Showing papers by "Masakazu Toi published in 2003"

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

Abstract: 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).

A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera.

Abstract: We have developed an apoptosis assay based on measurement of a neoepitope of cytokeratin-18 (CK18-Asp396) exposed after caspase-cleavage and detected by the monoclonal antibody M30. The total amount of caspase-cleaved CK18 which has accumulated in cells and tissue culture media during apoptosis is measured by ELISA. The sensitivity is sufficient for use in the 96-well format to allow high-through-put screening of drug libraries. We here describe strategies allowing classification of pro-apoptotic compounds according to their profiles of induction of apoptosis in the presence of pharmacological inhibitors. The time course of induction of CK18 cleavage can furthermore be used to distinguish structurally similar compounds. We propose that compounds that induce rapid CK18 cleavage have mechanisms of actions distinct from conventional genotoxic and microtubuli-targeting agents, and we present one example of an agent that induces almost immediate mitochondrial depolarization and cytochrome c release. Finally, CK18-Asp396 cleavage products are released from cells in tissue culture, and presumably from tumor cells in vivo. These products can be measured in sera from cancer patients. We present evidence suggesting that it will be possible to use the M30-ELISA assay for measuring chemotherapy-induced apoptosis in patient sera, opening possibilities for monitoring therapy.

Immunohistochemical analysis of estrone sulfatase and aromatase in human breast cancer tissues.

Abstract: We examined, by immunohistochemical analysis, the expression of aromatase and estrone sulfatase (E1-STS) which are the two major enzymes involved in in situ estrogen synthesis in breast cancer tissue. In the 83 cases examined, E1-STS, which hydrolyses estrone sulfate (E1S) to estrone (E1), was dominantly detected in tumor cells in 43 (59.0%) cases. Aromatase, which converts androgens to estrogens, was dominantly detected in stromal cells of the tumor. It was detected in 39 (47.0%) of the 83 cases. There was no significant correlation between the expression of these two enzymes and clinicopathological factors. We found a tendency for a correlation between aromatase expression and E1-STS expression in breast tumor (p=0.075). In terms of the possible use of these enzymes as prognostic indicators, patients who had aromatase in their tumor showed longer relapse-free survival than those lacking aromatase (p=0.045). Significant correlations between the expression of aromatase and the angiogenesis regulators, vascular endothelial growth factor and thymidine phosphorylase, were found (p=0.047 and p=0.046, respectively), though the presence of aromatase did not correlate with intratumoral microvessel density. This may indicate that aromatase is involved in vascular permeability and recruitment of endothelial cells rather than neovascularization. It may be useful to study the expression of aromatase and E1-STS using immunocytochemical analysis for understanding the tumor characteristics in breast cancer.

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

Abstract: 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.

Randomized Controlled Trial Comparing Oral Doxifluridine Plus Oral Cyclophosphamide With Doxifluridine Alone in Women With Node-Positive Breast Cancer After Primary Surgery

Abstract: 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 recei...

Protracted administration of weekly docetaxel in metastatic breast cancer.

Abstract: The purpose of this study was to evaluate the efficacy and toxicity of weekly docetaxel in metastatic breast cancer. Fifty-seven patients were enrolled in this study of weekly docetaxel given at 25 mg/m(2)/week as a 1-h infusion in out-patient setting. Each cycle consisted of 3 weeks of therapy followed by 1-week treatment break, and the patients received a median of 24 infusions with a median cumulative dose of 600 mg/m(2). Overall response rate was 30% [95% confidence interval (CI), 18-42%], and 31% (18-42%) of patients had stable disease for at least 6 months. With a median follow-up of 16 months, the median time to treatment failure was 11 months (6-14 M), and 3-year survival rate was 60%. There was no grade 4 toxicity, and myelosuppression, fatigue, nausea, vomiting was mild, thus the regimen was generally well tolerated. On the other hand, 44% of patients had grade 1-2 nail change, 21% had grade 3 pleural effusion, 17% had grade 1-2 tearing, and these became more common with prolonged administration of docetaxel. Thus, a weekly schedule of docetaxel at low dose maintains activity and is less myelosuppressive, however, one should be careful about cumulative toxicities.

Survival benefit of KRN7000 immune therapy in combination with TNP470 in hamster liver metastasis model of pancreatic cancer.

Abstract: Pancreatic cancer is a solid malignancy with the poor prognosis largely due to frequent and lethal liver metastases. The combination of immunotherapy and anti-angiogenesis therapy might be a hopeful strategy for the treatment of distant metastases. The benefits of the combination therapy by an immune stimulator alpha-galactosylceramide (KRN7000) and an angiogenesis inhibitor AGM-1470 (TNP470) were evaluated on the hamster highly aggressive liver metastasis model using the syngeneic pancreatic cancer cell line HPD-NR. KRN7000 immediately activated hepatic mono-nuclear cells to produce IFN-gamma in vitro. Intraportal injection of KRN7000 exhibited a dense accumulation of CD4-CD8- natural killer T cells, around the liver metastases in vivo. KRN7000 treatment significantly inhibited the growth of liver metastases, and importantly, significant survival prolongation was confirmed when TNP470 treatment was added to it. Furthermore, cytotoxic T lymphocytes were induced at the sites of a few residual metastases in the liver of a long-term survivor. Thus, the combination of KRN7000 and TNP470 showed a high effectiveness for the treatment of liver metastases of pancreatic cancer.

Male breast cancer

Abstract: 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.

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

Abstract: 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

Mutation analysis of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinomas

Abstract: A major obstacle in the treatment of human solid carcinomas is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. ATP7B is overexpressed in human solid carcinomas such as breast, gastric and oral squamous cell carcinomas. ATP7B expression has an influential effect on some subsets of patients with cisplatin-treated carcinomas. ATP7B mutation is well-known as a cause of Wilson's disease. In addition, the six copper-binding domain and ATP-binding domain of ATP7B are important for the transportation of metals. Therefore, we performed the mutation analysis at the six copper-binding domain and ATP-binding domain of ATP7B. No mutation at the six copper-binding domain and ATP-binding domain was observed in breast, gastric and oral squameous cell carcinomas. These results indicate that the analysis of the ATP7B gene and/or protein will be helpful for the choice of chemotherapy in patients with human solid carcinomas.