membrane domains of polarized epithelial cells, were investigated in a group of mouse skin tumors induced by a two-stage chemical carcinogenesis protocol and in cell lines derived from mouse skin papillomas and squamous cell carcinomas (SCC). Although these two markers were present in benign tumors and in nontumorigenic cell lines, the Na+,K(+)-ATPase showed an altered pattern of distribution that included the presence of enzyme not only in the basolateral domain but also on the apical domain of the cell membrane of basal and spinous cells in well-differentiated squamous cell carcinomas (SCC). In higher grade SCC, a loss of Na+,K(+)-ATPase immunoreactivity was simultaneously detected with a marginal or absent expression of uvomorulin. The more differentiated SCC and papillomas expressed less uvomorulin immunoreactivity than normal epidermal cells. Both markers were seen in tumor cell lines that produced well-differentiated SCC after subcutaneous inoculation into nude mice. Neither Na+,K(+)-ATPase nor uvomorulin could be detected in cell lines that produced high grade, poorly differentiated SCC. Northern blots confirmed the absence of uvomorulin mRNA in these highly malignant cell lines. These data indicate that progression from premalignant papilloma to low-grade SCC and subsequently to high-grade SCC is accompanied by loss of epithelial cell polarity as detected by changes in Na+,K(+)-ATPase and by decreased or absent expression of uvomorulin in tumors and cell lines characterized by an advanced malignant phenotype.

Animals↗
PubMed1992

An animal model for oral cancer.

Human head and neck squamous cell carcinogenesis (SCC) is a common malignancy that appears to be related to continuous exposure to putative carcinogens or promoters such as tobacco and alcohol. To understand the mechanisms of the development of head and neck cancer and to test the efficiency of new therapeutic approaches, the characterization of an animal model system is necessary. The check-pouch carcinogenesis model in Syrian golden hamsters is probably the best known animal system that is most closely comparable with the development of premalignant and malignant lesions in human oral cancer. Furthermore, it is one of the most well-characterized animal system models for SCC. Our first approach to understanding the cellular and molecular changes that occur in the hamster cheek-pouch carcinogenesis process was to compare this model to the mouse-skin system, in which a number of critical events have been well characterized. We examined the sequential expression of hyperplasia, micronucleated cells, ornithine decarboxylase activity, polyamine levels, transglutaminase I activity, epidermal growth factor receptor levels, expression of several keratins, gamma-glutamyl transpeptidase, and nucleolar organizer regions. We suggest that these markers can be used to understand mechanisms of carcinogenesis and, in addition, can serve as alternative shorter end points in studies of chemoprevention. We also present preliminary molecular studies in the experimental oral model. We obtained a partial sequence of exon 2 of the Ha-ras gene and detected an A182----T transversion in codon 61 in hamster cheek-pouch SCC induced by 7,12-dimethylbenz(a)anthracene.

Animals↗