A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase.
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3T3 Cells↗
Biomedical subjects
Y Monden
Publications and source records attributed to Y Monden.
High frequency expressions of CD44 standard and variant forms in non-small cell lung cancers, but not in small cell lung cancers.
BACKGROUND AND OBJECTIVES: Organ specificity has been demonstrated in the mode of CD44 expression among several cancers. METHODS: We examined the expressions of CD44 standard (CD44s) and CD44 variants (CD44v) in 14 cell lines (small cell lung cancer (SCLC): 5, non-small cell lung cancer (NSCLC): 9 and 20 surgically resected samples (SCLC: 7, NSCLC: 13) of lung cancer using reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: Although both NSCLC and SCLC expressed CD44s, the frequency and intensity of CD44s expression in NSCLC were different from those in SCLC: cell lines, 89% vs. 40%; tumor samples, 100% (diffusely stained) vs. 57% (focally stained). CD44s expression was partially or completely repressed in SCLC. However, NSCLC frequently expressed CD44v, but SCLC expressed infrequently: cell lines, 67% vs. 20%; tumor samples, 69% vs. 0%. The N-417 line, which only expressed some CD44v in SCLC, falls SCLC and NSCLC both in biomarkers and in growth patterns. CONCLUSIONS: CD44 expression was repressed in SCLC but was enhanced in NSCLC.
Adenocarcinoma↗
Value of mass screening for thyroid cancer.
This study aims to clarify the presently uncertain value of mass screening for thyroid cancer, which has been performed by physical examination along with mass screening for breast cancer in Zentsuji, Japan since 1983. Among 18,619 subjects, 36 individuals with thyroid cancer (0.19%) were found. The detection rate was 0.40% at the initial screening and 0.10% during subsequent periodic screening. All thyroid cancers were confirmed histologically as well differentiated carcinoma. The tumor size in the mass-screening group (14 +/- 6 mm) was significantly smaller than in patients presenting at an outpatient clinic during the same period (19 +/- 13 mm) (p < 0.05). The incidence of nodal metastases in the mass-screening group (38%) was significantly lower than in the outpatient group (68%) (p < 0.05). Thus mass screening seemed to find thyroid cancers in a relatively early stage. Mass screening for thyroid cancer was economic in this instance because it was performed together with screening for other cancers, such as breast cancer. Thyroid cancer screening required less than one additional minute per subject. The ultimate aim of mass screening is to reduce mortality. No improvement in prognosis from enforced mass screening for thyroid cancer was detected in this study. It cannot be demonstrated that there is sufficient value of mass screening for thyroid cancer to perform it independently despite early cancer detection.
Adult↗
A new surgical technique for deep lamellar keratoplasty with single running suture adjustment.
PURPOSE: To improve the technique of deep lamellar keratoplasty. METHODS: For the recipient eye, a divide-and-conquer technique was applied to deep lamellar keratoplasty. After trephinization, the recipient cornea within the trephine was divided into four quadrants to facilitate lamellar dissection at approximately 70% depth. This procedure of division was continued until the Descemet membrane was exposed in the central area. The corneal graft was placed with an adjusted single running suture. Seventeen eyes were treated with this technique. RESULTS: In 17 eyes of 15 patients, the mean visual acuity 6 months or more after deep lamellar keratoplasty was 20/52 with eyeglass correction and 20/80 without eyeglass correction. At 6 months or more after deep lamellar keratoplasty, the mean +/- SD keratometric astigmatism in 17 eyes was 3.2 +/- 2.3 diopters. CONCLUSION: This technique facilitates deep lamellar keratoplasty and prevents high or excessive astigmatism after surgery.
Astigmatism↗
OK-432 develops CTL and LAK activity in mononuclear cells from regional lymph nodes of lung cancer patients.
We examined the effect of OK-432 on induction of cytotoxic T lymphocytes (CTL) directed against autologous tumor cells (ATC) and lymphokine-activated killer (LAK) cells from mononuclear cells separated from regional lymph node cells (RLMNCs) of 49 lung cancer patients. We also examined the phenotypic changes of RLMNCs during incubation with or without OK-432. Significant CTL activity and LAK activity against ATC developed from RLMNCs after stimulation with OK-432 or IL-2. Sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432 also developed significant CTL activity and LAK activity from RLMNCs. The CTL activity produced by OK-432 alone was as high as the CTL activity developed by IL-2 alone, OK-432 plus IL-2, or IL-2 plus OK-432. There was no significant difference in the CTL activities achieved by these four treatments. The proportion of CD25+ cells in RLMNCs after incubation with OK-432 was twice that before incubation. Although OK-432 increased IL-2 receptor expression on RLMNCs, it showed no synergistic effect with IL-2 in developing CTL and LAK activity. After incubation with OK-432, the proportion of HLA-DR + cells was also increased significantly. Moreover, the proportions of HLA-ABC+ and HLA-DR+ (class I and class II major histocompatibility complex antigens) cells in ATC were significantly larger than in Daudi cells. OK-432 alone could develop CTL activity against ATC from the RLMNCs of lung cancer patients that was as high as that developed by IL-2 alone or by sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432. The CTL developed from the RLMNCs of lung cancer patients may recognize class I and/or II antigens on the surface of ATC. These results indicated that treatment with OK-432 might be therapeutically useful for lung cancer patients as a CTL inducer rather than a LAK inducer.
Aged↗
Cyclophosphamide, adriamycin, 5-fluorouracil and high-dose toremifene for patients with advanced/recurrent breast cancer. The Japan Toremifene Cooperative Study Group.
BACKGROUND: Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective. METHODS: In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996. RESULTS: Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen. CONCLUSIONS: Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer.
Adult↗
J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.
Farnesylation of the activated ras oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Because squalene synthase and FTase recruit farnesyl pyrophosphate as a common substrate, we modified squalene synthase (SS) inhibitors to develop FTase inhibitors. Among the compounds tested, a novel FTase inhibitor termed J-104,871 inhibited rat brain FTase with an IC50 of 3.9 nM in the presence of 0.6 microM farnesyl pyrophosphate (FPP), whereas it scarcely inhibited rat brain protein geranylgeranyltransferase-I or SS. The in vitro inhibition of rat brain FTase by J-104,871 depends on the FPP concentration but not on the concentration of Ras peptide. Thus, in vitro studies strongly suggest that J-series compounds have an FPP-competitive nature. J-104,871 also inhibited Ras processing in activated H-ras-transformed NIH3T3 cells with an IC50 value of 3.1 microM. We tested the effects of lovastatin and zaragozic acid A, which modify cellular FPP levels, on Ras processing of J-104,871. Lovastatin, a hepatic hydroxymenthyl coenzyme A reductase inhibitor that reduced the cellular FPP pool, increased the activity of J-104,871, whereas 3 microM zaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 microM. These results suggest that J-104,871 inhibits FTase in an FPP-competitive manner in whole cells as well as in the in vitro system. Furthermore, J-104,871 suppressed tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells.
3T3 Cells↗
T lymphocyte activation in myasthenic thymoma.
The functional and phenotypic characteristics of lymphocytes separated from myasthenic thymoma (Th-L) were compared with those of lymphocytes separated from non-thymomatous thymus associated with thymoma (NTh-L) of the same patients and NTh-L of myasthenia gravis (MG) patients without thymoma. We examined whether Th-L and NTh-L of MG patients reacted to interleukin-2 (IL-2) to develop lymphokine-activated killer (LAK) activity and/or cytolytic activity against K562 (natural killer (NK) activity), and the phenotypic changes in such cells during incubation. Ten MG patients with thymoma and six MG patients without thymoma, and four non-MG thymoma patients were included in this study. Th-L and NTh-L of MG patients reacted with IL-2 to develop LAK and NK activities. The LAK activity developed from Th-L was significantly higher than that from NTh-L, and the LAK activity developed from Th-L was as high as that from peripheral blood lymphocytes (PBL) in MG patients without thymoma. The proportions of CD3+ cells, CD4+/CD8- cells, and CD4-/CD8+ cells in Th-L of MG patients increased significantly during incubation. On the other hand, the proportion of CD4+/CD8+ cells in Th-L of MG patients decreased significantly. The proportions of CD4+/CD8- cells, CD4-/CD8+ cells, and CD4+/CD8+ cells in NTh-L of MG patients with and without thymoma exhibited no change during incubation. These findings suggest that CD4+/CD8+ Th-L of MG patients may have a higher potential to react to IL-2 than NTh-L, and that the former cells might develop LAK activity like that of PBL on maturation to CD4+/CD8- cells and CD4-/CD8+ cells. Our findings also suggested that Th-L might play an important role in the pathogenesis of MG with thymoma.
Adult↗
[Treatment for thymus-related malignant tumors].
Surgery is the first-line therapy for thymoma. Postoperative radiotherapy should be given for all invasive thymomas, followed by chemotherapy in some cases. Even if the resection is not complete, surgery is effective therapy because most thymomas are local and slow growing. Multidrug chemotherapy including cisplatin is effective against thymoma. Thymic cancer is histologically varied. Surgery is only one effective therapy for thymic cancer. Although no definitive chemotherapy regimen for thymic cancer has yet been established, we feel that the cisplatin, doxorubicin, cyclophosphamide, vincristine 4-drug combination regimen is effective in thymic cancer patients. Seminoma out of mediastinal germ cell tumor (GCT) is expected to have a good prognosis after surgery and radio-/chemotherapy. Although the prognosis for those with nonseminomatous GCT has recently improved due to chemotherapy and surgery, it is still poor.
Antineoplastic Combined Chemotherapy Protocols↗
Effects of interferon-alpha and gamma on development of LAK activity from mononuclear cells in breast cancer patients.
We examined the effect of recombinant IFN-alpha and IFN-gamma on induction of LAK cells from peripheral blood mononuclear cells (PBMNCs) in 7 pre-operative breast cancer patients and 4 healthy volunteers. Significant LAK activity was developed from PBMNCs of pre-operative breast cancer patients and healthy volunteers after incubation for 4 days with IL-2 (presence of IL-2 vs. absence of IL-2). Incubation of PBMNCs of pre-operative breast cancer patients with 1000 U/ml of IFN-alpha for 4 days suppressed the LAK activity significantly (P < 0.05). By contrast, incubation of PBMNCs of pre-operative patients with 1000 U/ml of IFN-gamma for 4 days increased the LAK activity significantly (P < 0.05). Significant cytotoxicity against MCF-7 cells (estrogen receptor positive human breast cancer cell line) was developed from PBMNCs of pre-operative breast cancer patients at 20:1 and 40:1 E/T ratios after incubation for 4 days with IL-2 (absence of IL-2 vs. 20:1 or 40:1, P < 0.05, P < 0.05), whereas PBMNCs of healthy volunteers did not. Stimulation of LAK cells with IFN-gamma produced a significant augmentation of cytotoxic activity against MCF-7 (P < 0.05), while IFN-alpha suppressed the cytotoxicity significantly (P < 0.05). These findings suggested that combined stimulation by IFN-gamma and IL-2 might be a reasonable treatment for breast cancer patients.
Breast Neoplasms↗
Mutations of the p53 gene in human lung cancer from chromate-exposed workers.
We examined p53 mutations in 20 cancer samples from 19 chromate workers with lung cancer by Polymerase chain reaction-Single strand conformation polymorphism analysis and direct sequencing. Six missense mutations were identified in 4 (20%) of the 20 chromate lung cancer samples. Fewer mutations were found in the patients with lung cancers who had been exposed to chromate than in those who had not. However, the pattern of p53 mutations in lung cancer patients exposed to chromate differed from that of common lung cancers in 3 respects. There were no apparent G to T transversions, which are common base changes in lung cancers. Half of the mutational sites (3/ 6) had changes of AT base-pairs, and 2 of 4 mutational tumor samples had double missense mutations. Our results suggested that chromate exposure may induce point mutation of the p53 gene.
Adenocarcinoma↗
Effects of dietary bile acids on formation of azoxymethane-induced aberrant crypt foci in F344 rats.
The present study has demonstrated the influence of bile acids (BAs) on the development and growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF). Male F344 rats were treated with two doses of AOM (15 mg/kg) at 7 days apart and fed either basal MF or MF plus 0.4% of cholic (CA), deoxycholic (DCA), chenodeoxycholic (CDCA), lithocholic (LCA) and ursodeoxycholic (UDCA) acid mixed diets for 8 weeks after the first AOM dose. The mean number of ACF/colon of the rats fed CA, DCA, CDCA and LCA were higher than that of MF-fed group and the differences were statistically significant (P < 0.005). But the mean number of ACFs/colon was significantly (P < 0.005) lower in UDCA diet-fed rats compared to MF. UDCA-fed rats also showed a significant decrease in average crypt multiplicity (number of crypts/focus) of ACF compared to MF alone. The mean number of ACF with > or =5 crypts was about 2.5-3.7 times higher in case of CA, DCA, CDCA and LCA and about 8.2 times lower in UDCA compared to the control MF diet group. In a parallel study, feeding for 18 weeks of the same BAs mixed diets without AOM administration did not significantly induce ACF. Therefore, these data suggest that dietary BAs by themselves do not induce ACF in F344 rats but enhance or, in the case of UDCA, suppress the development and growth of AOM-induced ACF.
Animals↗
Invasive thymoma with endobronchial polypoid growth.
A rare case of invasive thymoma with endobronchial polypoid growth is presented. A 68-year-old woman presented with coughing and sputum. The chest X-ray and computed tomography (CT) findings demonstrated a large mass with a calcified lesion in the left hilar region. A bronchoscopic examination showed a polypoid tumor in the left B3b bronchus. The tumor was surgically resected and revealed a unique polypoid endobronchial extension. This tumor was pathologically diagnosed to be invasive thymoma.
Aged↗
Bronchus-associated lymphoid tissue is targeted and damaged by recipient lymphocytes in long-term-surviving rat lung allograft.
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Animals↗
Relationship between prognostic score and thyrotropin receptor (TSH-R) in papillary thyroid carcinoma: immunohistochemical detection of TSH-R.
We have demonstrated the expression of thyrotropin receptor (TSH-R) in thyroid neoplasms (13 adenomas, 21 papillary carcinomas, two follicular carcinomas) and adjacent normal thyroid using the monoclonal antibody against human TSH-R and have also demonstrated a relationship between prognostic scores and the expression of TSH-R. Among the adenomas, eight showed an intensity similar to that of normal thyroid and five showed a higher intensity than normal. Two tumours exhibited heterogeneous distribution of TSH-R. Among the papillary carcinomas, seven showed similar intensity to normal tissue and four showed higher intensity and ten showed weaker intensity. Eight tumours showed heterogeneous distribution of the stain. Among the follicular carcinomas, one showed similar intensity to normal tissue and the other exhibited weaker intensity. Both cases showed homogeneous distribution of TSH-R. The adenomas never showed a weaker intensity than normal thyroid, but various intensities of TSH-R occurred in differentiated carcinomas. There was no significant relationship between the clinical data and the signal intensity in the adenomas. Among the papillary carcinomas, however, the group with weaker intensity had significantly poorer prognostic scores than the other two groups. Thus, we assume that low TSH-R may be expressed by the clinically high-risk group of patients with papillary thyroid carcinoma.
Adenocarcinoma, Follicular↗
High frequency of p53 protein expression in thymic carcinoma but not in thymoma.
Thymic epithelial tumours are broadly classified into thymomas and thymic carcinomas. Although both tumours occasionally show invasive growth, they exhibit different clinical and biological findings. The oncogene and anti-oncogene in thymic epithelial tumours have not been evaluated fully. We investigated the expression of p53 protein by immunohistochemical analysis using the anti-p53 polyclonal antibody (CM-1) in 17 thymomas and 19 thymic carcinomas. We also examined p53 gene (exon 5-8) mutation in 18 thymic carcinomas by using polymerase chain reaction-single-strand conformation polymorphism methods and direct sequencing. Of the thymoma cases, only one invasive thymoma showed focal nuclear staining. Fourteen of the 19 thymic carcinomas (74%) showed nuclear staining. Point mutations of the p53 gene were recognized in only 2 of the 18 thymic carcinomas (11%). One was the mutation C to T transition in the first letter of codon 222 in exon 6, which results in the amino acid substitution from proline to serine. Another was a silent mutation. p53 protein accumulation is highly frequent in thymic carcinomas but not in thymomas, and gene mutation is uncommon in thymic carcinomas.
Adult↗
Pleuropulmonary blastoma: fluorescence in situ hybridization analysis indicating trisomy 2.
We report a case of pleuropulmonary blastoma occurring in the right upper lobe and pleura of a 29-month-old boy. Histologically, the tumor was composed of undifferentiated mesenchymal cells with occasional rhabdomyoblastic and chondroid differentiation. Immunohistochemical analysis showed vimentin immunoreactivity in most of the tumor cells, myoglobin, desmin, and actin in the rhabdoid cells, and S-100 protein in the chondroid cells. Fluorescence in situ hybridization (FISH) analysis showed trisomy 2 and normal chromosomal copy numbers for chromosomes 7, 12, 17, 18, and X in the majority of the tumor cell nuclei. The identification of trisomy 2 in the current pleuropulmonary blastoma confirms a previous cytogenetic finding of chromosome 2 abnormality with cultured metaphase cells of a similar case, indicating that the acquisition of an additional chromosome 2 copy in pleuropulmonary blastoma is a nonrandom chromosomal alteration and that pleuropulmonary blastoma is cytogenetically distinct from pulmonary blastoma in which chromosome 2 is bisomic. It is also suggested that pleuropulmonary blastoma may have an intimate tumorigenetic relationship with embryonal rhabdomyosarcoma.
Actins↗
[Mechanism of action of azatyrosine: recent process].
Azatyrosine is known to convert ras, raf or c-erbB-2-transformed NIH3T3 cells to a normal phenotype. We attempted to identify the signal-transduction process triggered by oncogenic c-ErbB-2 that was inhibited by azatyrosine. Azatyrosine did not suppress activation of Ras induced by introduction of c-ErbB-2. However, it inhibited increases in phosphorylation of c-Raf-1 induced by oncogenic c-ErbB-2. Furthermore, azatyrosine inhibited activation of the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element in response to stimulation by oncogenic c-ErbB-2. These results suggest that this agent acts downstream of Ras in signal transduction from oncogenic c-ErbB-2 to nuclear factors. Moreover, we found that azatyrosine was incorporated into proteins instead of tyrosine. The simultaneous presence of a high concentration of tyrosine inhibited the conversion to a normal phenotype of transformed cells by azatyrosine. These results strongly suggest that incorporation of azatyrosine into proteins might convert the transformed cells in to cells with a normal phenotype.
3T3 Cells↗