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Biomedical subjects

Masakazu Toi

Publications and source records attributed to Masakazu Toi.

At least 55 records · Page 3Linked to original sources
PubMed2004

Novel sensitizing agents: potential contribution of COX-2 inhibitor for endocrine therapy of breast cancer.

Enhancement of the therapeutic effect of conventional drugs is currently an active treatment strategy for breast cancer, as shown in the clinical application of trastuzumab with chemotherapeutic agents, which prolonged survival even for metastatic disease. Cyclo-oxygenase 2(COX-2)inhibitors, which are chemoprevention agents for familial polyposis coli, are now contributing to this strategy in combination with chemotherapeutic and endocrine drugs. As an endocrine application, overexpression of COX-2 contributes to increased expression of aromatase in the breast tumor. In addition, it is also known to promote rich micro-vessels within the tumor through up-regulation of prostaglandin E2(PGE2), which can induce vascular endothelial growth factor(VEGF)and basic fibroblast growth factor(bFGF)in cancer cells, and can directly modulate endothelial cell proliferation. Since both rich vasculature and accelerated estrogen synthesis are thought to contribute to unfavorable conditions for the response to endocrine therapy, inhibiting COX-2 with COX-2 inhibitors is a promising strategy to potentiate endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed2004

Application of a continual reassessment method to a phase I clinical trial of capecitabine in combination with cyclophosphamide and epirubicin (CEX) for inoperable or recurrent breast cancer.

A phase I clinical trial was started in order to determine the recommended doses of capecitabine and epirubicin, when administered in combination with a fixed dose of cyclophosphamide (600 mg/m(2) day 1 q3 weeks) in patients with inoperable or recurrent breast cancer. This study consists of five dose levels with combinations of three levels of epirubicin (75, 90 and 100 mg/m(2) day 1 q3 weeks) and three levels of capecitabine (1255, 1657 and 1800 mg/m(2)/day consecutive administration for 2 weeks followed by 1 week of rest). Dose escalation and de-escalation decisions are based on a continual reassessment method (CRM). We conducted a survey of the clinical oncologists participating in this trial to determine the dose escalation/de-escalation rule, including a prior distribution for model parameters used in the CRM.

Adult↗
PubMed2004

Germline mutation of the LKB1/STK11 gene with loss of the normal allele in an aggressive breast cancer of Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant polyposis disorder with an increased risk of multiple cancer. The LKB1/STK11 gene, which acts as a tumor suppressor, is responsible for PJS and plays a role in suppressing breast cancer. The low expression of LKB1/STK11 in sporadic breast cancer is significantly associated with shorter survival. Here we describe a PJS patient with aggressive breast cancer that carried not only a germline mutation of LKB1/STK11 but also loss of the normal allele. The combination of these mutations may be associated with the poor prognosis of this patient. To our knowledge, we are the first to show that a germline mutation causing PJS is combined with the loss of the homologous normal allele of LKB1/STK11 in breast cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

[Controversies in endocrine therapy for breast cancer].

Major advances have been made in the treatment of postmenopausal women with hormone-sensitive breast cancer. Although tamoxifen has been the standard endocrine therapy for the past twenty years, the development of a third generation of aromatase inhibitors (Als), which effectively inhibit estrogen synthesis in extragonadal sites, gives us a wider range of choices in endocrine therapy. However, many questions remain with respect to the optimal use of Als. Differences between Als and tamoxifen as well as non-steroidal and steroidal Als in their long-term adverse effects on bone demineralization and lipid metabolism are only starting to emerge. The preferable orders for use of non-steroidal and steroidal Als, Als and pure anti-estrogen in patients with metastatic disease are emerging subjects to be examined, following several studies that showed non-cross reactivity between these types of drug. Neo-adjuvant endocrine therapy is now attempting to apply breast conserving surgery in larger numbers of elderly patients who are not suitable for neo-adjuvant chemotherapy. Moreover, many investigators are currently searching for surrogate markers in neo-adjuvant endocrine treatment that can predict the responsiveness and prognosis with adjuvant endocrine therapy. Further research concomitant with clinical trials may lead to a more reliable endocrine therapy modality in the treatment of breast cancer.

Anastrozole↗
PubMed2004

[Clinical usefulness of urinary diacetylpolyamines as novel tumor markers].

N1,N12-Diacetylspermine(DiAcSpm) and N1,N8-diacetylspermidine(DiAcSpd) are excreted in the urine of healthy persons as minor components of urinary polyamine, with small individual variations in amount. They are promising tumor markers, since their excretion is frequently elevated in patients with various types of cancers. DiAcSpm is sensitive in cancer detection, while DiAcSpd is highly specific for cancer. Diacetylpolyamines were initially characterized and determined by HPLC fractionation, followed by enzymatic detection. More recently, antibodies highly specific for DiAcSpm and DiAcSpd were developed, and an ELISA system applicable to the determination of urinary DiAcSpm was established. Measurement of urinary DiAcSpm using this ELISA system revealed that DiAcSpm is a more sensitive tumor marker than CEA, CA19-9 and CA15-3 for colon and breast cancers. More importantly, DiAcSpm efficiently detects patients at early stages. On the other hand, CEA, CA19-9 and CA15-3 are quite insensitive for early stage cancers. The urinary DiAcSpm level tends to remain low even in tumor-bearing individuals when their cancerous lesions remain static, while it rises rapidly concomitant with recurrence. DiAcSpm may serve as a prognostic indicator and marker for recurrence of prostate and colon cancers. Diacetylpolyamines may turn out to be general tumor markers, since active proliferation of any cancer tissues would likely be accompanied by activation of polyamine metabolism.

Biomarkers, Tumor↗
PubMed2004

DFU, a selective COX-2 inhibitor, suppresses MCF-7 xenograft tumor growth in mice.

Cyclooxygenase-2 (COX-2) inhibitors are regarded as potentially important in strategies for cancer treatment. however, the precise mechanisms of these anti-inflammatory drugs as anti-cancer therapy are still unknown. In this study, we examined the effect of DFU both in vitro on MCF-7 cell growth, as well as in vivo on tumor growth produced by MCF-7 cell injection in mice. DFU has growth inhibitory effects on tumor growth in mice compared to the control group. We examined the tumor tissues for apoptosis and angiogenesis by immunostaining. Apoptosis was detected only in the treatment group. DFU treatment also resulted in the inhibition of angiogenesis, as well as decreased COX-2 expression. Results of this study suggest that inhibitory effects of DFU might be COX-2 dependent.

Animals↗
PubMed2004

A close association between alteration in growth kinetics by neoadjuvant chemotherapy and survival outcome in primary breast cancer.

Few surrogate markers are available for predicting the survival benefit from chemotherapy in primary breast cancer. We examined tumor growth kinetics by assessing cytokeratin 18 neo-epitope (CK18NE), an apoptosis marker detected by M30 antibody and Ki-67 antigen, a proliferation marker detected by MIB-1 antibody in 72 primary breast cancer patients who underwent pre-operative anthracycline-based chemotherapy. Increase in M30 index and decrease in MIB-1 index after the exposure of 2 to 4 cycles of chemotherapy correlated significantly with pathological tumor response. Univariate survival analysis, conducted in the subgroup of 42 patients who underwent CAF (cyclophosphamide, adriamycin and 5-FU) therapy alone, showed that the patients with the high levels of M30 index (>35 counts/1000 tumor cells) and the low levels of MIB-1 index (<140 counts/1000 tumor cells) after chemotherapy had a remarkably favorable prognosis as compared with patients in other categories. In addition, the alteration in growth kinetics by the treatment showed a significant prognostic value. Multivariate analysis also confirmed that the post-treatment growth kinetics was an independent prognostic indicator. These findings suggest that the alteration in growth kinetics revealed by CK18NE and MIB-1 might be a surrogate marker for predicting the survival benefit from chemotherapy in primary breast cancer.

Adult↗
PubMed2004

[Trastuzumab treatment for breast cancer].

Trastuzumab is a recombinant humanized monoclonal antibody directed against the HER-2. HER-2 is overexpressed in 20-25% of invasive breast cancer and known as poor prognostic factor and its status of a tumor is related to response to trastuzumab. Combination therapy with trastuzumab and chemotherapy increases response rate, time to progression, and survival thus trastuzumab is perceived to be the first line treatment for HER-2 overexpressed metastatic breast cancer. The optimal duration and period of trastuzumab treatment are still unknown and result of large scale randomized trial will be expected.

Antibodies, Monoclonal↗
PubMed2004

1-hexylcarbamoyl-5-fluorouracil + cyclophosphamide + tamoxifen versus CMF + tamoxifen in women with lymph node-positive breast cancer after primary surgery: a randomized controlled trial.

We studied the usefulness of the oral 5-FU anti-cancer drug 1-hexylcarbamoyl-5-fluorouracil (HCFU) + cyclophosphamide (CPM) + tamoxifen (TAM) (HCT group) in comparison with CMF + TAM (CMFT group) in adjuvant therapy for breast cancer by a non-inferiority study based on a multi-institutional joint study. Clinical stage I, II primary breast cancers with histologically positive axillary lymph node metastasis were randomly assigned to the HCT group or the CMFT group after primary surgery. We registered 136 cases (HCT group 68 cases, CMFT group 68 cases). No significant difference in the 5-year overall survival rate (OS) and the 5-year disease-free survival rate (DFS) was found between the two groups. In the stratified analysis, DFS in cases in which the number of metastatic lymph nodes was 1-3 was significantly better in the HCT group (HCT group 84.3%, CMFT group 69.4%, log-rank test p=0.0496). No significant difference in the total incidence of adverse effects was found between the two groups, but there were significantly less adverse effects of grade 2 or over in the HCT group (p=0.034). The QOL survey at 3 months after surgery showed a significant decline of the QOL regarding lassitude, degree of difficulty in daily life, satisfaction with treatment and present mood in the CMFT group. Study results suggest that 2-year HCT therapy including the oral 5-FU anti-cancer drug HCFU is a useful adjuvant therapy which can replace CMFT therapy in early breast cancer cases with 3 or lower metastatic lymph nodes.

Adult↗
PubMed2004

The role of nuclear Y-box binding protein 1 as a global marker in drug resistance.

Gene expression can be regulated by nuclear factors at the transcriptional level. Many such factors regulate MDR1 gene expression, but what are the sequence elements and transcription factors that control the basal and inducible expression of this gene? The general principles through which transcription factors participate in drug resistance are now beginning to be understood. Here, we review the factors involved in the transcriptional regulation of the MDR1 gene. In particular, we focus on the transcription factor Y-box binding protein 1 and discuss the possible links between Y-box binding protein 1 expression and drug resistance in cancer, which are mediated by the transmembrane P-glycoprotein or non-P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.

Administration, Oral↗
PubMed2003

Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human breast carcinoma.

Drug resistance is a common clinical problem in cancer treatment. The overexpression of P-glycoprotein appears to be closely associated with multi-drug resistance to anticancer agents. YB-1 binds to the Y-box in the promoter region of MDR1, which encodes P-glycoprotein. We evaluated the correlation between nuclear YB-1 and P-glycoprotein expression and other molecules, such as hormonal receptors, angiogenic factors, immune factors, and methalloprotease in 63 human breast cancers. Nuclear YB-1 expression had a significant correlation with P-glycoprotein and PgR expression, and also with CD68 grade, concerning accumulation of tumor associated macrophages. This series did not demonstrate P-glycoprotein and nuclear YB-1 expression might be one of the useful prognostic marker of breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Expression of thymidylate synthase and thymidine phosphorylase in human breast carcinoma: implication for method to detect expression of these molecules in clinic.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor, and has an angiogenic activity in experimental models and human solid tumors. A critical step in the de novo pathway of DNA synthesis is the production of the pyrimidine nucleotide dTMP from dump and this reaction is catalyzed by thymidylate synthase (TS). Both dThdPase and TS levels seemed to be related to response to 5-fluorouracil (5-FU) therapy in different types of human solid tumors. The present study evaluated dThdPase and TS expression levels by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), using a same set of 39 breast carcinoma tissues for both methods. An inverted-relationship in the expression levels of TS and dThdPase was observed. Further, immunohistochemical analysis may be a better tool than analysis by RT-PCR in detection of dThdPase and TS, because of both dThdPase and TS expression in cells besides carcinoma cells. These imply that immunohistochemical analysis of dThdPase and TS is available for selection of patients who will be received 5-FU based chemotherapy.

Adult↗
PubMed2003

Weekly schedule of docetaxel in breast cancer: evaluation of response and toxicity.

Several recent studies have investigated the administration of docetaxel on a weekly basis. Here, we review the weekly use of docetaxel in breast cancer. To identify articles published on this topic we performed a computer-assisted MEDLINE search; additional references were found in the bibliographies of these articles. Several phase Tstudies of weekly docetaxel have provided encouraging data indicating that there is generally less myelosuppression than with the three week schedule in patients with a variety of advanced malignancies. Dose-limiting toxicities are reached at 43 to 50 mg/m(2), and the recommended dose ranges from 36 to 42 mg/m(2). Furthermore, five studies of weekly docetaxel in patients with metastatic breast cancer achieved 32 to 41% response rates using 25 to 40 mg/m(2) of docetaxel. Myelosuppression was mild, but fatigue was common and was the most common reason for dose reduction. In general, the planned dose intensity was equivalent to those used in standard three week schedules, and fatigue, asthenia, nail changes, excessive lacrimation (tearing), and fluid retention became more common with prolonged administration of docetaxel. Thus, weekly scheduling of docetaxel maintains efficacy and alters the toxicity profile, and the use of weekly docetaxel will become a promising alternative to three week dosing in the treatment of advanced breast cancer once randomized controlled studies confirm these results. However, there is still much to learn about the role of weekly docetaxel in adjuvant and neoadjuvant therapy.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Anti-angiogenic therapy in breast cancer.

Breast cancer is a worldwide epidemic among women, and one of the most rapidly increasing cancers. Not only the incidence rate but also the death rate is increasing. Despite enthusiastic efforts in early diagnosis, aggressive surgical treatment and application of additional non-operative modalities, its prognosis is still dismal. This emphasizes the necessity to develop new measures and strategies for its prevention. The understanding of the biology of angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of tumor neovasculature. Anti-angiogenic therapy is a promising, relatively new form of cancer treatment using drugs called angiogenesis inhibitors that specifically inhibit new blood vessel growth. Extensive studies conducted over the past few years have recognized that overexpression of COX-2, VEGF in the cancer might be the leading factors, can induce angiogenesis via induction of multiple pro-angiogenic regulators. Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to inhibit angiogenesis. Therefore, we should select a combination of angiogenesis inhibitors targeting COX-2, VEGF, and bFGF pathway. This article reviews the background and implementation of the current use of angiogenesis inhibitors and discusses the likely therapeutic roles in the early and advanced breast cancer together with its potential for chemoprevention.

Angiogenesis Inhibitors↗
PubMed2003

Genes commonly upregulated by hypoxia in human breast cancer cells MCF-7 and MDA-MB-231.

Hypoxia is a stress that causes alterations in signal transduction and gene instability. In the cancer microenvironment, hypoxia plays a significant role in forming a tumor phenotype and tumor progression. We aimed to identify the genes upregulated by hypoxia in human breast cancer cell lines, a hormone-dependent MCF-7 and a hormone-independent MDA-MB-231, using microarray analysis. These cells were exposed to two oxygen concentrations such as 21% and 1% in a time-course. Out of 12625 genes, 26 genes were identified as commonly upregulated in both MCF-7 and MDA-MB-231 cells. Some of these genes were already reported as hypoxia-related, but some of those were identified newly. These commonly upregulated genes between hormone-dependent and hormone-independent cells would be a clue to study hypoxia-related events and to explore the novel therapeutic targets in human breast cancer.

Breast Neoplasms↗
PubMed2003

Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer: preliminary report.

Anti-aromatase therapy is important in the treatment of breast cancer in postmenopausal women. Cyclooxygenase-2 (COX-2) inhibitors have been shown to be effective in chemoprevention in animal and clinical studies. A proof of principle study was performed to investigate the efficacy of combing anti-aromatase therapy (exemestane) and COX-2 inhibitors neoadjuvantly in hormone-sensitive postmenopausal breast cancers. The initial results are reported. The patients were randomly assigned to receive exemestane 25 mg daily and celecoxib 400 mg twice daily (group A), exemestane 25 mg daily (group B) and letrozole 2.5 mg daily (group C). The analysis was based on 20 patients who received at least one cycle of treatment. Fourteen patients completed two cycles and 12 patients three cycles. All groups showed clinical response and there was decrease in tumor area in each group. However, complete clinical response was only observed for group A patients. There was also progressive decline in blood CEA and CA15.3 levels but the differences between the three groups were not significant. The results of the preliminary analysis are encouraging but definitive conclusion could only be drawn after the completion of the study.

Androstadienes↗