Biomedical subjects

Masaki Kitajima

Publications and source records attributed to Masaki Kitajima.

At least 235 records · Page 13Linked to original sources

PubMedDate not supplied

A neo-esophagus reconstructed by cultured human esophageal epithelial cells, smooth muscle cells, fibroblasts, and collagen.

The scientists involved in this study attempted to develop an artificial esophagus constructed of autologous cells grown by cell culture methods on an extracellular matrix. An artificial esophagus consisting of human esophageal epithelial cells, dermal fibroblasts, and smooth muscle cells isolated from the aortic media, was attempted. The purpose of this study was to examine whether smooth muscle cells could be used in the transforming matrix. Human fibroblasts were embedded in Type I collagen superimposed on the collagen layer of smooth muscle cells. Next, human esophageal epithelial cells were cultured on the collagen layer of the fibroblasts. The resulting collagen sheets were cultured in vitro for 1 week, then transplanted on the latissimus dorsi muscles of athymic rats. The sheets were examined histologically at 1 and 2 weeks using hematoxylin eosin and immunologic stain methods (antiactin antibody). At the end of 2 weeks after transplantation, on microscopic observation of the collagen sheets, it appeared that the epithelial layer, the submucosal tissue layer, and the proper muscle layer had been reconstructed. Additionally, the authors successfully isolated smooth muscle cells from the media of the left gastric artery as a surgical specimen by explant cell culture. The ability to transform collagen sheets consisting of esophageal epithelial cells, fibroblasts, and smooth muscle cells from a surgical specimen into a luminal structure may enable clinical application of the artificial esophagus.

Animals↗

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Docetaxel enhances the cytotoxicity of anthracyclines by increasing intracellular drug accumulation.

We assessed the combined antitumor activity of docetaxel and doxorubicin (DXR) and tetrahydropyranyl-adriamycin (THP) using the human breast carcinoma cell lines R-27 and MDA-MB-231. Synergistic antitumor activity was observed for both combined docetaxel and DXR, and docetaxel and THP against R-27 cells when contacted simultaneously. However, only additive effects were observed against MDA-MB-231 cells. Intracellular concentrations of DXR and THP in R-27 cells were significantly increased by docetaxel pretreatment, however, this increase was not observed in MDA-MB-231 cells, which exhibited only additive sensitivity to the treatment. Thus, docetaxel increased the antitumor activity of anthracyclines by increasing their intracellular concentrations.

Antineoplastic Combined Chemotherapy Protocols↗

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Neoadjuvant chemotherapy of irinotecan, 5-fluorouracil and leucovorin in patients with advanced rectal cancer. Report of two cases.

We report on two patients with T3N1 rectal cancer treated with a combination of irinotecan, 5-fluorouracil and leucovorin as neoadjuvant chemotherapy. On days 1, 8 and 15 of this 4-week cycle, leucovorin (250 mg/m2) was administered in a 2-hour intravenous infusion, followed by 5-fluorouracil (500 mg/m2) in a 10-min intravenous bolus, and then irinotecan (80 mg/m2) in a 90-min intravenous infusion. During the chemotherapy, no grade 3-4 toxicities were observed. Two weeks after the completion of 2 cycles of this regimen, both patients underwent surgery without postoperative complications. The responses were one pathological and one macroscopic complete response. Both patients with T3 tumors were down-staged to pT0 and pT2, respectively. As for the N stage, both patients were down-staged to pN0. The combination of irinotecan/5-fluorouracil/leucovorin appears to be feasible and effective, and to have a potential as an optimal neoadjuvant therapy in patients with advanced rectal cancer.

Adenocarcinoma↗

PubMedDate not supplied

Clinical usefulness of chemosensitivity test for advanced colorectal cancer.

We assessed the usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in the evaluation of appropriate adjuvant cancer chemotherapy for patients with advanced colorectal cancer. We analyzed 405 cases of colorectal cancer treated between January 1990 and August 1999 in terms of the MTT assay and survival outcome. Patients with Dukes' C and D were classified into a "surgery alone" group (n = 53), a "sensitive" group who received drugs that had a greater than 50% inhibition rate by MTT assay (n = 23), or "resistant"" group who were insensitive to the chemotherapy drugs (n = 124). Statistically significant differences in survival outcome were observed between the groups, with the sensitive group showing significantly better survival compared with the resistant group (p = 0.0158) and the surgery-alone group (p = 0.0004). Our results suggest that the MTT assay may be useful in evaluating the optimum adjuvant chemotherapy for patients with advanced colorectal cancer.

Antineoplastic Combined Chemotherapy Protocols↗

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A potential important role for thymidylate synthetase inhibition on antitumor activity of fluoropyrimidine and raltitexed.

BACKGROUND: Because thymidylate synthetase (TS) is a key enzyme in DNA synthesis, it has been used as a target for cancer chemotherapy. MATERIALS AND METHODS: We investigated the combined antitumor activity of raltitexed, 5-FU and UFT on human tumor xenografts in nude mice and examined changes in TS activity and 5-FU-bound RNA (F-RNA) levels. Human gastric (SC-1-NU) or colon (HT-29) carcinoma xenografts were transplanted subcutaneously into nude mice, and drugs administered intraperitoneally (raltitexed and 5-FU) or perorally (UFT) daily for 5 days, and repeated once after a 2-day interval. RESULTS: The antitumor effects were mostly equivalent between the treatment groups despite the different drugs and sequence orders. TS inhibition rates correlated with the tumor inhibition rate, which was statistically significant, while F-RNA levels did not correlate with antitumor activity. CONCLUSION: Our results indicated that the combination of fluoropyrimidine-related agents should be directed towards increased TS inhibition rather than increased F-RNA levels.

Animals↗

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Different pathways of 5-fluorouracil metabolism after continuous venous or bolus injection in patients with colon carcinoma: possible predictive value of thymidylate synthetase mRNA and ribonucleotide reductase for 5-fluorouracil sensitivity.

BACKGROUND: The mode of action of 5-fluorouracil (5-FU) was evaluated in patients with advanced colon cancer treated preoperatively with 5-FU. PATIENTS AND METHODS: After obtaining informed consent, 30 patients were randomized into three groups: untreated controls (n = 16), continuous intravenous infusion of 5-FU for 5 days at a dose of 320 mg/m2 (CIV group, n = 6), or bolus intravenous injection of 5-FU for 5 days at the same dose (bolus group, n = 8). Surgically-resected samples were analyzed by 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to detect sensitivity to 5-FU. Samples were also assayed for thymidylate synthetase (TS) activity, levels of 5-FU RNA (F-RNA), ribonucleotide reductase (RNR) activity, and TS mRNA levels expressed as the ratio of TS mRNA to beta-actin mRNA. RESULTS: While similar levels of TS inhibition were observed in the civ and bolus groups, F-RNA levels were significantly increased in the bolus group. The TS mRNA ratio was significantly higher in the 5-FU-resistant group than 5-FU-sensitive group. In the control group, the 5-FU-sensitive group showed higher RNR enzymatic activity compared to the 5-FU-resistant group. CONCLUSION: Our results suggested that the method of administration resulted in the induction of different 5-FU metabolic pathways. High TS mRNA and low RNR activity may be concerned with 5-FU-resistance in patients with advanced colon carcinoma.

Colonic Neoplasms↗

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Independent antitumor spectrum of UCN-01 (7-hydroxystaurosporine) against gastric and colorectal cancers as detected by MTT assay.

To evaluate the clinical usefulness of 7-hydroxystaurosporine (UCN-01), we compared the antitumor spectrum of UCN-01 with those of conventional antitumor agents against 40 fresh gastric and 40 fresh colorectal cancer specimens using the MTT assay. At a cut-off concentration of 30 micrograms/ml, UCN-01 showed a higher efficacy rate than mitomycin C (MMC), cisplatin, and 5-fluorouracil (5-FU) against both gastric and colorectal cancers. With respect to the gastric cancer specimens, the antitumor spectrum of UCN-01 was independent from those of the other agents, while the patterns of antitumor effects of the conventional agents all correlated significantly with each other. For the colorectal cancer specimens, the pattern of UCN-01-sensitivity did not correlate with the patterns for 5-FU or MMC. In conclusion, UCN-01 may be useful for clinical application against gastric and colorectal cancer due to its different antitumor spectrum from conventionally available agents.

Aged↗

PubMedDate not supplied

The cytotoxicity of a conjugate composed of human epidermal growth factor and eosinophil cationic protein.

BACKGROUND: Conventional targeted therapy with foreign proteins is highly immunogenic. In this study, we developed targeted therapy composed of human endogenous proteins and evaluated its efficacy in vitro. MATERIALS AND METHODS: Human epidermal growth factor (EGF) was chemically linked to human eosinophil cationic protein (ECP). The cytotoxicity of the EGF-ECP conjugate was evaluated by MTT assay. RESULTS: The conjugate showed dose-dependent cytotoxicity on EGF receptor (EGFR)-overexpressing BT-20 cells with an IC50 of 1.5 x 10(-7) M, whereas the IC50 of ECP alone was almost 10(-4) M. The conjugate had no detectable cytotoxicity against EGF receptor-deficient H69 cells. Excess EGF protected BT-20 cells from the cytotoxicity of the conjugate. Comparing the cytotoxicity and the level of EGFR expression, the cytotoxicity of the conjugate was positively correlated with the level of EGFR expression of each cell line. CONCLUSION: Conjugates composed solely of human proteins might be useful with less immunogenicity and less toxicity than the conventional immunotoxins for targeted therapy.

Blood Proteins↗

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Preoperative combination chemotherapy with S-1 and low dose cisplatin against highly advanced gastric carcinoma.

We performed preoperative chemotherapy with S-1 and low-dose CDDP (TSLD) to treat 9 patients of highly advanced gastric cancer. Five cases showed significant effect with severe fibrosis diagnosed as grade 1b-2 effect in histology, and all 9 cases showed at least grade 1a effect in either primary lesion or lymph node. While toxicity of less than grade 3 (gastrointestinal disorder and/or bone marrow suppression) were observed in 5 out of 9 cases (55.6%), no symptom was observed in 3 out of the 5 patients. We conclude that the TSLD is useful to control highly advanced gastric cancer.

Adenocarcinoma↗

PubMedDate not supplied

Antitumor activity of doxorubicin in combination with docetaxel against human breast cancer xenografts.

In this study we assessed the in vivo antitumor activity of combined docetaxel (DOCE) and doxorubicin (DXR) treatment using 2 human breast carcinoma cell xenografts (R-27 and MX-1) in the nude mouse model. The transplanted tumors were allowed to reach exponential growth, whereupon 10 or 40 mg DOCE per kg alone (i.p.), 8 mg DXR per kg alone (i.v.), or 10 mg/kg DOCE (i.p.) and 8 mg/kg of DXR (i.v.), in the sequence of DOCE followed by DXR, were administered. The in vivo antitumor activity of combined DOCE and DXR was synergistic against R-27 and additive against MX-1. P-glycoprotein (P-gp) was detected immunohistochemically, and was highly expressed in R-27, but not in MX-1. In conclusion, DOCE may increase the antitumor activity of DXR against P-gp-positive breast cancer xenografts, such that the DOCE and DXR combination may be a useful treatment in clinical breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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Cancer chemotherapy chemosensitivity testing is useful in evaluating the appropriate adjuvant cancer chemotherapy for stages III/IV gastric cancers without peritoneal dissemination.

BACKGROUND: Because of the low chemosensitivity of gastric cancer to conventional antitumor agents, the role of adjuvant chemotherapy for patients with advanced gastric cancer is controversial. We have previously proposed the necessity to evaluate the appropriateness of particular adjuvant cancer chemotherapies in individual advanced gastric cancer patients using chemosensitivity testing. In the present study, we compared the chemosensitivity and clinical outcomes of patients with Stages III and IV gastric cancer. PATIENTS AND METHODS: A total of 282 patients with advanced gastric cancer were analyzed retrospectively in terms of chemosensitivity as detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and survival outcome after surgery. Patients were split into groups according to Stage III or IV gastric cancer, then categorized into those that received surgery without chemotherapy (surgery-alone), and those that received adjuvant chemotherapy, for which all the evaluable cases were further divided into sensitive and resistant cases as determined by MTT assay. RESULTS: For Stage III gastric cancer patients, the sensitive group had a more favorable survival outcome than the other two groups. For Stage IV gastric cancer patients, the sensitive groups, had a more favorable survival outcome than the other two groups, but only in the absence of peritoneal dissemination. CONCLUSION: Chemosensitivity testing, based on the MTT assay, was useful in evaluating the appropriate cancer chemotherapy for patients with Stages III/IV gastric cancer without peritoneal dissemination.

Aged↗

PubMedDate not supplied

Alteration of DNA methylation status induced by epidermal growth factor in gastric cancer cell line, MKN-74.

DNA methylation dynamics are an important key to understanding various biological events, particularly regulation of gene expressions. To test the hypothesis that epidermal growth factor (EGF) signaling may influence DNA methylation status in cancer cells, which will show several altered biological characters compared with those before EGF-stimulation, we evaluated DNA methylation status with/without EGF-stimulation. The specific alteration of biological character in the gastric cancer cell line, MKN-74, by EGF was demonstrated by DNA synthesis, apoptosis and morphology, revealing that high concentrations of EGF (10 nM) altered the morphology accompanying a moderate increase of cell growth with induction of apoptosis, while low concentrations of EGF (0.1 nM) induced a high increase of cell growth without either morphological change or apoptosis. Although DNA synthesis is almost the same between 0.1 nM of EGF (164%) and 10 nM of EGF (172%), 0.1 nM of EGF showed higher methyltransferase activity than 10 nM of EGF did with a significant difference. In addition, the studies for both the methyl-base uptake into DNA incorporated with DNA synthesis and the methyl-base accepting capacity in DNA showed that a high concentration of EGF (10 nM) induced the demethylated status of the DNA compared with that of 0.1 nM EGF. Thus, we demonstrated that DNA methylation status is affected by EGF-stimulation with alteration of cell biological character.

Adenocarcinoma↗

PubMedDate not supplied

The potential for a selective cyclooxygenase-2 inhibitor in the prevention of liver metastasis in human colorectal cancer.

UNLABELLED: In a previous report we noted that cyclooxygenase-2 (COX-2) expression in clinical colorectal cancer is closely related to liver metastasis and survival. The aim of the present study was to clarify the role of COX-2 in liver metastasis and to examine the potential for a selective COX-2 inhibitor as a novel therapeutic agent in the treatment of colorectal cancer. MATERIALS AND METHODS: COX-2 expression of 6 kinds of human colon cancer cell lines, with various potentials for liver metastasis, were assessed by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). In human tumor xenografts/severe combined immune-deficient (SCID) mouse, we examined the effects of a selective COX-2 inhibitor (JTE-522) on tumor growth or liver metastasis of HT-29, a highly-metastatic cell line, or on COLO205, a non-metastatic cell line. The effect of JTE-522 on vascular endothelial growth factor (VEGF) expression and the activity of matrix metalloproteinases (MMPs) in HT-29 and COLO205 were assessed by enzyme-linked immunosorbent assay (ELISA) and gelatin zymography, respectively. RESULTS: COX-2 was expressed in all metastatic cell lines but not in the non-metastatic lines. JTE-522 prevented the liver metastasis of HT-29, but not the subcutaneous growth of HT-29 and COLO205 in SCID mice. In vitro, JTE-522 suppressed VEGF expression, but did not affect MMP production in HT-29; an inhibitory effect was not found in COLO205. CONCLUSION: A selective COX-2 inhibitor of JTE-522, was found to prevent liver metastases of colon cancer by suppressing VEGF expression, and therefore, COX-2 possibly plays an important role in liver metastasis of human colon cancer via the regulation of VEGF expression.

Animals↗

PubMedDate not supplied

Oncologic outcome of laparoscopic surgery for T1 and T2 colorectal carcinoma.

BACKGROUND/AIMS: Laparoscopic surgery for colorectal carcinoma remains controversial because of the technical difficulties and uncertainty regarding the long-term oncologic outcome after laparoscopic surgery. The objective of this study was to evaluate the feasibility for the laparoscopic surgery in the treatment of pT1 and pT2 colorectal carcinoma. METHODOLOGY: A review was performed of a prospective registry of 226 patients who underwent curative laparoscopic resection for pT1 and pT2 colorectal carcinoma between December, 1992 and December, 2001. Patient demographics and outcomes were recorded prospectively. RESULTS: The median follow-up was 43 months. Three patients (2.0%) in the pT1 group and 3 patients (3.9%) in the pT2 group developed recurrence of carcinoma. The expected five-year survival and disease-free survival rates in the pT1 group were 98.9% and 97.6%, respectively, whereas they were 93.6% and 93.4% in the pT2 group. No patient had port-site or peritoneal recurrence during the follow-up period. CONCLUSIONS: The findings of current study demonstrate that oncologic outcome of laparoscopic surgery for patients with pT1 and pT2 colorectal carcinoma appear to be comparable with conventional surgery. Laparoscopic surgery is oncologically appropriate at least for patients with pT1 and pT2 colorectal carcinoma.

Adult↗

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No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay.

To evaluate the clinical usefulness of taxanes as antitumor agents, we compared the antitumor spectrum of taxanes with those of conventional antitumor agents against 88 fresh gastric cancer specimens by MTT assay. At cut-off concentrations of 100 micrograms/ml for taxotere (Docetaxel, DOC) and 300 micrograms/ml for taxol (Paclitaxel, PAC), both agents showed a higher efficacy rate than mitomycin C (MMC), cisplatin (CDDP) and 5-fluorouracil (5-FU) against the gastric cancer specimens. The patterns of antitumor activity of DOC and PAC were independent from those of the conventional agents, while the patterns of antitumor activity of the taxanes significantly correlated with each other. Conventional agent antitumor activity patterns tended to correlate with the patterns of other conventional agents. In conclusion, taxanes may be useful for clinical application against gastric cancer due to their different antitumor spectrum as compared to conventional agents.

Aged↗

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Combination chemotherapy with JTE-522, a novel selective cyclooxygenase-2 inhibitor, and cisplatin against gastric cancer cell lines in vitro and in vivo.

COX-2 over-expression occurs in various cancers, but the role of COX-2 in cancer progression remains to be elucidated. We examined the inhibitory effects of a novel selective COX-2 inhibitor, JTE-522 (JT), against gastric cancer cell lines (TMK-1, MKN-45 and MKN-74) alone and in combination with cisplatin (CDDP). The antitumor activity of JTE-522 was evaluated by MTT assay, which revealed that JT alone elicits a dose-dependent antitumor activity in vitro. The JT/CDDP combination elicited a synergistic antitumor effect in MKN-45 cells and an additive effect in the other cell lines. In an in vivo study, 10 mg/kg JT and 12 mg/kg CDDP together elicited a synergistic antitumor activity against MKN-45 cells that were subcutaneously transplanted into nude mice. We conclude that JT is a potent antitumor agent in vitro and in vivo and that, in combination with CDDP, it might be a useful treatment strategy for gastric cancer.

Animals↗

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Platelets counts closely correlate with the disease-free survival interval of pancreatic cancer patients.

BACKGROUND/AIMS: We investigated the relationship between preoperative platelets count and the outcome of pancreatic cancer patients. METHODOLOGY: We retrospectively reviewed the clinical records of 105 patients with invasive ductal carcinoma of the pancreas who underwent radical resection at our institution over a 20-year period. The patients were divided into two groups based on their preoperative platelets counts: a group with thrombocytosis (> or = 40x10(4)/mL) and a group with non-elevated platelets counts (< 40x10(4)/mL). Histopathological findings, survival rates, recurrence patterns, and disease-free survival intervals were compared between the two groups. RESULTS: The outcome of the group with thrombocytosis was significantly poorer than that of the group with non-elevated platelets counts (p=0.043). The mean disease-free interval of patients with thrombocytosis was 4.9 months as opposed to 46.5 months for those with non-elevated platelets counts (p=0.006). Patients were classified into four groups according to changes in platelets counts after surgery. Consistently, the outcome of the group with both pre- and postoperative non-elevated platelets counts was the best compared to groups with post- and/or postoperative thrombocytosis. CONCLUSIONS: Our clinical data suggest that high platelets counts in the preoperative and postoperative period may be associated with a poor outcome and shortening of postoperative disease-free survival interval.

Adult↗

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The risk of lymph node metastasis in T1 colorectal carcinoma.

BACKGROUND/AIMS: The purpose of this study was to evaluate the risk of lymph node metastasis in patients with T1 colorectal carcinoma based on a uniform histopathology system, and to accomplish guidelines for additional surgery for endoscopically or locally removed T1 colorectal carcinoma. METHODOLOGY: A review was performed of 301 patients who underwent curative resection for T1 colorectal carcinoma between January 1970 and March 2001. The following clinicopathologic variables were evaluated using univariate and multivariate analysis: sex, age, location, size of tumor, macroscopic appearance, depth of submucosal invasion, lymphovascular invasion, and histologic grade. Lesions were subdivided according to the depth of submucosal invasion: sm1, submucosal invasion up to 500 microm from the muscularis mucosa; sm2, submucosal invasion between 500 and 1000 microm; sm3, submucosal invasion beyond 1000 microm. RESULTS: The overall lymph node metastasis rate was 6.3 per cent (19 of 301). Depth of submucosal invasion (sm3) and presence of lymphovascular invasion were significant risk factors for lymph node metastasis both univariately and multivariately. CONCLUSIONS: The findings of the current study demonstrated that significant risk factors for lymph node metastasis were level of submucosal invasion (sm3) and the presence of lymphovascular invasion. Surgery is indicated for patients with adverse factors.

Aged↗