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S Fukushima

Publications and source records attributed to S Fukushima.

At least 55 records · Page 3Linked to original sources
PubMed2000

Chemopreventive effects of S-methylcysteine on rat hepatocarcinogenesis induced by concurrent administration of sodium nitrite and morpholine.

The aim of the present study was to examine the chemopreventive efficacy of S-methylcysteine (SMC) on rat hepatocarcinogenesis induced by concurrent administration of sodium nitrite (NaNO(2)) and morpholine (Mor) using a medium-term rat liver carcinogenesis bioassay (Ito test). Administration of SMC caused significant reduction in the areas of glutathione S-transferase placental form positive foci along with a significant decrease of hepatocyte 5-bromo-2'-deoxyuridine (BrdU) labeling indices. These results demonstrated potent chemopreventive effects of SMC against hepatocarcinogenesis due to concurrent administration of Mor and NaNO(2). SMC could thus be an effective chemopreventive agent for decreasing the risk of carcinogenicity from environmental precursors of N-nitroso compounds.

Animals↗
PubMed2000

Preparation and evaluation of o/w type emulsions containing antitumor prostaglandin.

Antitumor prostaglandins(PGs) such as Delta12-PGJ2 and Delta7-PGA1 possess a cyclopentenone or cross-conjugated dienone structures. Antitumor PGs are actively incorporated through cell membrane and control gene expression. Very recent studies clarified that P53 independent expression of p21 and gadd 45, activation of PPARgamma are involved in antitumor mechanism of these PGs. At the low concentration, these PGs exhibit physiological or pathological activity such as osteoblast calcification, promotion of colon cancer cell proliferation. COMPARE PROGRAM using human 38 tumor cell lines suggested that antitumor mechanism of Delta7-PGA1 and 13, 14-dihydro-15-deoxy-Delta7-PGA1 methyl ester (TEI-9826) are quite different from other anticancer agents which are clinically used. Lipid microspheres and Lipiodol formulation were examined as dosage form of the PGs and lipid microspheres were selected for further study. At first lipid microspheres integrated TEI-9038 (Lipo TEI-9038) was chosen as a candidate for clinical trial. However Lipo TEI-9038 failed to exhibit substantial antitumor effect because of its enzymatic instability and toxicity in vivo. Lipo TEI-9826 was then selected as promising candidate for clinical trial because of its stability in serum. Lipo TEI-9826 exhibited marked antitumor effect in several animal models including CDDP resistant nude mice model. Pharmacokinetic and toxicological studies using rats suggested that continuous infusion is the most suitable administration method for Lipo TEI-9826. New type emulsifier, Controlled High Pressure Process Homogenizer (De-BEE 2000 and mini De-BEE) was developed during the preclinical studies on manufacturing process of Lipo TEI-9826. These results warrant the clinical trial for Lipo TEI-9826 in CDDP resistant cancer.

Animals↗
PubMed2000

Increased oxidative stress with gene alteration in urinary bladder urothelium after the Chernobyl accident.

We have previously shown that bladder urothelium of people living in the cesium-137 ((137)Cs)-contaminated areas of Ukraine demonstrates accumulation of stable p53 and p53 mutational inactivation, preferentially through G:C to A:T transition mutations at CpG dinucleotides, with a codon 245 hot spot. In the present study, we analyzed immuno-histochemically the relationship between oxidative stress markers and over-expression of p53 and H-ras in urinary bladder urothelium from 42 men with benign prostatic hyperplasia. Bladder mapping biopsies were obtained from 15 patients from a highly radiocontaminated area (group I), 14 patients from the less contaminated city of Kiev (group II) and 13 patients as a control group from "clean" (without radiocontamination) areas of Ukraine (group III). Irradiation cystitis with multiple foci of severe dysplasia and carcinoma in situ were observed in 15 of 15 (100%, group I) and 9 of 14 (64%, group II) cases, with 4 small transitional-cell carcinomas incidentally detected in groups I and II. Markedly elevated levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and 8-hydroxy-2;-deoxyguanosine (8-OHdG) were noted in these bladder urothelial lesions from groups I and II, accompanied by strong over-expression of p53 and less H-ras expression. These findings support the hypothesis that iNOS, COX-2 and 8-OHdG in bladder urothelium are induced by long-term exposure to low-dose radiation with a close relationship to p53 over-expression that could predispose to bladder carcinogenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Synchronous multiple primary gastrointestinal cancer exhibits frequent microsatellite instability.

Colorectal (CRC) and gastric cancers (GC), the most common gastrointestinal malignancies, have been known to develop occasionally in a same patient. Previous studies have focused on the etiology of patients with multiple primary gastric and colorectal cancer (MPGCC); however, the carcinogenic process of MPGCC remains unclear. In this study, we have examined the genetic alterations in MPGCC in order to clarify the carcinogenic pathway. Twenty patients with sporadic MPGCC were examined for microsatellite instability (MSI) and frameshift mutations of target genes such as TGFbetaRII, BAX and IGFIIR. In 10 (50%) of 20 patients with MPGCC, MSI was present at least at 1 lesion of GC or CRC. Four (50%) of 8 cases with synchronous MPGCC displayed MSI in both GC and CRC, while only 1 (8%) of 12 cases of metachronous MPGCC exhibited MSI in both organs. Carcinogenic process of MPGCC was fairly associated with the MSI pathway, particularly in cases of synchronous MPGCC. MSI was found in 5 (25%) of 20 GCs and in 10 (50%) of 20 CRCs. MSI was involved more closely in CRC than in GC among MPGCC. Although most frameshift mutations at target genes were found in the MSI-positive MPGCC, infrequent mutations were observed in the genes. Frameshift mutation was found in only 1 of 5 cases of MSI-positive GC at TGFbetaRII. Only 2 of 10 cases of CRC with MSI showed mutation at TGFbetaRII, and 1 case also showed mutation at BAX and IGFIIR. Our findings suggest that TGFbetaRII, BAX and IGFIIR are not the main target genes for carcinogenesis in MSI-positive MPGCC.

Aged↗
PubMed2000

Doxorubicin-loaded poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance.

Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o/w emulsion method with a substantial drug loading level (15 to 20 w/w%). DOX-loaded micelles were narrowly distributed in size with diameters of approximately 50-70 nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped in the micelle, the former seems to improve micelle stability due to its low water solubility and possible interaction with benzyl residues of PBLA segments through pi-pi stacking. Release of DOX compounds from the micelles proceeded in two stages: an initial rapid release was followed by a stage of slow and long-lasting release of DOX. Acceleration of DOX release can be obtained by lowering the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from the micelles. A remarkable improvement in blood circulation of DOX was achieved by use of PEG-PBLA micelle as a carrier presumably due to the reduced reticuloendothelial system uptake of the micelles through a steric stabilization mechanism. Finally, DOX loaded in the micelle showed a considerably higher antitumor activity compared to free DOX against mouse C26 tumor by i.v. injection, indicating a promising feature for PEG-PBLA micelle as a long-circulating carrier system useful in modulated drug delivery.

Adenosarcoma↗
PubMed2000

Organ-specific, carcinogen-induced increases in cell proliferation in p53-deficient mice.

Transgenic mice with germ-line p53 alleles disrupted by gene targeting are sensitive to the development of some spontaneous tumors and have provided researchers with much information with respect to cancer. In the present study, to cast light on the organ specificity of chemically induced carcinogenesis, we evaluated carcinogen-induced cell proliferation in target organs in heterozygote p53 knockout mice (p53-deficient mice). Groups of 9- or 10-week-old wild-type(+/+) and p53-deficient mice were respectively treated with one of the following carcinogens for 4 weeks: N-butyl-N-(4-hydroxybutyl)nitrosamine (0.0075% in drinking water); dimethylnitrosamine (0.001% in drinking water); dihydroxy-di-N-propylnitrosamine (0.1% in drinking water); 1,2-dimethylhydrazine (10 mg/kg body weight s.c. injection once a week); 4-nitroquinoline 1-oxide (4-NQO, 10 mg/kg b.w. s.c. injection once a week); or 7,12-dimethylbenz(a)anthracene (25 microg/kg body weight dermal application once a week). Cell proliferation was evaluated by measuring the 5-bromo-2'-deoxyuridine labeling indices in each target organ. The p53 and p21 statuses were evaluated by comparing the expressions of p53 protein, p21waf1/cip1 mRNA, and p21waf1/cip1 protein between the mice. 5-Bromo-2'-deoxyuridine labeling indices of the urinary bladder and the skin were significantly increased in p53-deficient mice as compared with the wild-type(+/+) mice. In the all organs examined, carcinogen-induced p21waf1/cip1 mRNA overexpression was detected with levels obviously lower in the p53-deficient animals. These data suggest that p53-deficient mice have an organ-specific increased sensitivity to the induction of cell proliferation in the urinary bladder and the skin. These are the same organs for which sensitivity to carcinogenesis has been reported. Because a decrease of p21waf1/cip1 protein overexpression was also observed in the organs in which cell proliferation did not appreciably differ from the level in wild-type(+/+) mice, this decrease might have no effect on sensitivity to cell proliferation and carcinogenesis. Alternatively, it might play an important role in the cell cycle regulation of only the sensitive organs.

Animals↗
PubMed2000

Inhibition of chemically induced liver carcinogenesis in Wistar rats by garlic (Allium sativum).

The effects of garlic on diethylnitrosoamine (DEN)-induced hepatocarcinogenesis were examined in male Wistar rats using the medium term bioassay system of Ito based on the two-step model of hepatocarcinogenesis. Carcinogenic potential was scored by comparing the number and area/cm(2) of induced glutathione S-transferase placental form (GST-P) positive foci in the liver with those of the corresponding group (control) of rats given diethylnitrosoamine alone. Treatment with garlic (therapeutic dose 20 mg/kg body wt/day) reduced significantly the number (50% reduction, p < 0.003) and area (48% reduction, p < 0.0007) of GST-P positive foci compared with the control group of animals receiving distilled water. Histopathological examination of rat livers using H & E staining indicated that there was no significant difference between the control group and the garlic treated group in the two pathological parameters namely granularity and vacuolation of the cytoplasm. Our results provide strong supportive evidence for the anticarcinogenic activity of garlic.

Animals↗
PubMed2000

Concomitant aortic root remodeling and coronary bypass in a patient with poor left ventricular function.

A 58-year-old man who had previously undergone rectal cancer surgery and who had poor left ventricular function underwent concomitant aortic root remodeling and coronary bypass for aortic root aneurysm with aortic regurgitation and severe coronary artery disease. Intermittent retrograde cold blood cardioplegia and leukocyte-depleted terminal blood cardioplegia were used for myocardial protection. Angiographic studies 1 month after surgery showed improved left ventricular function at an ejection fraction from 24 to 46%. During a 1-year follow-up, he has remained free of any cardiac event. Even though this report is limited to a case and follow-up, this technique is expected to be beneficial even in patients with severely depressed left ventricular function when the postoperative quality of life is considered.

Aortic Aneurysm↗
PubMed2000

N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test.

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is may be initiated or precipitated by endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. The higher cerebrospinal fluid levels of N-methylated azaheterocyclic amines, such as beta-carboline and tetrahydroisoquinoline, have been found in parkinsonian patients compared with age-matched controls. To estimate the N-methylation ability for azaheterocyclic amines in parkinsonian patient, nicotinamide was dosed with 100 mg to 26 parkinsonians and 20 controls consisted of 16 other neurogenic disease patients and 4 healthy volunteers. The urine was collected for 4 h, and then analyzed urinary its metabolites by an improved HPLC method. Nicotinamide has a pyridine ring in its structure and may be metabolized through the pathways similar to those for the endogenous neurotoxins. The urinary excretions of nicotinamide metabolites were significantly affected by aging. The excretion of N1-methylnicotinamide decreased along with aging both in PD patients and controls. In younger (65 years old or younger) PD patients, the excretion amount of N1-methylnicotinamide was significantly higher than that in younger controls. The decline rate of N1-methylnicotinamide excretion in parkinsonians was significantly greater than that in controls; the rate is more than 2-fold higher in parkinsonian patients. The age-associated decrease in 1-methyl-2-pyridone-5-carboxyamide excretion was observed only in parkinsonian patients, but not in controls. The total excreted amount of N-methylated metabolites (N1-methylnicotinamide plus 1-methyl-2-pyridone-5-carboxyamide) was also observed the age-related decline in both groups. The urinary excretions of nicotinamide and nicotinamide-N-oxide were not influenced by aging. These results would indicate that the excess N-methylation ability for azaheterocyclic amines before the onset had been implicated in PD. On the other hand, the present results suggested that the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.

Aged↗
PubMed2000

Augmentation of human leukemic cell invasion by activation of a small GTP-binding protein Rho.

OBJECTIVE: The functions of a small GTP-binding protein, Rho, in human leukemic cell invasion was investigated in vivo and in vitro. MATERIALS AND METHODS: Human leukemic KM3 and Reh cells (derived from B-cell-type common acute lymphoid leukemias) were inoculated into severe combined immundeficiency (SCID) mice. Alteration of invasion in SCID mice inoculated with KM3 cells that were introduced with the expression vector for Rho Val14 (Rho V14), an activated mutant form of Rho, was observed. RESULTS: SCID mice inoculated with KM3 and Reh cells developed paraplegia 21 days after inoculation. All died by day 26-27. The leukemic cells were localized to bone marrow and around the spinal cord, with no infiltration into peripheral blood, spleen, liver, thymus, or lymph nodes. SCID mice inoculated with Rho V14-transfected KM3 cells showed a 5-day reduction in the time to paraplegia and death compared with SCID mice inoculated with hygromycin-resistance gene-transfected KM3 (hyg(r)) cells. In addition, the mice inoculated with Rho V14 cells showed leukemic cell infiltration, not only into bone marrow and around the spinal cord but also into peripheral blood, liver, and spleen. There were no in vitro or in vivo differences in growth rates of Rho V14 and hyg(r) cells. However, the Rho V14 cells showed markedly increased cell adhesion compared to the hyg(r) cells. CONCLUSION: Results suggest that Rho activation accelerates human leukemic cell invasion via augmentation of cell adhesion.

Animals↗
PubMed2000

The diagnostic value of intraoperative measurement of choline acetyltransferase activity during brachial plexus surgery.

We used the measurement of choline acetyltransferase (CAT) activity to distinguish between preganglionic and postganglionic injuries of the spinal roots during brachial plexus surgery. This study includes ten spinal roots in six patients with traumatic brachial plexus injuries. The results of CAT activity were compared with myelographic findings, the operative findings and the intraoperative evoked spinal cord potentials. The results of CAT activity and the operative findings were consistent in all roots. Whereas CAT activity in fascicles in preganglionic injured roots was below 500 cpm, it was above 2000 cpm in postganglionic injured roots. This study shows that intraoperative measurement of CAT activity can provide useful information on the site and severity of brachial plexus injuries and the assessment of the motor function status of the injured spinal root, both directly and quantitatively.

Adult↗
PubMed2000

Chemopreventive effect of 24R,25-dihydroxyvitamin D(3) in N, N'-dimethylhydrazine-induced rat colon carcinogenesis.

In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs. In conclusion, these results strongly indicate that 24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.

1,2-Dimethylhydrazine↗
PubMed2000

Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Overexpression of ornithine decarboxylase (ODC) has been shown to be characteristic of tumor development and progression in humans and experimental animals. Therefore, we have examined the effects of 1, 3-diaminopropane dihydrochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In experiment 1 (36 weeks), 6-week-old F344 male rats were administered 0.05% BBN in drinking water for 4 weeks and then divided into four groups. Animals of groups 1 and 2 received basal diet and drinking water supplemented with or without DAP (2 g/l). Groups 3 and 4 were given diet containing 5% sodium L-ascorbate (NaAsA), a typical urinary bladder tumor promoter, and drinking water with or without DAP. Administration of DAP to group 1 significantly reduced tumor size, multiplicity and incidence, particularly of papillomas, when compared with group 2 values. DAP together with NaAsA (group 3) also decreased tumor size relative to the group 4 case. To determine the effects of DAP on the early stages of bladder carcinogenesis and its mechanisms, a similar protocol was conducted (experiment 2) with death after 20 weeks. DAP treatment caused complete inhibition (0% incidence) of papillary and/or nodular hyperplasia in group 1 but was without influence in group 3, as compared with the respective controls. Moreover, the ODC activity, bromodeoxyuridine labeling indices and mRNA expression levels of cyclin D1 in the urinary bladder mucosa, determined by northern blotting, were markedly lower in group 1 than in group 2, but values were comparable for both groups administered NaAsA. Assessment of mRNA expression levels of the angiogenic vascular endothelial growth factor suggested no involvement in the inhibitory effects of DAP on urinary bladder carcinogenesis. The results indicate that inhibition of ODC could reduce urinary bladder carcinogenesis in rats, particularly in the early stages, through antiproliferative mechanisms.

Acetyltransferases↗
PubMed2000

Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate.

Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1-6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4-6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G(1) cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.

Animals↗
PubMed2000

In vitro antitumor activity, intracellular accumulation, and DNA adduct formation of cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)] platinum (II) suspended in lipiodol.

SM-11355, cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)] platinum (II), is a lipophilic platinum complex under clinical development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. SM-11355 was compared with cisplatin (CDDP) using an in vitro evaluation system capable of examining the release characteristics and the cytotoxicity of drugs suspended in Lipiodol. SM-11355 suspended in Lipiodol (SM-11355/Lipiodol) and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascites hepatoma AH-109A cells in a dose-dependent manner. Their IC50 values following 7-day exposure were 22.3 and 0.40 microg/ml, respectively. Following the subsequent 7-day exposure, from day 7 to day 14 after preparation of the suspension, SM-11355/Lipiodol showed an almost equivalent activity, but CDDP/Lipiodol did not show any activity at all. SM-11355/Lipiodol showed a sustained release into the culture medium over the course of a 14-day exposure. Following the exposure to CDDP/Lipiodol, the platinum concentration in the medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and formation of platinum-DNA adducts were dependent on the release characteristics of each drug suspension. For SM-11355/Lipiodol, the drug release, intracellular drug uptake, and formation of platinum-DNA adducts over the course of the subsequent 7-day exposure were similar to those observed during the first 7 days. DPC, one of the compounds released from SM-11355/Lipiodol, was taken up by cells and showed formation of platinum-DNA adducts. Thus, this study suggests that SM-11355/Lipiodol may release active platinum compound(s) that bind to nuclear DNA and mediate the cytotoxic activity of SM-11355/Lipiodol.

Animals↗
PubMed2000

Isolation of differentiated squamous and undifferentiated spindle carcinoma cell lines with differing metastatic potential from a 4-nitroquinoline N-Oxide-induced tongue carcinoma in a F344 rat.

One differentiated squamous cell carcinoma (SCC) cell line (RSC3-E2) and two undifferentiated tumor cell lines (RSC3-LM and RSC3-E2R) with different metastatic potential were established from a 4-nitroquinoline N-oxide (4NQO)-induced differentiated SCC in F344 rat tongue. The RSC3-E2 subline was isolated from a parental cell line (RSC3-P) by single cell cloning in vitro, whereas the RSC3-LM subline was isolated from a lung metastatic focus after subcutaneous (s.c.) injection of RSC3-P cells. The RSC3-E2R cell line was isolated from a lung metastatic focus following s.c. injection of RSC3-E2 cells after X-irradiation in vitro. The RSC3-E2 cell line is keratin-positive and grows as a keratinizing tumor in nude mice, whereas RSC3-LM and RSC3-E2R cells are keratin-negative, vimentin-positive and form undifferentiated tumors. When s.c. injected into nude mice, the RSC3-E2 cell line proved to be non-metastatic, while the RSC3-LM cell line was metastatic by both hematogenous and lymphogenous routes, and the RSC3-E2R cell line was metastatic only hematogenously. In vitro relative growth rates and in vitro invasion activity of these cell lines were in the order RSC3-LM > RSC3-E2R > RSC3-E2. Chromosome analysis revealed two peaks with modal chromosome numbers of 83 and 78 for RSC3-P cells and single peaks at 83, 78 and 56 for RSC3-LM, RSC3-E2 and RSC3-E2R cell lines, respectively. Common structural abnormalities on chromosome 11 were shared by all cell lines. Mutation analysis of the p53 gene using a yeast functional assay demonstrated RSC3-LM cell line to have a point mutation at codon 269, whereas RSC3-E2 and RSC3-E2R had double mutations at codons 106 and 170 on each allele. These results suggest that the two undifferentiated RSC3-LM and RSC3-E2R tumor cell lines with different metastatic potential were generated from differentiated SCC cells via different genetic pathways as a consequence of tumor progression in vivo and in vitro, respectively. These cell lines should provide a useful model for understanding mechanisms of hematogenous and lymphogenous metastasis, as well as tumor progression of oral SCCs.

4-Nitroquinoline-1-oxide↗
PubMed2000

Cytotoxicity of cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)]-platinum (II) suspended in Lipiodol in a newly established cisplatin-resistant rat hepatoma cell line.

The cytotoxic activity of cis-[((1R,2R)-1,2-cyclohexanediamine-N, N')bis(myristato)]platinum (II) (SM-11355) was evaluated in a cisplatin (CDDP)-resistant tumor cell line, and compared with that of CDDP. H4-II-E / CDDP with acquired resistance to CDDP was established by continuous exposure of a rat hepatic tumor line, H4-II-E, to increasing concentrations of CDDP over 12 months. Compared with the parental cell line, this cell line exhibited an 8.8-fold increase in resistance to CDDP and was not cross-resistant to 1,2-diaminocyclohexane platinum (II) dichloride (DPC). There were no differences in sensitivity to six non-platinum antitumor drugs between H4-II-E and H4-II-E / CDDP, which suggests that H4-II-E / CDDP is not multidrug-resistant. Intracellular platinum accumulation and the formation of a platinum-DNA adduct following CDDP exposure were significantly reduced in H4-II-E / CDDP compared to the parental cell line. The acquired CDDP resistance in H4-II-E / CDDP appeared to be predominantly due to reduced CDDP uptake. H4-II-E / CDDP was also resistant to CDDP suspended in Lipiodol (CDDP / Lipiodol), but was not cross-resistant to SM-11355 suspended in Lipiodol (SM-11355 / Lipiodol). Also, there were no differences in intracellular platinum accumulation or the formation of platinum-DNA adducts after SM-11355 / Lipiodol exposure between H4-II-E and H4-II-E / CDDP. These results suggest that acquired CDDP resistance in H4-II-E / CDDP does not influence the cytotoxic activity of SM-11355 / Lipiodol.

Animals↗