BACKGROUND: MIB-1 was found to be detectable in formalin fixed, paraffin embedded materials with microwave treatment using Ki-67 monoclonal antibody, and immunostaining has been widely documented as a useful marker of proliferation. Because atypical fibroxanthoma (AFX) is regarded as a fibrohistiocytic tumor with an intermediate potential, the proliferative activity of AFX was compared with that of benign and malignant fibrous histiocytomas. METHODS: Thirty-eight soft tissue tumors including atypical fibroxanthoma (n = 5), benign fibrous histiocytoma (FH) (n = 17) and malignant fibrous histiocytoma (MFH) (n = 16) were examined using immunohistochemistry to determine MIB-1, DNA flow cytometry, and p53 (PAb 1801) immunostaining. RESULTS: The mean of the MIB-1 labeling index (MIB-1 LI), defined as the percentage of positive cells for more than 500 cells, was determined in an increasing order as follows: FH, 3.3 +/- 1.8; AFX, 12.2 +/- 6.3; and MFH, 21.5 +/- 10.2. However, the MIB-1 LI of each case in AFX was considerably scattered, and the MIB-1 LI of AFX and MFH overlapped each other. A DNA analysis revealed that the proliferative index (S+G2+M fraction) showed no significant correlation with the MIB-1 LI, and an aneuploid pattern was present in only five (42%) of 12 cases of MFH. p53 positivity was detected in 2 (40%) of 5 cases of AFX and 6 (38%) of 16 cases of MFH. CONCLUSIONS: Although AFX shows a lower degree in the MIB-1 LI than MFH, the MIB-1 LI shows a limited value in relation to the biologic activity of fibrohistiocytic tumors. Aneuploidy demonstrates a malignant potential in fibrohistiocytic tumors.

Adult↗

PubMed1995

7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity.

The effects of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)- quinolinone (OPC-14597), a derivative of the dopamine (DA) autoreceptor agonist 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on DA receptors were biochemically and behaviorally studied and compared with those of OPC-4392. Both OPC-14597 and OPC-4392 inhibited reserpine- and gamma-butyrolactone (GBL)-induced increase in tyrosine hydroxylase activity in the mouse and rat brain. The effects of OPC-14597 were comparable to those of OPC-4392 and were completely antagonized by haloperidol. OPC-14597, unlike apomorphine, did not evoke postsynaptic DA receptor-stimulating behavioral signs such as hyperlocomotion in the reserpinized mice and contralateral rotation in rats with unilateral striatal 6-hydroxydopamine lesions. Both OPC-14597 and OPC-4392 inhibited such apomorphine-induced postsynaptic behavioral changes as stereotypy and hyperlocomotion in mice and rats and rotation in rats with unilateral striatal kainic acid lesions. The anti-apomorphine effects of OPC-14597 were about 30 to 140 times greater than those of OPC-4392 and were observed at doses that inhibit the increases in tyrosine hydroxylase activity. The affinities of OPC-14597 for 3H-spiperone-labeled D2 receptors in the rat frontal cortex, limbic forebrain and striatum were higher than those of OPC-4392. These results suggest that OPC-14597 is a unique antipsychotic drug candidate, being a DA autoreceptor agonist that has a stronger postsynaptic D2 receptor antagonistic activity than that of OPC-4392.

4-Butyrolactone↗

PubMed1995

Contribution of neutrophils and effect of monoclonal antibodies to adhesion molecules on ischemia and reperfusion injury in rat livers.

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Adenosine Triphosphate↗

PubMed1994

Fibrosarcoma versus fibromatoses and cellular nodular fasciitis. A comparative study of their proliferative activity using proliferating cell nuclear antigen, DNA flow cytometry, and p53.

We analyzed the proliferative activities, immunoreactivity of the p53 protein, and aneuploidy in patients with benign and malignant fibrous lesions, including 19 with nodular fasciitis (cellular type) (6-88 years old, mean 42.9), 11 with abdominal fibromatoses (22-74 years old, mean 37.9), 13 with extraabdominal fibromatoses (2-38 years old, mean 19.5), and 23 with fibrosarcomas (adult type: 16-71 years old, mean 47.3; infantile type: 3 months to 9 years, mean 2.9) using immunohistochemistry to determine proliferating cell nuclear antigen (PC10) and p53 protein (CM1) as well as performing DNA flow cytometry. The proliferating cell nuclear antigen (PCNA) score was measured as the ratio of PCNA-positive nuclear size/total nuclear size determined by an image analysis computer system. The distribution pattern of the PCNA-positive cells was uneven in each instance of nodular fasciitis, in contrast to the distribution in abdominal fibromatosis, extraabdominal fibromatosis, and fibrosarcoma. Both fibrosarcoma (28.4 +/- 20.0) and nodular fasciitis (33.6 +/- 20.9) exhibited a larger value and a greater variation in the PCNA score than did either abdominal (13.5 +/- 14.5) or extraabdominal fibromatosis (19.9 +/- 21.5). Abdominal fibromatosis exhibited a smaller value and less variation in the score. In short, the PCNA score did not correlate with the malignant potential. The proliferative index (S + G2 + M fraction) in fibrosarcoma was significantly higher than in either nodular fasciitis or abdominal fibromatosis. Aneuploidy was detected in five cases (26%) of fibrosarcoma, while six (26%) fibrosarcomas showed p53 positivity. Furthermore, p53-positive patients had a worse survival (0.01 < p < 0.05), and p53 positivity correlated with the proliferative index (p < 0.01). In conclusion, the PCNA score simply indicates the proliferative activity independent of malignant potential. On the other hand, p53 positivity, proliferative index, and aneuploidy are all indicators of malignant potential in fibroblastic lesions, and p53 positivity may reflect a poor prognosis.

Adolescent↗

PubMed1992

Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643).

Bemitradine (SC-33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2-year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg-1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5-15% in the female and 10-12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg-1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC-36741; desethylbemitradine) were tested and found to be non-genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/- (bemitradine only) assays. Finally, in an altered hepatic foci (Y-glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non-genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.

Animals↗

PubMed1992

Genotoxic properties of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU).

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU)is a 5-substituted 2'-deoxyuridine antiviral compound that inhibits thymidylate synthetase. The selectivity of BVDU for virus-infected cells has been attributed to phosphorylation of BVDU by a virus-induced thymidine kinase. Since the closely related compounds 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine are in vitro and in vivo mutagens, BVDU was tested for genotoxic activity in bacterial and mammalian cell mutation assays as well as in assays measuring DNA damage/repair and clastogenic activity. Mutation assays with BVDU at concentrations ranging from 10 to 5000 micrograms/plate using Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100 were negative, both with and without S9 activation. BVDU was also negative in the in vitro rat hepatocyte unscheduled DNA synthesis assay at concentrations of 750 and 1000 micrograms/ml. In contrast, BVDU was positive in the L5178Y TK +/- mouse lymphoma mutation assay without S9 activation at five concentrations ranging from 500 to 2000 micrograms/ml. A Chinese hamster ovary cell (CHO)/hypoxanthine guanine phosphoribosyl transferase gene mutation assay conducted without S9 over similar concentrations was negative. However, micronucleus induction by BVDU was detected without S9 activation at concentrations between 500 and 1750 micrograms/ml using both CHO and L5178Y cells. These results indicate that BVDU is a potential human clastogen.

Animals↗

PubMed1992

Genetic toxicology studies of an anti-AIDS drug.

SC-48334 (N-butyldeoxynojirimycin) is an experimental anti-AIDS drug which is currently in clinical trials. This drug is an aminosugar derivative. Its biological properties have been previously published [1]. Since many antiviral agents which are nucleic acid analogs exhibit mutagenic and/or clastogenic properties, the genotoxic potential of SC-48334 was examined in the Ames Salmonella/microsome assay, the Chinese hamster ovary cell/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) assay and the mouse bone marrow micronucleus assay. No toxic or mutagenic effects were observed in either the bacterial or mammalian in vitro mutation assays. Likewise, no clastogenic activity was observed in the in vivo micronucleus assay. Therefore, the administration of this drug in humans is not likely to have mutagenic effects and would probably not have a carcinogenic effect.

1-Deoxynojirimycin↗

PubMed1991

Chinese hamster ovary cell assays for mutation and chromosome damage: data from non-carcinogens.

In vitro genotoxicity tests are employed to screen chemicals for their capability to cause various DNA and chromosomal alterations, and the results are often used to predict their potential for carcinogenicity. However, there is controversy regarding the apparent low specificity of some in vitro genotoxicity assays, which result in a high false positive rate. Since we use and rely upon in vitro assays for risk assessment and prediction of carcinogenicity, this specificity issue is of serious concern to us. Hence, we selected ten compounds deemed non-carcinogens in the literature to test for the induction of gene mutation and chromosomal damage using the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) mutation assay performed concurrently with a CHO micronucleus assay. The chemical exposures for the two end-points were done simultaneously. The protocol for the two end-points was developed using the carcinogens N-methyl-N'-nitro-N-nitrosoguanidine, 3-methylcholanthrene, cyclophosphamide and 7,12-dimethylbenzanthracene. The non-carcinogens chosen were 4-nitro-o-phenylenediamine, p-phenylenediamine dihydrochloride, 3-nitropropionic acid, dichlorvos, 2-(chloromethyl)pyridine, N-(1-naphthyl)ethylenediamine 2HCl, O-anthranilic acid, 4-nitroanthranilic acid, anilazine and triphenyltin hydroxide. Each of these chemicals had been reported positive in the Ames test and/or the mouse lymphoma TK+/- mutation assay. In addition, eight of them were also reported positive in in vitro assays for chromosome aberrations and/or sister chromatid exchange (SCE). We found four of the ten chemicals negative for gene mutation and micronucleus induction without and with activation in the CHO/HGPRT mutation and CHO micronucleus assays. However, one of these four chemicals may be a potential carcinogen according to other carcinogenicity reviewers. Four other chemicals that induced only micronuclei were negative for gene mutation. Dichlorvos was positive for gene mutation and micronucleus induction without and with activation. This chemical has been shown recently to cause various tumors in rodents. One of the non-carcinogens was positive in the micronucleus test and equivocally positive in the mutation test. These results indicate that the CHO/HGPRT mutation assay may provide more relevant results than the CHO micronucleus assay, the mouse lymphoma mutation assay, or in vitro SCE and chromosome aberration assays when screening chemicals for potential carcinogenicity.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1991

Novel cerebroprotective agents with central nervous system stimulating activity. 1. Synthesis and pharmacology of 1-amino-7-hydroxyindan derivatives.

To develop a novel cerebroprotective agent with central nervous system (CNS) stimulating activity, a series of 1-amino-7-hydroxyindan derivatives was synthesized, and their effects on the survival time of mice under hypoxic conditions were tested. CNS-stimulating activity was also evaluated by examining the promotional effect on the recovery from cerebral concussion induced coma in mice. Several compounds prolonged the survival time of mice in hypoxic conditions at a dose of 30 mg/kg (sc or ip) and 100 mg/kg (po). They also exhibited the promotional effects on recovery from coma at a dose of 100 mg/kg po. The three most potent compounds in both tests, 1-amino-7-hydroxy-6-(1-methylpropyl)indan, 1-amino-7-hydroxy-4, 6-dimethyl-2-phenylindan, and 1-amino-7-hydroxy-2,2,4,6-tetramethylindan were selected for further investigations. Structure-activity relationships were also discussed.

Animals↗

PubMed1991

Novel cerebroprotective agents with central nervous system stimulating activity. 2. Synthesis and pharmacology of the 1-(acylamino)-7-hydroxyindan derivatives.

In a continuous search for a novel cerebroprotective drug with a central nervous system (CNS) stimulating activity, a series of 1-(acylamino)-7-hydroxyindan derivatives has been synthesized and tested for its dual activities. The cerebroprotective activities of the compounds in this series were evaluated in terms of their effect on the survival of mice in hypoxic conditions (210 mmHg), and their CNS stimulating activities were examined by evaluating their promotional effects on the recovery from coma induced by cerebral concussion in mice. Several compounds prolonged the survival of mice in the hypoxic conditions at a dose of 30 mg/kg po. Four compounds in this series showed the CNS-stimulating effect at the same dose. Among them, 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2,2,4, 6-tetramethylindan (18, OPC-14117), which was active in the two tests with no side effect up to 500 mg/kg po daily for 2 weeks of administration to rats, was selected for preclinical investigations.

Animals↗

PubMed1991

Evaluation of superoxide scavenging activity of OPC-14117 by electron spin resonance technique.

OPC-14117 is a potent drug which has both brain function activating effect and protective effect against cerebral ischemia. Occurrences of these effects might be expected due to superoxide dismutase-like activity of OPC-14117. The present study has been conducted to evaluate the active oxygen scavenging activity of OPC-14117 and to explain the mechanisms of its pharmacological activities. The reaction of OPC-14117 and superoxide anion, generated in potassium superoxide, was examined by electron spin resonance technique at both liquid nitrogen (77 K) and room (22 degrees C) temperatures. OPC-14117 showed a higher superoxide scavenging activity than that of alpha-tocopherol in an aprotic solvent system. The active moiety of OPC-14117 to provide the scavenging effect was found due to the phenolic hydroxyl group of its indan skeleton.

Electron Spin Resonance Spectroscopy↗

PubMed1990

Genetic toxicity of the benzene metabolite trans, trans-muconaldehyde in mammalian and bacterial cells.

Previous studies in our laboratory identified trans,trans-muconaldehyde (MUC), a six-carbon diene dialdehyde, as a microsomal metabolite of benzene. This ring-opened metabolite of benzene was also shown to be hematotoxic in mice in a manner similar to benzene. To further explore the role of MUC in relation to benzene toxicity, a number of test systems were utilized to determine its genotoxic potential. In B6C3F1 mice, MUC induced a highly significant increase in sister-chromatid exchange (SCE), the lowest effective dose being 3 mg/kg, but failed to induce any micronuclei (MN). In Chinese hamster ovary (CHO) cells, MUC at concentrations up to 0.8 micrograms/ml was negative in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) assay. Dose-related increases in the percentage of cells with MN were observed in CHO cells treated with 0.4-0.8 micrograms/ml MUC. MUC did not-cause unscheduled DNA synthesis in rat primary hepatocytes. Treatment of Salmonella typhimurium TA97 with MUC induced a low level of mutations at concentrations ranging from 10 to 70 micrograms/ml with or without S9 activation. MUC was inactive in strains TA1535, TA100, TA1538 and TA98. In CHO cells and rat primary hepatocytes, MUC was cytotoxic at 0.4 and 4.0 micrograms/ml, respectively. Concentrations of 100 micrograms/plate MUC were toxic for bacterial cells. The present findings indicate that MUC is nonmutagenic or minimally mutagenic in bacterial and mammalian in vitro systems. In mammalian cells, MUC is highly cytotoxic and genotoxic.

Aldehydes↗

PubMed1988

Evaluation of the division arrest method of the CHO/HGPRT mutation assay.

We have evaluated the division arrest method of the CHO/HGPRT mutation assay following the procedure described by O'Neill et al. Environ. Mutagen. 4, 421-434 (1982). This method simplifies the culture manipulations required during the expression period and can be readily adopted for screening mutagenic compounds. The mutation frequencies derived from the subculture method and the division arrest (no subculture) method after treatment of CHO-K1-BH4 cells with ethyl methanesulfonate were similar at all concentrations. The background mutation frequencies observed in the medium and solvent (0.5% DMSO) controls ranged from 0 to 9 colonies per 1 X 10(6) cells. Twenty to 24 h treatments, using the direct-acting compounds ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, ICR-191 acridine, 5-Bromo-2'-deoxyuridine, mitomycin C and high concentrations of thymidine produced positive mutagenic responses, while 2'-deoxyuridine and trifluorothymidine gave negative responses. Four-h treatments with Benzo[a]pyrene, diethylnitrosamine, 2-acetylaminofluorene, 3-methylcholanthrene and 2-aminoanthracene in the presence of S9 also produced positive results. Anthracene, fluorene and pyrene with S9 were negative. However we found that a toxic, non-mutagenic compound (anthracene) can yield sporadic increases in mutation frequencies (1 out of 10 replicates). Overall, our results indicate that the division arrest method of the CHO/HGPRT mutation assay can be reliably used for routine screening.

Animals↗

PubMed1988

Experimental design for the C3H/10T1/2 CL8 cell transformation assay.

The C3H/10T1/2 CL8(10T1/2) cell transformation assay has been used as an important in vitro tool for screening potential carcinogens. In this paper we describe an experimental design that increases the sensitivity and specificity of the assay. One half of the total dishes was allocated to the solvent control and the other half was equally subdivided into four treatment dose groups of low to high cytotoxic effects. The transformation frequency was calculated on the basis of the number of dishes with Type III foci. Each treatment group, as well as the pooled treatment groups, was compared to the solvent control using Fisher's exact test. The sensitivity of our design, as evaluated by power analyses, greatly exceeded that of a standard test design in which about 20 dishes are allocated to each of the control and treatment groups. Furthermore, our use of an expanded number of control and treatment dishes reduces the chance for both false positive and false negative responses. Our experimental design is illustrated with data from experiments in which the transforming potential of two drugs, dimenhydrinate and SC-32006, was examined.

Animals↗