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Biomedical subjects

M Watatani

Publications and source records attributed to M Watatani.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Analysis of genetic changes in progression of colorectal cancer].

To investigate whether genetic changes of the p53 gene and genetic defects in DNA-mismatch repair systems are involved in progression of colorectal carcinomas (CRCs), we examined loss of heterozygosity (LOH) on 17p and mutations in exon 5 through 8 of the p53 gene as well as replication errors (RER) at four microsatellite loci in DNAs from 108 CRCs at all clinical stages (20 Dukes A, 40 Dukes b, 48 Dukes C). We observed that LOH on 17p and/or p53 mutation were detected in 93% of Dukes A carcinomas and in 84% of Dukes C carcinomas, suggesting that the p53 gene is mutated and/or deleted before carcinoma has been produced. RER-positive phenotype was observed in approximately 30% of CRCs, irrespective of clinical stage. These results suggest that genetic instability is likely to play an important role in development of a subpopulation of sporadic CRCs, but not in progression of CRCs. In addition, we found no significant association between genetic alterations and progression of CRCs. We consider that genetic defects in DNA-mismatch repair pathway do not necessarily promote genomic instability at the p53 sequences in CRCs.

Chromosomes, Human, Pair 17↗
PubMed1995

[Prognostic predictors in colorectal cancer].

The prognostic significance of clinicopathologic factors in colorectal cancer was evaluated in a multivariate analysis. The most important independent factor affecting survival was stage (depth of penetration through the bowel wall and the presence of positive lymph nodes). All other clinicopathologic factors were of less importance than stage in determining prognosis. Although the prognostic relevance of biologic and molecular variables has been investigated extensively, the importance of these factors as prognostic predictors remains uncertain and further studies are needed.

Colorectal Neoplasms↗
PubMed1995

[Analysis of malignant potential on colorectal carcinoma utilizing expression of epidermal growth factor and DNA ploidy patterns].

Human epidermal growth factor (EGF) and DNA ploidy patterns were investigated in order to elucidate malignant potential of 216 surgically resected colorectal carcinomas. EGF positive was detected in 140 out of 216 (64.8%) cases and DNA aneuploidy was found in 137 out of 216 (63.4%). No significant correlations were recognized between EGF expressions and DNA ploidy patterns. We subclassified the cases into four groups according to their histological EGF expressions and DNA ploidy patterns. In these groups, the relationship among EGF expressions, DNA ploidy patterns and clinicopathological findings was studied. Subgroups had a significant relation to depth of invasion, lymph node metastasis, lymphatic invasion and clinical stage. In patients with curative operation, the prognosis was significantly lower in EGF-positive-DNA aneuploidy group than in EGF-negative-DNA diploidy group. In DNA diploidy, the prognosis of EGF-positive group was poorer than in the EGF-negative group. In conclusion, the EGF expression as well as DNA ploidy patterns may be useful to assess malignant potential in colorectal carcinoma.

Colorectal Neoplasms↗
PubMed1994

Low Grade Amplification of MDM2 Gene in a Subset of Human Breast Cancers without p53 Alterations.

MDM2 protein is thought to bind to p53 tumor suppressor protein leading to inhibition of p53-mediated transactivation. Amplification of the MDM2 gene has been frequently observed in human sarcoma, and relevant overexpression of the MDM2 protein is assumed to contribute to tumorigenesis through inactivation of the p53 function. In order to determine whether MDM2 amplification plays a role in the development of human breast cancer without genetic alteration of p53, we analyzed, MDM2 gene amplification by quantitative hybridization and genetic alteration of p53, in 32 primary tumors and 26 metastatic lymph nodes. Low grade amplification of the MDM2 gene (2-6 fold) was observed in four cases, none of which showed even subtle genetic alterations of p53 or loss of alleles on 17p. Moreover, in three of the four cases with MDM2 gene amplification, the level of gene amplification in the metastatic lymph nodes was slightly higher than that in the primary tumors. These results, taken together with previous findings, suggest that a subset of breast cancers without genetic alteration of p53 may also arise by inactivation of the p53 function through interaction with the overexpressed MDM2 protein induced by gene amplification.

Journal Article↗
PubMed1994

Conventional Dose CAF Therapy versus Low Dose Adriamycin Therapy in the Treatment of Advanced Breast Cancer.

A controlled randomized trial was conducted to compare the effectiveness of a conventional dose of CAF therapy with that of a low dose of adriamycin (ADR) therapy for the treatment of advanced Breast Cancer. The doses of medication for the conventional CAF therapy were 100 mg/body of cyclophosphamide (CPA) p.o. daily fort wo weeks, 30 mg/m(2) of ADR and 500 mg/m(2) of 5-fluorouracil (5-FU) i.v. on days 1 and 8 for induction, and 200 mg/body of 5-FU and 20 mg/body of tamoxifen (TAM) p.o. daily for maintenance. Those for the low dose ADR therapy were 15mg/m(2) of ADR i.v. at two-week intervals for one year and 200 mg/body of 5-FU and 20 mg/body of TAM p.o. daily. Eighty patients were entered in this trial. All patients were randomly divided into two groups with stratification for estrogen receptor status. Of 78 patients among them, 38 undergoing the CAF therapy and 40 undergoing the low dose ADR therapy, were evaluated for efficacy assesment. The background factors analyzed were well balanced in both groups. The response rate was 47%(6CR, 12PR out of 38) in the CAF group and 43% (3CR, 14PR out of 40) in the low dose ADR group. There was no significant difference in response rates and survival rates as determined by the Kaplan Meier method between the two groups. The CAF therapy had significantly more toxicity than the low dose ADR therapy. Therefore, it was concluded that this low dose ADR therapy can be regarded as a treatment of choice for advanced breast cancer.

Journal Article↗
PubMed1994

Comparison of O6-methylguanine-DNA methyltransferase mRNA levels in Ha-ras mutated and non-mutated rat mammary tumors induced by N-methyl-N-nitrosourea.

Activation of the Ha-ras oncogene in N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors has been well documented. Such Ha-ras activation is thought to be brought about by direct action of carcinogens resulting in a G-->A transition at the second nucleotide of codon 12. However, a DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT), can specifically remove methyl groups from O6-methylguanine, which is a major mutagenic and carcinogenic DNA lesion leading to the G-->A transition. In this study, we compared the amount of MGMT mRNA in MNU-induced rat mammary tumors with and without such Ha-ras activation. A single injection of MNU into 82 female Sprague-Dawley rats induced 80 mammary carcinomas. RNase protection analysis and subsequent sequencing revealed that 42 of 65 randomly selected tumors contained Ha-ras oncogenes activated by the G-->A transition. The amount of MGMT mRNA was then measured by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR) amplification and Southern hybridization. No obvious difference in the level of MGMT mRNA was detected between the two tumor groups. In addition, in the course of our experiment, five of 42 tumors classified as containing activated Ha-ras oncogenes proved to contain low percentages of tumor cells with the Ha-ras activation. These results suggest that Ha-ras activation in MNU-induced rat mammary tumors may not necessarily be influenced by differences in MGMT activity. They also raise the possibility that activation of other oncogenes and/or inactivation of unidentified tumor suppressor gene(s) may be involved in development of a certain proportion of tumors with activated Ha-ras oncogenes, as is suspected in the case of tumors without Ha-ras activation.

Animals↗
PubMed1993

Adrenal metastasis from carcinoma of the colon and rectum: a report of three cases.

We report herein three cases of patients with adrenal metastases from colorectal carcinoma. Recurrent disease was suspected following markedly elevated levels of serum carcinoembryonic antigen (CEA), and adrenal metastases were confirmed by computed tomography (CT) scanning in all three patients. The adrenal metastasis was solitary in one patient and this patient is still alive and free from disease 1 year after undergoing complete removal of the adrenal metastasis. On the other hand, metastatic disease was not limited to the adrenal gland in the other two patients and both died of recurrent disease, 33 months and 4 months after undergoing removal of the adrenal metastases, respectively. Thus, although the prognosis of adrenal metastasis from colorectal cancer is usually poor, we believe that patients with a solitary adrenal metastasis will benefit from complete removal of the metastasis.

Adenocarcinoma↗
PubMed1993

Genetic alterations on chromosome 17 in human breast cancer: relationships to clinical features and DNA ploidy.

We analyzed DNA from 105 primary breast cancers to assess amplification of the ERBB2 gene and loss of heterozygosity (LOH) on chromosome 17 using 4 polymorphic markers, and investigated the relationships of these genetic alterations to clinicopathological characteristics including DNA ploidy. Amplification of the ERBB2 gene was observed in 28% of the tumors. ERBB2 was amplified in tumors of all clinical stages and amplification was significantly linked to lymph node metastasis. LOH at D17S5 was observed in 28 of 57 informative tumors, while 17 of 62 informative tumors showed allelic loss at TP53. Among the 37 tumors informative for both loci, 32% showed LOH at these loci and 49% retained both alleles, indicating that there was a significant relationship between LOH at D17S5 and at TP53. We also examined LOH at the D17S74 and NME1 loci on chromosome 17q. LOH at D17S74 and NME1 was observed in 20% and 22% of the informative tumors, respectively, but there was no significant association between LOH at these loci. Of the 4 loci tested, LOH at TP53, D17S74, and NME1 was associated with clinical stage. Lymph node metastasis was correlated with LOH at NME1. Moreover, allelic loss was more frequent in aneuploid tumors than in diploid tumors. These results suggest that certain combinations of genetic alterations on chromosome 17 may cooperate in the development and/or progression of breast cancer. Furthermore, it seems likely that analysis of these alterations in breast cancer patients may provide useful prognostic information.

Alleles↗
PubMed1993

Analysis of genetic alterations related to the development and progression of breast carcinoma.

To study genetic alterations related to the development and/or progression of breast carcinoma, we examined amplification of the ERBB2, INT2, and MYC genes, as well as loss of heterozygosity (LOH) at loci on 11p, 16q, 17p (D17S5 and TP53), 17q (D17S74 and NME1), and 18q by restriction fragment length polymorphism analysis. The subjects were 26 patients with small breast carcinomas (< or = 2 cm) and 88 patients with larger breast carcinomas (2 to < 5 cm). All patients were free of distant metastasis. As tumor diameter increased, the frequency of oncogene amplification and LOH at all loci except D17S5 increased. However, there was no relationship between tumor diameter and amplification of specific oncogenes or allelic loss at specific loci. LOH at D17S5 was detected in 40% of small breast carcinomas (< or = 2 cm) and 43% of larger breast carcinomas (2 to < 5 cm). There was a significant correlation of LOH at D17S5 with INT2 amplification or with LOH on 11p, 16q, and 18q. These findings suggest that LOH at D17S5 may be involved in the early stage of breast carcinoma development, while INT2 amplification and LOH at 11p, 16q, and 18q appear to be genetic alterations that occur with tumor progression. In addition, as lymph node metastases were significantly related to amplification of the ERBB2 and MYC genes, and LOH of the NME1 gene, these genetic alterations may play a role in the mechanism of lymph node metastases.

Breast Neoplasms↗
PubMed1993

[The significance of c-erbB-2 and int-2 gene alterations and DNA ploidy pattern for aggressiveness of breast cancer].

We have analyzed amplification of the c-erbB-2 and int-2 genes, and restriction fragment length polymorphisms (RFLPs) of the int-2 gene in 105 primary breast carcinomas. In 90 of 105 samples, overexpression of the c-erbB-2 protein and the DNA ploidy pattern were also analyzed. Amplification of the c-erbB-2 and int-2 gene was found in 27% and in 17%, respectively. No statistical correlation between c-erbB-2 and int-2 genes amplification was observed. Overexpression of the c-erbB-2 protein was detected in 28% of samples. A correlation was observed between amplification of the c-erbB-2 gene and positive nodal status. Amplification of the int-2 gene showed no correlation with clinicopathological parameters, except that a significantly higher incidence of amplification was observed in breast carcinoma with more than 4 positive lymph nodes. Genotypes of the int-2 gene identified by RFLPs analysis revealed no correlation with clinicopathological parameters. DNA ploidy pattern, which showed neither correlation with c-erbB-2 nor int-2 genetic alterations, was associated with tumor size and TNM classification. Our result suggests that analysis of genetic alterations of the c-erbB-2 and int-2 genes and the DNA ploidy pattern may be a useful adjunct in the assessment of aggressiveness of breast carcinoma.

Breast Neoplasms↗
PubMed1993

[Immunohistochemical analysis of overexpression of c-erbB-2 protein in node-positive breast carcinoma].

We studied the overexpression of c-erbB-2 protein in formalin-fixed, paraffin-embedded tissues from matched primary tumors and metastatic lymph nodes derived from each of 95 breast carcinoma patients. Twenty of 95 primary tumors (21%) exhibited positive membrane staining. Positive staining was also detected in the metastatic lymph nodes from 20 patients. In 19 patients overexpression of c-erbB-2 protein was observed in both primary and metastatic lymph nodes, indicating that there is a significant correlation between c-erbB-2 protein overexpression of primary and secondary metastatic lesion. Overexpression of the c-erbB-2 protein was observed at almost the same frequency regardless of clinical stage. The c-erbB-2 protein overexpression was associated with an absence of estrogen and progesterone receptors. Furthermore the overall survival and disease-free survival were reduced, although not significantly, in the patients with c-erbB-2 protein overexpression. Multivariate analysis indicated that overexpression of c-erbB-2 protein was a significant predictor of early relapse for node-positive patients. These results suggest that overexpression of the c-erbB-2 protein plays a role not only in an early stage but also in a metastatic stage in a certain patient subpopulation with breast carcinoma, and that c-erbB-2 protein overexpression analyzed by immunohistochemical techniques is of clinical significance in these patients.

Analysis of Variance↗
PubMed1992

Correlation of loss of alleles on the short arms of chromosomes 11 and 17 with metastasis of primary breast cancer to lymph nodes.

To examine the role of loss of heterozygosity (LOH) during tumor development and/or progression, we looked for correlations between metastasis of breast cancer to a regional lymph node(s) and LOH of chromosomal arms 11p, 13q, 16q, 17p, and 17q, where frequent losses in primary tumors have been detected. No correlation between lymph node metastasis and LOH of chromosomes 13q, 16q, or 17q was observed. However, tumors showing LOH of chromosomes 11p (chi 2 = 10.82, P less than 0.01) and 17p (chi 2 = 6.78, P less than 0.01) revealed a significantly higher incidence of metastasis to a regional lymph node(s) than tumors without LOH on these chromosomal arms. Furthermore, only four of 30 (13%) patients with tumors that retained both 11p and 17p had metastasis to a regional lymph node(s), compared with 24 of 32 (75%) patients with tumors that had lost both 11p and 17p. Analysis of LOH with markers on chromosomes 11p and 17p in a large number of tumors indicated that the peritelomeric region of each of these chromosomal arms contains a tumor suppressor gene that may be associated with tumor progression, particularly metastasis to a regional lymph node(s).

Alleles↗
PubMed1992

Proliferating cell nuclear antigen in breast lesions: correlation of c-erbB-2 oncoprotein and EGF receptor and its clinicopathological significance in breast cancer.

Monoclonal anti-proliferating cell nuclear antigen (PCNA PC10), which is directed against a 36 kDa auxiliary protein for DNA polymerase delta specific for the S-phase of cell cycle, was used to measure tumour cell proliferation in 4 lactating breasts and 98 benign and malignant breast tumours. The percentage of PCNA-positive cells determined by point counting was significantly lower in the lactating breast [mean 3.6%, standard deviation (SD) 0.67, n = 5] than in fibroadenoma and mastopathy (mean 23.7, SD 5.0, n = 2). Primary breast carcinoma showed a PCNA index ranging from 2% to 36% (mean 12.3, SD 9.3, n = 50), whereas in recurrent carcinoma the index was mean 28.5, SD 4.0. A high index was correlated with c-erbB-2 and epidermal growth factor (EGF) receptor membrane reactivity, worsening histological grade, poor survival and disease-free survival. The expression of c-erbB-2 and EGF receptor was associated with poor survival and disease-free survival in primary breast cancer patients.

Breast Neoplasms↗
PubMed1991

[The elevation of serum iron level with oral administration of medroxyprogesterone acetate (MPA) in patients with breast cancer].

The elevation of serum iron level was noted in six out of 45 patients with breast cancers who were treated by medroxyprogesterone acetate (MPA) in Kinki University Hospital. Those six patients were not found to be involved in hemolysis and liver dysfunction during the treatment. The level of serum iron was demonstrated 205-338 micrograms/dl in the blood after MPA treatment. This elevation of serum iron level was not related with another anti-cancer agents. There was no observed serious complication with high level of serum iron. This is the first report of the elevation of serum iron level following MPA therapy for the patients with breast cancers.

Aged↗
PubMed1990

[Clinical evaluation of estramustine phosphate in the treatment of patients with advanced breast cancers].

Estramustine phosphate, an anti-prostatic cancer agent, was investigated on eleven patients to evaluate the efficacy in a treatment of advanced breast cancers. The daily dose of medication was 840 mg. According to criteria of Japan Society for Cancer Therapy, none was assessed as CR, three as PR, four as NC and PD. The response rate was 27.3%. There was no differences in response rates among estrogen receptor status. A favourable response was observed in postmenopausal patients but no response in premenopausal, as well as a good response in lesions of soft tissue and lung, a poor response in lesions of liver and bone. As to toxicity of estramustine phosphate, gastrointestinal disorders such as nausea, vomiting and diarrhea were noted frequently during the treatment, and a long term administration was not able to perform in premenopausal patients because of vaginal bleeding and discharge, and pain in breast. The estramustine phosphate therapy for advanced breast cancers was regarded as one of modalities for a treatment of postmenopausal patients as a second line therapy. This is the first report in Japan discussing the efficacy of estramustine phosphate for a treatment of breast cancer.

Administration, Oral↗
PubMed1989

Infrequent activation of K-ras, H-ras, and other oncogenes in hepatocellular neoplasms initiated by methyl(acetoxymethyl)nitrosamine, a methylating agent, and promoted by phenobarbital in F344 rats.

Fischer 344/Ncr rats of both sexes were subjected to partial hepatectomy and then initiated 21-24 h later by a single injection of methyl(acetoxymethyl)nitrosamine at 0.1 mmol/kg body weight via the portal vein. Beginning 3 weeks later, development of hepatocellular neoplasms in initiated rats was promoted by feeding 0.05% phenobarbital (PB) in the diet. Not only intrahepatic lesions but also a variety of extrahepatic tumors were induced. High-molecular-weight DNAs were prepared from 67 samples of grossly normal liver containing multiple preneoplastic foci/areas of microscopic dimensions, 137 hepatocellular adenomas (nodules), 93 hepatocellular carcinomas (HCC), 10 cholangiomas, and 25 extrahepatic tumors in 95 rats and tested for transforming activity in the NIH 3T3 transfection assay. DNA preparations from 7 of 93 HCCs, 2 of 10 cholangiomas, 2 of 137 nodules, 1 histiocytic sarcoma, and 1 thyroid carcinoma were positive in the transfection assay. Southern blot analysis showed that NIH 3T3 transformants induced by DNA from 5 HCCs, 1 hepatocellular adenoma, 1 cholangioma, 1 histiocytic sarcoma, and 1 thyroid carcinoma contained an activated K-ras gene of rat origin. Rat-derived H-ras was identified in transformants from 2 additional HCCs and rat c-raf from 1 hepatocellular adenoma. The transforming gene from one cholangioma showed no sequence homology to the ras genes, neu, or c-raf. Immunoprecipitation analysis of ras Mr 21,000 protein in 11 transformants indicated that, based upon protein electrophoretic mobilities, activation of the ras genes consistently resulted from mutations in codon 12 of these genes. Selective oligonucleotide analysis revealed that a G----A transition in the second base of codon 12 of K-ras was present in the 9 K-ras-positive transformants and also in DNAs prepared from the original tumors. In contrast, oligonucleotide hybridization experiments with DNAs from 35 hepatocellular tumors that were negative in transfection assays revealed the presence of mutant K-ras in 1 of 15 HCCs; no mutation could be detected in 20 transfection-negative adenomas. The infrequency of detection of a specific oncogene, more frequent detection of oncogenes in malignant tumors, and failure to observe activated oncogenes in preneoplastic lesions suggest that activation of ras oncogenes may occur as a late and infrequent event in the evolution of some rat hepatocellular neoplasms and that mutation of a specific ras locus is not an obligatory early event in the genesis of these neoplasms.

Animals↗