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Biomedical subjects

H Kawamata

Publications and source records attributed to H Kawamata.

At least 73 records · Page 4Linked to original sources
PubMed1997

Induction of cyclin-dependent kinase inhibitor, p21WAF1, by treatment with 3,4-dihydro-6-[4-(3,4)-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinoline (vesnarinone) in a human salivary cancer cell line with mutant p53 gene.

It has been found by PCR-SSCP analysis and direct DNA sequencing that a human salivary adenosquamous carcinoma-forming cell line, TYS, has a mutant p53 gene at codon 281Asp-->His. When TYS cells were treated with a differentiation-inducing agent, vesnarinone, cellular proliferation was significantly inhibited on the basis of MTT assay. In addition, it has been found by Northern blotting and/or immunoblotting that expression of p21WAF1 and transforming growth factor-beta (TGF-beta) is up-regulated by treating TYS cells with vesnarinone. TGF-beta 1 alone also induced p21WAF1 expression in TYS cells. Moreover, it has been shown by ELISA that the treatment of TYS cells with vesnarinone results in the enhanced generation of latent TGF-beta 1. The expression of TGF-beta receptor (T beta R), including T beta R-I, T beta R-II and T beta R-III, on TYS cells was detected by affinity cross-linking using 125I-TGF-beta 1 and addition of active TGF-beta 1 into serum-free culture medium inhibited the growth of TYS cells in a concentration-dependent manner. These findings suggest that vesnarinone might directly induce expression of p21WAF1 gene in TYS cells, the product of which may be associated with the inhibition of cell growth and induce differentiation.

Antineoplastic Agents↗
PubMed1997

Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines.

We have established human oral-squamous-cancer cell lines, BHY and HN, derived from non-metastatic cancer and metastatic cancer respectively. We examined the expression of matrix-degrading enzymes and their inhibitors in these cell lines. Both cell lines expressed pro-matrix metalloproteinase (MMP)1, proMMP2, proMMP9, membrane-type MMP and urokinase-type plasminogen activator. In addition to these enzymes, BHY cells secreted proMMP7 and procathepsin L, while HN cells secreted a large amount of active MMP2. BHY cells secreted a tissue inhibitor of matrix metalloproteinase, TIMP2, but only a trace level of TIMP1. Contrary to BHY cells, HN cells secreted TIMP1, but only a trace level of TIMP2. When we inoculated these cells into the masseter muscle of nude mice, both types of cell formed solid tumors, whose microscopic appearance was identical to that of the original tumors. BHY tumors were highly differentiated squamous-cell carcinomas, and invasive to the masseter muscle and the mandibular bone. Despite their local aggressiveness, BHY tumors did not metastasize to any distant organs. HN tumors were poorly differentiated squamous-cell carcinomas, weakly invasive to the muscle, but not to the mandibular bone. However, HN tumors frequently metastasized to cervical lymph nodes. These results suggest that the net activity of MMP2 (active MMP2/TIMP2) and cathepsin L secreted from cancer cells may contribute respectively to lymph-node metastasis and to bone invasion by oral cancer cells.

Animals↗
PubMed1997

Induction of tumour differentiation and apoptosis and LeY antigen expression in treatment with differentiation-inducing agent, vesnarinone, of a patient with salivary adenoid cystic carcinoma.

A patient with locally-advanced submandibular adenoid cystic carcinoma with poorly differentiated solid type, was treated with differentiation-inducing agent, vesnarinone, per os at a dose of 60 mg/day daily for 8 weeks. The vesnarinone administration caused marked regression of the tumour. In addition to conversion into the well-differentiated tubular type from the poorly differentiated solid type, the induction of apoptosis and LeY antigen was observed in the treated tumour. These findings indicate that vesnarinone might be a useful therapeutic agent for treatment of salivary cancer. Since we found the new expression of LeY antigen in the well-differentiated tubular lesion in the salivary adenoid cystic carcinoma treated with vesnarinone, we examined the LeY antigen expression in relation to tumour differentiation in five cases of salivary adenoid cystic carcinoma. Consequently, tissue sections from all of the adenoid cystic carcinoma examined showed no positive LeY staining, except for some areas in the tumour lesion with the tubular pattern including the histologically normal-appearing tissue adjacent to the tumour tissue. These findings suggest that there is the intimate relationship between the LeY antigen expression and tumour differentiation in human salivary adenoid cystic carcinoma.

Journal Article↗
PubMed1997

Therapy for oral squamous cell carcinoma by tegafur and streptococcal agent OK-432 in combination with radiotherapy: association of the therapeutic effect with differentiation and apoptosis in the cancer cells.

Twenty patients with oral squamous cell carcinoma having mainly stage II or III lesions without distant metastasis, were treated with tegafur and streptococcal agent, OK-432, in combination with radiotherapy. As a consequence, 16 cases among the treated 20 cases showed complete remission by this therapy alone. Especially, we have found that the squamous cell carcinoma arising in non-keratinizing oral epithelium rather than in keratinizing oral epithelium has better response to this therapy. Among the 16 cases with complete remission (CR) by the current therapy, 10 cases were histopathologically diagnosed as well-differentiated squamous cell carcinoma and six cases as moderately differentiated squamous cell carcinoma. When we examined immunohistochemically the expression of various antigens such as proliferating cell nuclear antigen (PCNA), p53 and LeY or the presence of DNA fragmentation by nick-end labelling in the biopsy materials taken at the first visit to our clinic from 20 patients treated with the current therapy, the CR group showed a significantly increased LeY expres-sion level ( p< 0.05) and DNA fragmentation rate (p< 0.05) as compared with the partial response (PR, n= 3) + no change (NC, n= 1) group. On the other hand, the CR group with respect to PCNA expression level was significantly decreased as compared with the PR + NC group ( p< 0.05). From these findings, it can be considered that the therapy for oral squamous cell carcinoma by UFT and OK-432 in combination with radiotherapy is very effective, which may be associated with differentiation or apoptosis in oral squamous carcinoma cells. In addition, we present the clinical findings and results of immunohistochemical staining for the biopsy materials obtained from four CR cases treated with the current therapeutic method.

Journal Article↗
PubMed1997

The treatment with differentiation- and apoptosis-inducing agent, vesnarinone, of a patient with oral squamous cell carcinoma.

A patient with histopathological recurrent oral cancer with well-differentiated squamous cell carcinoma, was treated with differentiation- and apoptosis-inducing agent, vesnarinone, per os at a dose of 180 mg/day for 56 days and then at a dose of 60 mg/day for 93 days. The vesnarinone administration caused complete remission of the tumour. It has been found by immunohistochemical staining and PCR-SSCP analysis that the recurrent tumour has wild type p53 gene and relative high level of LeY expression as well as DNA fragmentation in the cancer cells, as assessed by nick-end labelling. These findings suggest that the cure of oral squamous cell carcinoma observed in this case might be associated with induction of differentiation and apoptosis of cancer cells by vesnarinone.

Journal Article↗
PubMed1997

Angiogenesis inhibitor TNP-470 suppresses tumorigenesis in rat urinary bladder.

PURPOSE: The efficacy of the anti-angiogenic factor TNP-470, an analogue of fumagillin, in controlling the development of bladder tumors was investigated. MATERIALS AND METHODS: The anti-angiogenic activity of TNP-470 was evaluated in vitro by its capacity to suppress the growth and migration of bovine capillary endothelial cells. To investigate its effect in vivo on the development of tumors, we instilled 0.5 microgram of TNP-470 dissolved in rat urine into heterotopically transplanted rat urinary bladders in which carcinogenesis had been initiated by N-methyl-N-nitrosourea. RESULTS: In vitro, TNP-470 selectively inhibited the growth and migration of endothelial cells. Instillation of TNP-470 shortly after treatment with carcinogen reduced the tumor incidence significantly (p < 0.05) as compared with that in control animals receiving urine only. CONCLUSIONS: TNP-470 suppresses the development of bladder tumors when the treatment is started at an early stage of neoplasia. It may be useful in preventing recurrences or new growth of bladder tumors.

Animals↗
PubMed1997

Contribution of tumor necrosis factor alpha and interleukin-1 alpha on the production of macrophage inflammatory protein-2 in response to respiratory syncytial virus infection in a murine macrophage cell line, RAW264.7.

The production of several inflammatory cytokines, such as murine macrophage inflammatory protein-2 (MIP-2), tumor necrosis factor (TNF), and interleukin (IL)-1, was investigated in response to respiratory syncytial virus (RSV) infection in a murine macrophage cell line, RAW264.7, with special reference to mutual relation of their productions. The kinetics of MIP-2 production showed a trend for a biphasic pattern, that is, MIP-2 levels became detectable from 2 h postinfection (p.i.) and increased markedly until 8 h p.i. Thereafter, this level fell to the same level until 16 h p.i. and then increased again. TNF alpha was also detectable at 2 h p.i. and then increased sharply until 8 h p.i., when the peak level attained. Compared with the levels of MIP-2 and TNF alpha, that of IL-1 alpha/beta, especially IL-1 beta, was lower (ng versus pg/ml order). The presence of anti-TNF alpha or anti-IL-1 alpha antibody did not influence the early phase of MIP-2 production but significantly inhibited the late phase, suggesting that MIP-2 is induced by the combined effects of RSV infection via direct induction and indirectly after initial induction of TNF alpha and IL-1 alpha productions. Although RSV-infected RAW264.7 cells had no alteration in viability compared with mock-infected control, these data demonstrate that RSV is a potent inducer of inflammatory cytokines by direct induction and indirectly via the initial production of other cytokines.

Animals↗
PubMed1995

Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma.

The balance between matrix metalloproteinases and their inhibitors is a critical factor which affects tumor invasion and metastasis. We have established a rat bladder carcinoma cell line, LMC19, which is tumorigenic, invasive and metastatic to the retroperitoneal lymph nodes and to the lungs in nude mice. LMC19 cells secrete pro-gelatinases A and B as well as tissue inhibitors of matrix metalloproteinase (TIMP1 and TIMP2). We conducted the present study to determine whether or not over-expression of TIMP1 and TIMP2 can affect the metastatic potential of LMC19 cells. We transfected the cells with an expression vector containing TIMP1 or TIMP2 cDNA, isolated several clones over-expressing TIMP1 or TIMP2 and assessed their invasive and metastatic potential by inoculation at an orthotopic site (urinary bladder) in nude mice. Our results show that the transfectants over-expressing TIMP1 and TIMP2 marginally affect primary tumor growth, local invasion or metastasis to the retroperitoneal lymph nodes but significantly inhibit extravascular growth of pulmonary tumor emboli. Our results suggest that the net activity of matrix metalloproteinases of tumor cells may be a critical factor that controls extravasation at this distant metastatic site.

Animals↗
PubMed1995

Marked acceleration of the metastatic phenotype of a rat bladder carcinoma cell line by the expression of human gelatinase A.

Numerous studies have reported a correlation between the production of gelatinases A and B by cancer cells and invasive and metastatic potential. It has been suggested that the expression of gelatinase A (72-kDa type IV collagenase) is associated more closely with the metastatic phenotype of malignant cells in vitro and in vivo than that of gelatinase B (92-kDa type IV collagenase). We have established a rat bladder carcinoma cell line, MYU3L, which is tumorigenic and locally invasive but is not metastatic to the distal organs in nude mice. The MYU3L cell line secretes pro-gelatinase B but not any detectable level of pro-gelatinase A. We undertook the present study to determine whether over-expression of gelatinase A can affect the metastatic potential of MYU3L cells. We transfected MYU3L cells with an expression vector containing human pro-gelatinase A cDNA under the transcriptional control of the SR alpha promoter. Two stable transfectants over-expressing gelatinase A activity were isolated. We assessed the biological behavior of the transfectants by an orthotopic site (urinary bladder) inoculation and an i.v. injection in nude mice. Our results demonstrate that the induced expression of human gelatinase A enzyme markedly accelerates the metastatic phenotype of the rat bladder carcinoma cell line MYU3L. Our results suggest that gelatinase A produced by tumor cells plays a major role in the metastatic process.

Animals↗
PubMed1995

Enhancement of transformation in vitro of a nontumorigenic rat urothelial cell line by interleukin 6.

Chronic inflammation of the urinary tract is a significant risk factor for the development of bladder cancer. We have shown that acute and chronic inflammation induced by intravesical instillations of killed Escherichia coli strikingly enhances N-methyl-N-nitrosourea (MNU)-initiated rat bladder carcinogenesis. To test the hypothesis that cytokines released during inflammation may be involved in the enhancement of bladder carcinogenesis, we conducted an in vitro experiment. Using soft agar growth as an index of transformation, we examined the effect of inflammation-associated cytokines on the enhancement of MNU-initiated transformation of MYP3 cells, an anchorage-dependent nontumorigenic rat bladder epithelial cell line. In the first experiment, after 1-h exposure to MNU (50 micrograms/ml), cells (5 x 10(4)) were grown in soft agar in the presence of interleukin (IL)-1 alpha, IL-6, IL-8, or tumor necrosis factor-alpha (10 to 100 ng/ml). Colonies consisting of more than 20 cells were counted 4 weeks later. Among the cytokines tested, IL-6 (100 ng/ml) significantly increased colony counts over those for the untreated controls (P < 0.001). In the second experiment, the cells treated with MNU similarly as in the first experiment were cultured with or without IL-6 (100 ng/ml) for 1 week before the cells (5 x 10(4)) were grown in soft agar in the presence or absence of IL-6. IL-6 pretreatment increased colony counts irrespective of subsequent IL-6 treatment (P < 0.05). Moreover, IL-6-stimulated anchorage-dependent growth of MNU transformants far exceeded that of the parental MYP3. However, among the transformants, there was no parallel relationship in response to IL-6 between anchorage-dependent and -independent growth. Our results suggest that IL-6 may provide a selective growth advantage to MNU-initiated bladder epithelial cells in vitro and that it may be a factor accounting for the marked enhancement of inflammation-associated rat bladder carcinogenesis.

Animals↗
PubMed1995

Intraluminal epidermal growth factor affects growth of N-methyl-N-nitrosourea-initiated rat bladder carcinoma.

To confirm our recent finding that epidermal growth factor (EGF) appeared to contribute to the tumor-enhancing effect demonstrated by normal rat urine, we conducted 2 experiments using our heterotopically transplanted rat urinary bladder model. In experiment 1, after a single dose (0.25 mg) of N-methyl-N-nitrosourea (MNU), we intravesically administered EGF (0.05 ml of 500 ng/ml phosphate-buffered saline) once a week for 30 weeks. Instillation of EGF induced a significantly larger number of tumors than did instillation of the vehicle (P = 0.03). EGF without MNU initiation did not induce tumors. In experiment 2, 2 groups received instillation of killed Escherichia coli (5 x 10(8) cells)/0.5 ml phosphate-buffered saline once a week for 4 weeks to expand the MNU-initiated cell population. Subsequent EGF treatment significantly increased the incidence of tumors (P = 0.01). In the groups which did not receive killed E. coli, EGF treatment induced a significantly higher number of tumors than did vehicle treatment (P < 0.001). All of the tumors were low-grade, superficial transitional cell carcinomas. These observations indicate that EGF acts as a growth-stimulating factor on dormant neoplastic cells and thereby increases the number of tumors.

Animals↗
PubMed1995

[CT analysis of aortic cobwebs in aortic dissection].

Contrast-enhanced CT images in patients with acute or chronic aortic dissection were evaluated for the purpose of determining the clinical usefulness of "aortic cobwebs", which were originally reported by Williams et al. as an anatomical marker of the false lumen. Aortic cobwebs were detected in 13 of 44 cases (30%), demonstrating as low density structures in the false lumen continuing from the intimal flap. The aortic cobwebs were mainly linear in shape, and the size ranged from 5 x 1 to 15 x 3 mm (mean: 9 x 2 mm). Aortic cobwebs were more frequently demonstrated in chronic than in acute cases, and were more often detected in the abdominal aorta. Follow-up CT examinations of the cobwebs revealed no interval change in six cases, disappearance in three cases and thickening in one case. There was no significant correlation between the sequential changes in the cobwebs and dilatation or thrombus formation in the false lumen. Aortic cobwebs seem to represent partially residual bands of the aortic media incompletely sheared from the aortic wall during the initial processes of aortic dissection. These structures are considered to be a reliable anatomic marker and to be useful for CT identification of the false lumen in aortic dissection.

Adult↗
PubMed1995

[Superselective local infusion therapy with tissue-plasminogen activator for acute massive pulmonary thromboembolism: preliminary clinical experience].

Three cases of acute massive pulmonary thromboembolism were treated with the superselective infusion of tissue-plasminogen activator. Superselective pulmonary angiography immediately after administration of tissue-plasminogen activator demonstrated angiographic improvement in all patients. No complications were encountered during or after the procedure. It is considered that superselective infusion of tissue-plasminogen activator can be an effective therapy for massive pulmonary thromboembolism.

Acute Disease↗
PubMed1995

p53 gene mutations in human urothelial carcinomas: analysis by immunohistochemistry and single-strand conformation polymorphism.

We examined 60 cases of human urothelial carcinomas (27 superficial and 33 deeply invasive) for the frequency of p53 gene mutations. Forty-two cases were analyzed by both the immunohistochemical and the single-strand conformation polymorphism (SSCP) methods, and the remaining 18 cases were assayed by SSCP alone. For the latter assay, exons 4 to 8 were amplified by polymerase chain reaction, and the amplified nucleotides were analyzed for the evidence of mutations by gel electrophoresis. When mobility shift was observed, direct nucleotide sequencing was performed to determine mutation sequence. Three superficial and eight deeply invasive carcinomas demonstrated evidence of mutations. Mutations involved various codons randomly. The fact that all tumors with mutations of the p53 gene except for one were of high nuclear grade (grade III) suggests that p53 mutation is associated with the progression of bladder cancers. Our results indicate that SSCP is a sensitive screening assay for detecting gene mutations. Immunohistochemical analysis is also a sensitive method but may yield false positive as well as false negative results.

Adult↗
PubMed1995

[Late phase contrast enhanced-CT analysis of thrombosed type aortic dissection].

Seven patients with thrombosed type aortic dissection who underwent both early- and late-phase contrast enhanced (CE)-CT scans were analyzed. The image acquisition of early-phase CE-CT began 30 seconds after the intravenous administration of contrast material at an injection rate of 1.5 ml per second. Late-phase CE-CT began 6 minutes after contrast material injection. The thrombosed false lumens were not enhanced on early-phase CE-CTs in any of the cases. In five of seven cases, on the other hand, false lumens of the descending aorta were enhanced on late-phase images. Late enhancement in the false lumen was roughly divided into two patterns; (1) a crescentic enhancement of the sub-adventitial region (3 cases), and (2) a vague enhancement around the ulcerlike projection (2 cases). The mechanism of late enhancement in the false lumen was not fully elucidated. Although the clinical significance of late enhancement has not yet been established, it will be useful to demonstrate an unstable status of the thrombosed false lumens before organization.

Aged↗
PubMed1994

[Stent placement without thrombolysis in chronic iliac arterial occlusion: preliminary clinical evaluation].

Intra-arterial stent placement without thrombolytic therapy was performed in four patients with chronic iliac arterial occlusion. The length of angiographically observed occluded lesions ranged from 2.0 cm to 14.0 cm (mean: 5.1 cm). The implanted stents included four Wall stents, two Strecker stents and one Palmaz stent. The mean ankle-arm index before and after stenting improved from 0.48 to 0.77, while the mean pressure gradient improved from 82.5 mmHg to 3.0 mmHg. Symptoms were eliminated in all patients after the procedure. No major complications were encountered during the procedure. Primary stent implantation in chronic iliac occlusions is useful to avoid bypass surgery.

Aged↗
PubMed1994

[Thrombosed type aortic dissection showing changes in the false lumen to the patent type].

Thirty-four patients with acute aortic dissection with thrombosed false lumen were reviewed. In 4 cases (12%), the false lumens changed to the patent type. Changes in the false lumens were revealed by contrast-enhanced CT performed from day 2 to day 19 (mean, day 12.5) after the onset. The entry site was located at the descending aorta in 3 cases, and was unknown in 1 case. In 2 cases, the entry site corresponded with ulcer-like projections that had been pointed out at the thrombosed false lumen. One patient presented with moderate back pain when the false lumen changed, while the others were symptom free. During the follow-up period, 2 patients died of rupture of the false lumen. One patient was treated with a surgical operation. The patent false lumen became re-thrombosed in 1 patient. Although the majority of cases of thrombosed aortic dissection are considered to have a good prognosis, some cases change to the patent type without clinical symptoms. Radiologists should be aware of the unstable nature of the thrombosed type aortic dissection, and follow-up examinations should be performed at least once a week for three weeks after the onset of dissection.

Acute Disease↗