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C J Conti

Publications and source records attributed to C J Conti.

At least 55 records · Page 3Linked to original sources
PubMed1998

Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion.

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti-beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8-OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Papillomas at high risk for malignant progression arising both early and late during two-stage carcinogenesis in SENCAR mice.

The current study was designed to further establish that most papillomas produced in SENCAR mice during two-stage skin carcinogenesis are, in fact, premalignant lesions and to specifically determine the malignant conversion potential of papillomas that arise at different times during the carcinogenesis process. A method was established to physically map and monitor the lifespan of all papillomas produced in SENCAR mice during the course of an initiation-promotion experiment using DMBA as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The results from these experiments showed that in groups of mice initiated with either 0.5 or 2.0 microg DMBA, long-term (60 weeks) treatment with TPA yielded a significantly higher number of SCCs compared to short-term treatment (7 weeks). Papillomas that emerged after 11 weeks and thereafter in all treatment groups had the ability to progress to SCCs. The median conversion time for all papillomas in all groups was 26 weeks. When corrected for median conversion time, papillomas that emerged in week 11 and thereafter in all treatment groups had similar or greater conversion ratios compared to those that emerged within the first 10 weeks. Interestingly, the median conversion time was significantly shorter (18 versus 27 weeks, respectively; P<0.0002) for papillomas that emerged in week 11 and thereafter compared to those that emerged at or prior to 10 weeks for all groups. The data in this study demonstrate that papillomas arising throughout a two-stage carcinogenesis protocol in SENCAR mice progress to SCCs. Many papillomas that arise later in two-stage carcinogenesis protocols do not have sufficient time to allow for conversion and should be excluded from the analyses. Furthermore, another novel finding of the current study was the observation that papillomas arising later in the two-stage protocol (>11 weeks) progressed to SCCs at a faster rate than those that arose earliest in the protocol.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Synchronized proliferation induced by 12-O-tetradecanoylphorbol-13-acetate treatment of mouse skin: an in vivo model for cell cycle regulation.

Much of what is known about the mammalian cell cycle comes from studies using established cell lines in culture. In this study, cell cycle-regulatory events were analyzed in vivo after treatment of mouse epidermis with 12-O-tetradecanoylphorbol-13-acetate. A synchronized wave of basal keratinocyte proliferation occurred; over 80% of the cells were in S phase 15 h after treatment. c-myc protein expression was induced, and p57Kip2 protein levels dropped early after stimulation. Before S phase, cyclin D1 and cyclin-dependent kinase (CDK) 6 levels increased, and expression of cyclins E and A was induced. Rb was phosphorylated in late G1, and this correlates with the formation of cyclin D1/CDK4 and cyclin D1/CDK6 complexes. At the end of S phase, the p57Kip2 and p21Cip1 protein levels increased. These findings demonstrate that stimulation of basal epidermal cells by 12-O-tetradecanoylphorbol-13-acetate results in several classic cell cycle events and suggests that p57Kip2 plays a key role in regulating proliferation in the epidermis.

Animals↗
PubMed1997

Loss of heterozygosity on murine chromosome 6 in two-stage carcinogenesis: evidence for a conserved tumor suppressor gene.

We have recently demonstrated that loss of heterozygosity (LOH) at 7q31 is frequent in many kinds of human primary tumors and that introducing a single human chromosome (hchr) 7 into a murine squamous cell carcinoma (SCC)-derived cell line suppresses the malignant phenotype. To investigate whether the putative tumor suppressor gene on hchr 7 is conserved in mice, we studied LOH on mouse chromosome (mchr) 6 in chemically induced SCCs in (C57BL x DBA2) F1 (B6D2F1) females. LOH analysis was performed by polymerase chain reaction amplification of 17 (CA)n microsatellite repeats in mchr 6 A1-C3. As expected, all the B6D2F1-derived tumors were informative for all the locus assayed. The highest percentage of LOH in the hchr 7q-homologous segment was found at D6Mit50 (60.0%) and the other markers in this segment had LOH incidences normally distributed around the peak. The high incidence of LOH in the tumors studied suggests that a tumor suppressor gene relevant to the development of epithelial cancers is present on mchr 6 A2. As this segment is homologous with hchr 7q31, these data suggest that the putative tumor suppressor gene is conserved in the two species and explains the suppression of tumorigenicity when a single hchr 7 is introduced to a murine SCC cell line.

Animals↗
PubMed1997

Increased apoptosis during papilloma development in mice susceptible to tumor progression.

Programmed cell death (apoptosis) is known to occur not only during normal development and tissue remodeling but also during neoplasia. Despite the suggested role of apoptosis in preventing the proliferation of malignant cells, a positive correlation between tumor progression and the presence of apoptotic cells has been found in different types of cancer, including epithelial tumors. In normal mouse skin, the role of apoptosis is not completely understood, and it has been suggested that terminal differentiation may be a special case of apoptosis. In the work reported here, we counted apoptotic cells in mouse skin tumors generated with a two-stage chemical carcinogenesis protocol. We analyzed papillomas from outbred SENCAR mice at different times during promotion, and to better determine the correlation between apoptosis and tumor progression, we compared papillomas generated from two inbred strains derived from the SENCAR stock that differ in their susceptibility to tumor progression. Our results showed that in mouse skin chemical carcinogenesis, the number of apoptotic cells was greater in papillomas that may have been in the process of progressing to squamous cell carcinomas. This conclusion is also supported by the fact that papillomas from SENCAR P/Bt. mice, a tumor progression-susceptible strain derived from outbred SENCAR mice, had more apoptotic cells than papillomas from progression-resistant SSIN mice.

Animals↗
PubMed1997

Evidence that initiated keratinocytes clonally expand into multiple existing hair follicles during papilloma histogenesis in SENCAR mouse skin.

We have previously shown that the precursors of cutaneous papillomas in SENCAR mice initiated with 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate are focal hyperplastic lesions that we refer to as squamous cell hyperplastic foci (SCHF). Ha-ras gene codon 61 mutations were frequently found in SCHF, providing evidence that these lesions represent clones of initiated cells. We report here the pathogenesis of multiple hair follicle involvement in more advanced SCHF and describe the role of the hair follicle in papilloma histogenesis. Detailed histological evaluation of 83 SCHF and 25 early papillomas revealed a morphological continuum from the least developed SCHF, involving only one hair follicle, to advanced SCHF and early papillomas, which involved more than 10 hair follicles. These results provide evidence of the recruitment of additional hair follicles as SCHF progress. In advanced SCHF and early papillomas the bulk of the epithelial component in all cases consisted of several markedly hyperplastic adjacent hair follicles, whereas the involved interfollicular epidermis (IFE) was generally less hyperplastic. All of the hair follicles involved in SCHF appeared to have been preexisting, based on their pattern of spacing, that they were consistently normal appearing below the level of the sebaceous glands, and that they were in the same phase of the hair cycle as surrounding, uninvolved hair follicles. Also, no evidence of follicular neogenesis was observed in serially sectioned SCHF, and coalescence of smaller lesions was rare. To investigate whether the involvement of multiple hair follicles in SCHF was due to expansion of initiated cells into existing hair follicles or, possibly, to a paracrine mechanism, we analyzed different levels of three serially sectioned SCHF and one early papilloma for Ha-ras mutations. These analyses revealed cells with Ha-ras gene codon 61 mutations at multiple levels that involved different hair follicles. Overall, our results provide evidence that as initiated cells clonally expand, they spread across the IFE and populate the upper permanent portions of existing hair follicles. The abnormal proliferation of the infundibula of the hair follicles involved in SCHF appears to give rise to most of the epithelial component of papillomas.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Transplantation analyses of the immunogenicity of epidermal tumors generated in murine skin two-stage carcinogenesis protocols.

SSIN mice are very sensitive to tumor promoters in two-stage skin carcinogenesis protocols. It was recently reported that SSIN mice have fewer CD8+ T-cells than other strains of mice and develop a weaker cytotoxic T-cell response upon challenge with an allogeneic tumor transplant. The significance of this muted immune response to processes involved in two-stage carcinogenesis depends on the immunogenicity of the tumors generated in such protocols. Although they have low CD8+ T-cell contents, SSIN rejected a variety of subcutaneously transplanted allogeneic murine tumors. Analyses of the growth of primary papillomas derived from 7,12-dimethylbenz[a]anthracene-initiated/12-O-tetradecanoylphorbol-13-ac etate-promoted SSIN mice and then subcutaneously transplanted into triple-deficient (bg-nu-xid), athymic nude and immune-competent and immunosuppressed SSIN mice revealed that few tumors took and tumor takes were not markedly influenced by the immumological status of the transplant recipient. Two tumor cell lines (RS1 and RS2) were derived from the transplantation studies and could be passaged in normal SSIN mice (H-2q haplotype). Both tumors were squamous cell carcinomas (SCCs) by the second in vivo passage and were rejected in allogeneic mice (BALB/c) but grew in FVB/N mice, a strain having the H-2q haplotype. Transplantation studies revealed that prior exposure to RS1 and RS2 did not prime SSIN mice to reject a subsequent tumor challenge. Three primary SCC tumors derived from SSIN mice in a two-stage carcinogenesis protocol also grew when subcutaneously transplanted in SSIN mice and could be serially passaged. Consequently, the epidermal SCCs that develop in two-stage carcinogenesis protocols appear to be nonimmunogenic.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Effect of spray-dried yogurt and lactic acid bacteria on the initiation and promotion stages of chemically induced skin carcinogenesis in mice.

The effects of dietary spray-dried yogurt powder product (YPP) and two strains of lactic acid bacteria on the initiation and promotion stages of carcinogenesis were investigated using the 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model. In two independent studies, Sencar mice were fed a diet containing 86%, 43%, or 0% YPP or the 0% YPP diet supplemented with viable cultures of Lactobacillus acidophilus or bifidobacteria. Animals were initiated with a single topical application of DMBA (10 nmol). Promotion began three weeks later with twice weekly treatment of TPA (1 microgram/200 microliters acetone). During the initiation study (Study 1) the experimental diets were fed for four weeks before and one week after DMBA treatment. All mice were then switched to the AIN-76 diet. For the promotion study (Study 2) the experimental diets were begun one week after initiation and fed during the remainder of the study. Gross appearance of tumors was assessed weekly. No statistically significant differences in body weight or food disappearance were observed among the diet groups during the studies. For Studies 1 and 2, final histologically verified papilloma incidence and multiplicity and carcinoma incidence were not statistically different. These data suggest that different levels of YPP or lactic acid bacteria fed during the initiation or promotion stage of carcinogenesis do not significantly affect chemically induced skin tumor development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Induction of mammary cancer and lymphoma by multiple, low oral doses of 7,12-dimethylbenz[a]anthracene in SENCAR mice.

Existing models of mouse mammary carcinogenesis induced by the model polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) typically use a small number of bolus doses applied intragastrically. In contrast to this, typical human exposures to carcinogens are thought to be at lower doses and to occur with chronic or sporadic timing. When the classical dosage (1 mg DMBA given once a week for 6 weeks) was split into five daily doses of 200 microg given intragastrically to female SENCAR mice each week for 6 weeks, toxicity was high and the major tumor type seen was lymphoma. Lowering the dose to 60 microg/day gave less toxicity, a 75% incidence of lymphoma and a 30% incidence of mammary carcinoma. However, 20 microg DMBA given five times per week for 6 weeks resulted in a 65-70% incidence of mammary carcinoma within approximately 50 weeks. This represents a 50-fold lower daily dosage of DMBA than that used in the classical model. DNA was prepared from 10 mammary adenocarcinomas and 10 lymphomas and exons 1 and 2 of the H-ras1, K-ras and N-ras genes were sequenced using PCR techniques. Mutations altering codons 12 or 61 of one of the ras family genes were found in 4/10 mammary carcinomas and 5/10 lymphomas. Three mammary tumors exhibited codon 61 mutations, one in each of the genes studied, and a fourth tumor contained a codon 12 mutation in the K-ras gene. Among the lymphomas, two mutations in codon 12 of K-ras, one mutation in codon 61 of K-ras and two mutations in codon 61 of N-ras were also found. Each of the mutations could be interpreted as a G-->T or A-->T transversion. It is suggested that the high incidence of lymphoma at the higher, repetitive doses may be related to immunotoxicity. These low dose models of lymphomagenesis and mammary carcinogenesis should prove useful for tests of chemopreventive agents that target the initiation phase of carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

During development, 17alpha-estradiol is a potent estrogen and carcinogen.

Neonatal administration of estradiol-17beta (E2-17beta) increases the nuclear DNA content in the mouse reproductive tract. Similar responses have been demonstrated for synthetic estrogens such as diethylstilbestrol. One of the questions raised regarding environmental estrogens such as organochlorines is whether they are potent enough to result in abnormal changes such as those demonstrated by both natural and synthetic estrogens. To test this hypothesis, female BALB/c mice were treated neonatally (days 1-5) with either E2-17beta or estradiol-17alpha (E2-17alpha), an inactive stereoisomer in adult reproductive tissues. We also proposed whether neonatal administration of (E2-17alpha) was tumorigenic and whether the effects were age dependent. To answer these questions, one set each of 10 day-old treated and control mice received short-term secondary administration of E2-17beta, E2-17alpha, or cholesterol. Cervicovaginal tracts from intact BALB/c mice were examined histologically and by flow cytometry at 70 days of age and by histology alone at 18 to 22 months of age. The results include several important findings: a) like E2-17beta, neonatal E2-17alpha treatment induced persistent vaginal cornification, hypospadias, vaginal concretions, and hyperproliferation in nearly 100% of the animals regardless of the secondary treatment for most groups; b) neonatal E2-17alpha treatment increased the nuclear DNA content of cervicovaginal epithelium at one-half both the level (mean DNA index of 1.02 vs 1.04) and incidence (22 vs 46% of the animals) of E2-17beta; c) short-term secondary treatment with E2-17alpha, unlike E2-17beta, did not significantly augment the increase in DNA content (13% for E2-17alpha vs 37 and 56% for control and E2-17beta, respectively); and d) neonatal administration with E2-17alpha induced adenosquamous tumors in the reproductive tract in 25% of the animals. Therefore, the biological effects (estrogenic potency) of E2-17alpha may be age dependent.

Animals↗
PubMed1997

Changes in protein expression during multistage mouse skin carcinogenesis.

To directly compare the expression patterns of different proteins known to be altered during mouse skin carcinogenesis, serial sections of normal and hyperplastic skin and tumors from various stages of 7,12-dimethylbenz[a]anthracene-initiated, 12-O-tetradecanoylphorbol-13-acetate-promoted female SENCAR mice were examined by immunohistochemistry. In untreated, normal mouse skin, keratin 1 (K1) and transforming growth factor-beta1 (TGFbeta1) were strongly expressed in the suprabasal layers, whereas integrin alpha6beta4 was expressed only in basal cells and only moderate staining for transforming growth factor-alpha (TGFalpha) was seen. In hyperplastic skin, TGFalpha expression became stronger, whereas expression of another epidermal growth factor (EGF) receptor ligand, heparin-binding EGF-like growth factor (HB-EGF), was strongly induced in all epidermal layers from no expression in normal skin. Likewise, the gap-junctional protein connexin 26 (Cx26) became highly expressed in the differentiated granular layers of hyperplastic skin relative to undetectable expression in normal skin. Expression of cyclin D1 in the proliferative cell compartment was seen in all benign and malignant tumors but not in hyperplastic skin. Beginning with very early papillomas (after 10 wk of promotion), expression of alpha6beta4 in suprabasal cells and small, focal staining for keratin 13 (K13) were seen in some tumors. Later (after 20-30 wk), focal areas of gamma-glutamyl transpeptidase (GGT) activity appeared in a few papillomas, whereas TGFbeta1 expression began to decrease. Cx26 and TGFalpha staining became patchier in some late-stage papillomas (30-40 wk), whereas suprabasal alpha6beta4, K13, and GGT expression progressively increased and K1 expression decreased. Finally, in squamous cell carcinomas (SCCs), there was an almost complete loss of K1 and a further decline in TGFalpha, HB-EGF, TGFbeta1, and Cx26 expression. On the other hand, almost all SCCs showed suprabasal staining for alpha6beta4 and widespread cyclin D1 and K13 expression, whereas only about half showed positive focal staining for GGT activity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels.

Angiogenesis is a crucial process for tumor growth and metastasis regulated by the balance of positive and negative factors. Vascular endothelial growth factor (VEGF/VPF) is a specific mitogen for endothelial cells that has been shown to be overexpressed in a variety of tumors and other inflammatory diseases. To analyze the implication of VEGF/VPF during tumorigenesis, we have studied its expression at different stages of tumor development using the mouse skin carcinogenesis model. VEGF/VPF mRNA was induced in skin in vivo after 12-O-tetradecanoylphorbol-13-acetate treatment. Constitutive up-regulation of VEGF/VPF at the mRNA and protein levels was also observed in premalignant papillomas and, at a higher level, in squamous carcinomas, suggesting a correlation between VEGF/VPF expression and tumor progression. A direct positive correlation between VEGF/VPF mRNA expression and the level of activated H-ras gene was found in a series of cell lines representing different stages of epidermal tumor development. Consequently, a clone of one of these cell lines, HaCa4, which has lost most of its v-ras expression, down-regulated VEGF mRNA expression concomitantly with its metastatic potential. Direct evidence of H-ras involvement in VEGF induction was obtained when an immortalized mouse keratinocyte cell line transduced with a retrovirus carrying v-H-ras showed highly increased VEGF/VPF mRNA levels. These data show that in mouse skin carcinogenesis, the VEGF/VPF angiogenic stimulus occurs early during premalignant papilloma development and further increases at later stages. Moreover, we demonstrate that increasing the activated H-ras dose, a phenomenon that takes place sequentially throughout mouse skin tumor development, may play an additional role by facilitating malignant in vivo progression through the modulation of VEGF/VPF-mediated angiogenesis.

Animals↗
PubMed1996

Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia.

To study the involvement of cyclin D1 in epithelial growth and differentiation and its putative role as an oncogene in skin, transgenic mice were developed carrying the human cyclin D1 gene driven by a bovine keratin 5 promoter. As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartment of the thymus expressed aberrant levels of cyclin D1. The rate of epidermal proliferation increased dramatically in transgenic mice, which also showed basal cell hyperplasia. However, epidermal differentiation was unaffected, as shown by normal growth arrest of newborn primary keratinocytes in response to high extracellular calcium. Moreover, an unexpected phenotype was observed in the thymus. Transgenic mice developed a severe thymic hyperplasia that caused premature death due to cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representing 10% of total body weight. The hyperplastic thymi had normal histology revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distribution of thymocyte subsets. These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin D1 can modulate epithelial proliferation without altering the initiation of differentiation programs. No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of life, although they continue under observation. This model provides in vivo evidence of the action of cyclin D1 as a pure mediator of proliferation in epithelial cells.

Aging↗
PubMed1996

p53, Rb, and cyclin D1 expression in human oral verrucous carcinomas.

BACKGROUND: The verrucous carcinoma (VC), a tumor with low grade malignancy, appears to be associated with tobacco and human papillomavirus. The pathobiology of these tumors has not been extensively studied, and molecular genetic alterations have not been reported. In this study we investigated by immunohistochemistry the expression of p53, Rb, and cyclin D1 in a series of well-defined oral VC. Changes in the expression of these genes have been commonly reported in a variety of human tumors. METHODS: We studied 29 cases of VC, fixed in formalin and embedded in paraffin. Immunohistochemistry was carried out using the avidin-biotin immunoperoxidase technique. Polyclonal antibody CM-1 was used for p53, a rabbit polyclonal human RB antibody, Rb-WL-1 antibody for Rb and a rabbit polyclonal human cyclin D antibody for cyclin D1. RESULTS: Positive p53 expression (protein accumulation) was detected in 15 of the 29 VC analyzed. In some cases, p53-positive areas were small foci but in most of the cases extensive positive areas were observed. None of the cases studied showed alterations of Rb protein. The expression of cyclin D1 was determined in 18 cases of VC. Positive nuclear immunostaining was seen in 11 cases. CONCLUSIONS: p53 protein accumulation is frequently observed in these tumors suggesting possible mutations of this gene in VC. Overexpression of cyclin D1 but no alterations of Rb staining were also observed in this low grade tumor suggesting that Rb may be functionally inactivated by overexpression of cyclin D1 or HPV infection.

Adult↗
PubMed1996

Characterization of mutant HA-ras gene expression in transformed murine keratinocyte lines grown under in vitro and in vivo conditions.

We investigated the Ha-ras and Ki-ras gene status, tumorigenicity, pathology, line derivation, and intercellular communication of 7,12-dimethylbenz[a]anthracene-initiated papilloma-, carcinoma-, and hyperplastic skin-producing cell lines to further characterize them. Six of nine tumor cell lines grown in vitro expressed both mutant and normal Ha-ras proteins, and three lines expressed only normal Ha-ras. However, when grown subcutaneously in nude mice, seven of the nine lines expressed both mutant and normal Ha-ras, one line expressed normal Ha-ras, and one line did not grow subcutaneously. One papilloma line, P2/15, appeared to have an inducible mutant Ha-ras gene, as it was expressed only in vivo. These findings suggest that mutant Ha-ras genes may be lost in only a minor population of tumor lines during growth in culture. Finally, we found that mutant Ha-ras gene expression was strongly correlated with tumorigenicity in nude mice and that intercellular communication was strongly correlated with the derivation of the lines.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Comparison of ultraviolet light-induced skin carcinogenesis and ornithine decarboxylase activity in sencar and hairless SKH-1 mice fed a constant level of dietary lipid varying in corn and coconut oil.

To investigate the effect of various levels of corn oil and coconut oil on ultraviolet (UV) light-induced skin tumorigenesis and ornithine decarboxylase (ODC) activity, Sencar and SKH-1 mice were fed one of three 15% (weight) fat semipurified diets containing three ratios of corn oil to coconut oil: 1.0%:14.0%, 7.9%:7.1%, and 15.0%:0.0% in Diets A, B, and C, respectively. Groups of 30 Sencar and SKH-1 mice were fed one of the diets for three weeks before UV irradiation; then both strains were UV irradiated with an initial dose of 90 mJ/cm2. The dose was given three times a week and increased 25% each week. For Sencar mice (irradiated 33 wks for a total dose of 48 J/cm2), tumor incidence reached a maximum of 60%, 60%, and 53% for Diets A, B, and C, respectively, with an overall average of one to two tumors per tumor-bearing animal. For the SKH-1 mice (irradiated 29 wks for a total dose of 18 J/cm2), all diet groups reached 100% incidence by 29 weeks, with approximately 12 tumors per tumor-bearing mouse. No significant effect of dietary corn oil/coconut oil was found for tumor latency, incidence, or yield in either strain. The effect of increasing corn oil on epidermal ODC activity in chronically UV-irradiated Sencar and SKH-1 mice was assessed. Three groups of mice from each strain were fed one of the experimental diets and UV irradiated for six weeks. Sencar mice showed no increase in ODC activity until six weeks of treatment, when the levels of ODC activity in the UV-irradiated mice fed Diet A were significantly higher than those in mice fed Diet B or Diet C: 1.27, 0.55, and 0.52 nmol/mg protein/hr, respectively. In the SKH-1 mice, ODC activity was increased by the first week of UV treatment, and by three weeks of treatment a dietary effect was observed; ODC activity was significantly higher in mice fed Diet C (0.70 nmol/mg protein/hr) than in mice fed Diet A (0.18 nmol/mg protein/hr). Although there was no significant effect of dietary corn oil/coconut oil on UV-induced tumor incidence, the data indicate that chronically UV-irradiated hairless SKH-1 mice are more susceptible to UV-induced skin carcinogenesis than Sencar mice and that this susceptibility is correlated with increased in ODC activity, a parameter of cell proliferation.

Animals↗
PubMed1996

Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice.

The present study was designed to test the effects of a free radical generating tumor promoter, chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone), on the growth and progression of papillomas generated in the skin of SENCAR mice. In the first set of experiments, papillomas were generated by initiation with 6.4 microg of 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with once-weekly applications of 52.8 microg chrysarobin for 10 weeks. The fate of individual papillomas was then monitored for a 20 week interval following cessation of promoter treatment. Five weeks after the cessation of chrysarobin treatment, the papilloma response reached a maximum of 13.2 papillomas/mouse. By the end of the 20 week interval 19% and 18% of the papillomas had regressed or coalesced respectively. A three-stage treatment protocol was also utilized to test the ability of chrysarobin to enhance the progression of pre-existing papillomas to squamous cell carcinomas (SCCs). In stage I, mice were initiated with 0.5 microg of DMBA. In stage II, mice were promoted with twice-weekly applications of 1 or 2 microg of 12-0-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. Then, in stage III, mice were treated with acetone, TPA (1 or 2 microg), chrysarobin (52.8 microg) or benzoyl peroxide (BzPo; 20 mg) for the next 45 weeks. The mean number of papillomas per mouse at plateau was very similar for all groups. The carcinoma incidence was also similar for all groups regardless of the treatment protocol used, as was the mean number of carcinomas per mouse. The ratio of papillomas that converted to SCCs in mice treated with chrysarobin during stage III was not significantly different from the acetone controls or any of the other treatment groups (P > 0.05, Kruskal-Wallis analysis). In addition, BzPo did not enhance the progression of papillomas to SCCs under the current experimental conditions. Collectively, the results indicate that papillomas promoted by chrysarobin have growth properties similar to those promoted by TPA under similar experimental conditions. Furthermore, despite its ability to generate free radical intermediates, chrysarobin does not enhance the malignant progression of pre-existing papillomas induced by TPA treatment.

9,10-Dimethyl-1,2-benzanthracene↗