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Masakazu Toi

Publications and source records attributed to Masakazu Toi.

At least 73 records · Page 4Linked to original sources
PubMed2003

Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo.

We previously showed pomegranate seed oil and fermented juice polyphenols to retard oxidation and prostaglandin synthesis, to inhibit breast cancer cell proliferation and invasion, and to promote breast cancer cell apoptosis. Here we evaluated the anti-angiogenic potential of these materials in several ways. We checked a possible effect on angiogenic regulation by measuring vascular endothelial growth factor (VEGF), interleukin-4 (IL-4) and migration inhibitory factor (MIF) in the conditioned media of estrogen sensitive (MCF-7) or estrogen resistant (MDA-MB-231) human breast cancer cells, or immortalized normal human breast epithelial cells (MCF-10A), grown in the presence or absence of pomegranate seed oil (SESCO) or fermented juice polyphenols (W). VEGF was strongly downregulated in MCF-10A and MCF-7, and MIF upregulated in MDA-MB-231, overall showing significant potential for downregulation of angiogenesis by pomegranate fractions. An anti-proliferative effect on angiogenic cells was shown in human umbilical vein endothelial cell (HUVEC) and in myometrial and amniotic fluid fibroblasts, and inhibition of HUVEC tubule formation demonstrated in an in vitro model employing glass carrier beads. Finally, we showed a significant decrease in new blood vessel formation using the chicken chorioallantoic membrane (CAM) model in vivo. 'In sum, these varied studies employing different models in different laboratories overall demonstrate for the first time an anti-angiogenic potential of pomegranate fractions, suggesting further in vivo and clinical investigations (for updates: info@rimonest.com).

Angiogenesis Inhibitors↗
PubMed2003

Decision tree and paradigms of primary breast cancer: changes elicited by preoperative therapy.

A small difference in decision-making causes a big impact on the long-term outcome in cancer treatment. Novel methods such as preoperative systemic treatment or sentinel node biopsy (SNB) may alter the decision-trees in primary breast cancer management. Recent data showed that preoperative chemotherapy drives pathological complete response (pCR) that implies long-term relapse-free, for about 25% to 30% of early breast cancer patients. In fact, preoperative systemic therapy has come to be used regardless of the tumor stage. From the point of the clinical trial, pCR can be recognized as a new endpoint, which promises to speed up new therapy development. Therefore, it is crucial to consider new paradigms including preoperative therapy in the decision-tree. There are several criticisms regarding the preoperative therapy, such as a possibility of over-treatment, however these issues might be resolved by changing the concept or procedures slightly. For instance, if SNB is conducted before the treatment, the over-treatment issue can be eliminated. In this article, we will discuss the changes in decision-tree and paradigms for primary

Antineoplastic Agents↗
PubMed2003

[Male breast cancer].

As male breast cancer remains rare entity (less than 1% of cases of breast cancer), most of our current knowledge of it has been extrapolated from its female counterpart. The prevalence of male breast cancer increases with age, and the presentation occurs at an average age of approximately 60 years, 10 years older than in females with the disease. The majority of patients present with a painless, firm, subareolar mass, and the tumors are usually larger than 2 cm in diameter. There may be fixation to skin. Mammography and ultrasonography are useful to distinguish between breast cancer and gynecomastia. Pathologically, invasive ductal carcinoma is the predominant subtype, and lobular carcinoma is rare. Modified radical mastectomy is a principal surgical approach, and adjuvant therapy has been advocated in men based on the beneficial results of it in women. Hormonal manipulations constitute an essential part of adjuvant therapy, as male breast cancers have a high rate of hormone-receptor positivity. Although orchiectomy was practiced in the past, today, tamoxifen is the standard hormone therapy. With respect to systemic chemotherapy, the most common regimens are CMF (cyclophosphamide, methotrexate, 5-fluorouracil), or other anthracyclin-based regimens. In cases of disease recurrence, hormonal manipulations, chemotherapy, or radiotherapy can be administered for palliative purposes. Several selective aromatase inhibitors are now available; however, there are limited data regarding their efficacy in men. The prognosis does not seem to be poor compared to that of females when age and stage are matched. Further studies are needed to characterize the biologic and molecular properties of male breast cancer and their prognostic significance, and to devise optimal treatment strategies. However, it is interesting to note that p53 and c-erbB-2, are expressed and angiogenesis occurs in male breast cancer. Moreover, male breast cancer patients can carry BRCA2 mutations.

Aged↗
PubMed2002

Expression of estrogen receptor (ER) (beta)cx protein in ER(alpha)-positive breast cancer: specific correlation with progesterone receptor.

Estrogen receptor (ER) (beta)cx, a splice variant of ERbeta, is a dominant repressor of ER(alpha) function. In this study we investigated the possibility that because the progesterone receptor (PR) gene is a downstream target of activated ER(alpha), in ER(alpha)-positive breast cancers, expression of ER(beta)cx would result in repression of PR. In ER(alpha)-positive MCF-7 cells, stable transfection of an ER(beta)cx expression vector resulted in reduced expression of PR without affecting ER(alpha) expression. In breast cancers, immunohistochemical evaluation of ER(alpha)-positive foci for the expression of PR and ER(beta)cx revealed a significant correlation between a PR-negative phenotype and the presence of ER(beta)cx within the foci. However, when entire lesions were evaluated by Allred scoring in 115 ER(alpha)-positive breast cancer specimens, the presence of two distinct groups of patients could be discerned. One group expressed ER(beta)cx and had very reduced levels of PR expression, as expected. The second group showed both ER(beta)cx and high levels of PR. To evaluate the role of ER(beta)cx in sensitivity to tamoxifen, 18 core needle biopsies, obtained before preoperative treatment with tamoxifen, were investigated. The results show that expression of ER(beta)cx in primary lesions correlated with a poor response to tamoxifen, especially in cancers with a low PR expression in Allred score. This is the first evidence that evaluation of ER(beta)cx along with PR may contribute to a better characterization of ER(alpha)-positive breast cancers.

Amino Acid Sequence↗
PubMed2002

Pharmacokinetic and pharmacodynamic study of IST-622, a novel synthetic derivative of chartreusin, by oral administration in a phase II study of patients with breast cancer.

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC 0-24h =C 8h x17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.

Administration, Oral↗
PubMed2002

Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer.

Angiogenesis, the formation of new blood vessels, is controlled by a balance between positive and negative endothelial regulatory factors. Soluble vascular endothelial growth factor receptor-1 (sVEGFR1), a naturally occurring soluble form of VEGFR1, is a negative counterpart of the vascular endothelial growth factor (VEGF) signaling pathway, which has been characterized as one of the most important endothelial regulators in human tumor angiogenesis. In our study, we examined the expression of sVEGFR1 in 110 primary breast carcinomas, and assessed its clinical significance. Ninety-four of 110 tumors showed > or = 0.1 ng/mg protein of sVEGFR1 (range:0. 1-6.9 ng/mg protein; median: 1.03 ng/mg protein) as determined by a specific enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis confirmed the presence of sVEGFR1 in breast tumor tissues. The levels of sVEGFR1 were correlated significantly with the levels of VEGF. There was no significant correlation between the levels of sVEGFR1 and any clinico-pathological factors including age, menopause, nodal involvement and hormone receptor status. A univariate prognosis analysis showed that the intratumoral VEGF status, as determined by ELISA, was a significant prognostic indicator, but sVEGFR1 status was not. In the combined analysis, however, the ratio of sVEGFR1 and VEGF levels provided more statistically significant prognostic value than VEGF status alone. Tumors in which the sVEGFR1 levels exceeded VEGF levels 10-fold had a markedly favorable prognosis. Multivariate analysis also demonstrated that the ratio of sVEGFR1 and VEGF was an independent prognostic indicator after nodal status. In conclusion, sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The intratumoral balance between sVEGFR1 and VEGF levels might be crucial for the progression of breast cancer.

Angiogenesis Inhibitors↗
PubMed2002

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma.

Uridine phosphorylase (UPase) and an angiogenic enzyme, thymidine phosphorylase (dThdPase) are involved in degradation of the pyrimidine nucleosides through phosphorolysis. The expression levels of UPase and dThdPase are higher in human solid tumors including breast carcinomas than in normal tissues. To clarify the correlation between the expression levels of UPase and dThdPase genes and the clinicopathological factors, mRNA levels of these enzymes were examined by RT-PCR in 43 breast carcinomas. UPase gene expression was not correlated with dThdPase gene expression (regression coefficient R = 0.032). Although the expression level of the dThdPase gene was correlated with angiogenesis, detected by immunostaining endothelial cells (R = 0.66), that of UPase gene was not (R = 0.044). These results suggest that UPase does not have a strong angiogenic activity. The UPase gene expression levels in tumors of patients who relapsed were significantly higher than in those from patients who did not (p = 0.039). Although the expression levels of neither UPase or dThdPase were associated with age, pT, pN, pM, estrogen or progesterone receptor positivity, the patients with the higher levels of UPase gene expression had worse survival (p = 0.0038) than those with lower levels. In contrast, the expression of dThdPase gene was not related to relapse or survival of these patients with breast carcinoma. Our findings suggest that the expression level of UPase gene may be an independent prognostic marker in human breast carcinoma.

Adult↗
PubMed2002

Clinical impact of assay of estrogen receptor beta cx in breast cancer.

Since 1996 when estrogen receptor beta(ER beta) was discovered, much effort has been devoted to the question of the value of ER beta as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. When estrogen receptors are applied on sucrose gradients and quantified by ligand binding, we found that in contrast to ER alpha, which has a narrow tissue distribution, ER beta is expressed in many tissues including both normal and malignant breast tissue. Receptor protein levels in tissues can also be measured from the intensities of bands after Western blotting and can be quantified when purified and quantified receptor is used as a standard. With this technique, we found that there were some tumors which had over 600 fmol/mg of ER beta protein but no detectable estradiol binding. In such tumors, RT-PCR analysis revealed that ER beta cx is the only ER beta isoform present. ER beta cx is a splice variant which utilizes an alternative exon 8. This change in the C-terminus results in very poor binding to estradiol (E2) and has a dominant negative effect on ER alpha function. Immunohistochemical analysis with an ER beta cx specific antibody in 115 ER alpha-positive breast cancers revealed that about half of the samples expressed ER beta cx protein. Initial analysis of samples from patients with preoperative tamoxifen treatment revealed that ER alpha-positive tumors expressing ER beta cx and lacking PR seemed to be resistant to the anti-estrogen. We conclude that, in order to better characterize breast cancers and design appropriate therapy for individual patients, assays for ER beta cx must be made available to clinicians.

Blotting, Western↗
PubMed2002

Dynamism of tumour vasculature in the early phase of cancer progression: outcomes from oesophageal cancer research.

The vascular structure of cancer changes during tumour progression. A particularly dramatic change occurs during the early phase of progression when in situ tumour is transformed to invasive cancer. Recent advances in morphological investigations have made it possible to visualise and characterise the microvascular-network alterations. In addition, laboratory studies have also revealed the molecular profile--the changing levels of expression of different proteins--of cancer progression, which has helped to advance understanding of the mechanism of carcinogenesis. In this review, we discuss recent outcomes of research of oesophageal cancer and consider the responses of the vascular network and the development of new blood vessels during the early phase of cancer progression. Such considerations will be useful not only for understanding vascular biology but also for exploring novel diagnostic, therapeutic, and preventive approaches targeting early stage or latent phase human cancer.

Cell Transformation, Neoplastic↗
PubMed2002

Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma.

This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread.

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti-inflammatory and immunosuppressive activity of glucocorticoids. Ninety-three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico-pathological significance of MIF expression was evaluated. It was found that MIF was frequently over-expressed in primary breast cancer tissues. RT-PCR and western blotting analysis confirmed that wild-type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor-associated macrophages. Intratumoral MIF protein concentrations detected by enzyme-linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8 - 8126 ng/mg protein), and correlated inversely with nodal involvement (P = 0.039). No significant correlation was observed with other clinico-pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes (P = 0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin-1 beta, suggesting that interactions between tumor cells and tumor-associated macrophages play an important role in the up-regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor-stroma interactions of primary breast cancers, particularly those with a phenotype of node-negative or minimal nodal spread.

Adult↗
PubMed2002

Aromatase inhibitors and other novel agents in breast cancer treatment.

Thirty years after the introduction of tamoxifen, which was expanded from palliation of metastatic cancer to recent application for chemoprevention, the primacy of this drug as the mainline pharmacological intervention is currently being challenged by the third generation aromatase inhibitors and inactivators. In contrast to the oestrogen receptor blockade provided by tamoxifen, aromatase inhibitors result in deprivation of oestrogens in postmenopausal women both through paracrine/intracrine and endocrine modulation. Experimental evidence has shown a significant (97-99%) reduction of in vivo aromatase activity and an equal or sometimes better antitumour activity compared with megestrol acetate when these drugs are used as second-line treatment for metastatic breast cancer. Recent pivotal studies in first-line settings comparing tamoxifen for metastatic breast cancer and preliminary results from the neoadjuvant trials demonstrate that third generation aromatase inhibitors are superior to tamoxifen. With a better understanding of local tissue production of oestrogen through oestrone sulfatase, which hydrolyses oestrone sulfate to oestrone, and 17-beta-hydroxysteroid dehydrogenase Type 1, which in turn catalyses the reduction of oestrone to oestradiol, more powerful tactics for oestrogen starvation of cancer may be realised in future.

Journal Article↗
PubMed2002

Prognostic and predictive value of thymidine phosphorylase activity in early-stage breast cancer patients.

The antitumor effects of 5-fluorouracil (5-FU) and its derivatives depend upon the activity of nucleoside metabolic enzymes in tumor tissues. Thymidine phosphorylase (TP) converts 5'-deoxy-5-fluorouridine (5'-DFUR), an intermediate metabolite of capecitabine, to 5-FU. The relationship between TP expression in tumor tissues and patient survival was retrospectively examined in early-stage breast cancer patients treated with either oral 5'-DFUR administered for 6 months or surgery alone in a prospective randomized controlled trial. Thymidine phosphorylase expression in tumor cells and tumor-associated stromal (TAS) cells was examined by immunohistochemistry in 650 tissue samples from patients in this trial (n = 1217). Eight-year follow-up data showed that high TP expression in tumor cells was a significant prognostic indicator of a favorable outcome only for the patients in the 5'-DFUR group. Thus, TP expression was shown to be a predictive factor of 5'-DFUR efficacy. Conversely, a low TP expression in TAS cells was also a potent favorable prognostic indicator. These results on TP status in 2 tumor cell types could provide novel information for predicting prognosis for a patient subgroup, which would receive a probable therapeutic effect from 5'-DFUR, and presumably, from adjuvant therapy of capecitabine in early-stage breast cancer. Determination of TP status might also identify a patient subgroup whose prognosis is quite favorable even without adjuvant therapy. Further investigations on prognostic and predictive implications of TP activity in a clinical setting are warranted.

Administration, Oral↗
PubMed2002

[Efficacy of biweekly paclitaxel therapy in advanced or recurrent breast cancer].

To evaluate the feasibility and efficacy of a biweekly schedule of paclitaxel in advanced or recurrent breast cancer, 18 patients were enrolled in this pilot study. Paclitaxel of 120 mg/m2 was administered over 3 hours, and cycles were repeated every two weeks until disease progression or toxicity precluded further treatment. Patients received a median of 10 infusions with actual dose intensity of 55.9 mg/m2/wk, and median time to progression was 4.8 months. The overall response rate was 33.3%, and one patient achieved stable disease for at least 6 months. The responders included patients who received prior anthracycline and/or docetaxel treatment, and the response rate was consistent regardless of metastatic sites. Myelosuppression was the most common toxicity, and a few patients needed G-CSF support, treatment delay or dose reduction because of grade 3 or 4 neutropenia or leukopenia. Although one patient withdrew from this study because of grade 3 sensory disturbance, this regimen was generally well tolerated. A biweekly schedule of paclitaxel seems to be feasible and effective in patients with advanced or recurrent breast cancer.

Adult↗
PubMed2002

The effect of adjuvant 5'-deoxy-5-fluorouridine in early stage breast cancer patients: results from a multicenter randomized controlled trial.

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer.

Adult↗
PubMed2002

[Late phase II study of exemestane in postmenopausal patients with breast cancer resistant to anti-estrogenic agents].

A multi-center trial of exemestane 25 mg, an oral aromatase irreversible inactivator, was conducted to evaluate its efficacy and safety in 33 postmenopausal patients, and to investigate the pharmacokinetics/serum hormone levels in 16 postmenopausal patients, respectively, with breast cancer and anti-estrogen resistance. Exemestane 25 mg was given once daily for up to 48 weeks (maximum). The objective of this study was to confirm the reproducibility of the results shown in two studies in other countries with similar patients, to investigate the possibility of extrapolating the overseas data to Japanese. The response rate (CR + PR) was 24.2% (8.33%), which exceeded the minimum number (6 cases) required to evaluate efficacy. The response rate in this study was very similar to that observed in the two international open studies. Adverse events (subjective/objective symptoms), in which a causal relationship with exemestane administration could not be excluded, were observed in 26 cases (78.8%). Of these, hot flushes, increased sweating, fatigue, and insomnia occurred in more than 10% of patients, which was similar to that observed in the two international open studies. Abnormal laboratory results occurring in more than 10% of patients, in which a causal relationship with exemestane administration could not be excluded, were as follows: lymphocyte count decrease, alkaline phosphate increase, GOT increase, GPT increase, gamma-GTP increase, triglyceride increase, and inorganic phosphate increase, most of which were either grade 1 or 2. A remarkable decrease in serum hormone concentration was observed only for estrogen. The values of AUC0-infinity at day 1 and AUC0-24 h at day 29 (steady state) were similar, suggesting no accumulative effect of exemestane. These results demonstrate the anti-tumor effect and safety of exemestane in postmenopausal anti-estrogen resistant breast cancer patients. The reproducibility of the results of the two foreign studies was verified in Japanese patients, and it is concluded that the foreign trial data on exemestane can be extrapolated to Japanese.

Adult↗
PubMed2002

[Current indications for mastectomy in patients with breast cancer].

Recent aggressive changes in the strategy for breast cancer treatment have reduced the frequency of mastectomy as the primary surgery. In addition to the current expanded indications for breast-conserving therapy (BCT), the introduction of preoperative chemotherapy for patients with operable tumors allows BCT to be performed in a larger population of patients. The results of a questionnaire on breast cancer surgery conducted in Japan in 2000 revealed that the frequency of radical modified mastectomy had decreased by 52.2%. However, mastectomy cannot be completely eliminated, since some patients still present with locally advanced tumors and preoperative chemotherapy cannot remove the requirement for mastectomy in all patients. The current standard procedure for mastectomy appears to be the Auchincloss operation. The Halsted radical mastectomy is performed only for patients with cancer involving the pectoralis major muscle or the chest wall, and/or with marked axillary lymph node metastasis and Rotter's node metastasis. Simple mastectomy is selected for wide-spread noninvasive cancer and recently in our department for patients confirmed to be node negative by preoperative sentinely lymph node biopsy. In dealing with the changes in the treatment algorithm, we need to select the appropriate surgical options flexibly.

Algorithms↗