Biomedical subjects

Y Sakaguchi

Publications and source records attributed to Y Sakaguchi.

212 records · Page 12Linked to original sources

PubMedDate not supplied

Apoptosis and p53 overexpression in human rectal cancer; relationship with response to hyperthermo-chemo-radiotherapy.

Hyperthermo-chemo-radio (HCR) therapy has been found to be effective for rectal cancer. Biomarkers for predicting the effect of HCR therapy are important in determining optimum treatment regimens. Hyperthermo-chemo-radiotherapy (HCR therapy), consisting of hyperthermia at 42 degrees C to 45 degrees C for 40 minutes (twice per week for two weeks), a total of 60 Gy irradiation and administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) (total 8400 mg), were prescribed pre-operatively for 29 patients with rectal cancer, using tissue specimens collected at pre-treatment biopsy. Apoptosis and overexpression of p53 protein were investigated histopathologically and immunohistochemically. On termination of HCR therapy, all the tumors were surgically resected and effectiveness of the therapy was evaluated histologically. Spontaneous apoptosis was evident in the pre-treatment cancer tissues of 14 patients (48.2%). In this apoptosis-positive group, the positive rate of expression of the p53 protein (21.4%, 3 out of 14) was lower as compared to findings in the apoptosis-negative group (66.7%, 10 out of 15). The response to HCR therapy was better in the apoptosis-positive group than in the apoptosis-negative group. We propose that spontaneous apoptosis is closely related to the function of wild-type p53 protein and is also a predictive biomarker of the effect of HCR therapy for patients with rectal cancer.

Antineoplastic Agents↗

PubMedDate not supplied

Dipyridamole augments the antitumor effects of fluorinated pyrimidines.

The antitumor effects of 5-fluorouracil (5-FU) and its analogues when combined with dipyridamole (DP) were investigated using B16 melanoma cells, in vitro and in vivo. First, the enhancement of 5-FU cytotoxicity by DP was examined in vitro. Cell growth was suppressed significantly by combining 5-FU and a nontoxic dose of DP (2.5 micrograms/ml) as compared to 5-FU alone. Next, the effect of DP was examined in vivo in combination with 5-FU, tegafur (FT) and UFT. UFT had the most remarkable antitumor effect when given in a single equimolar dose. Although DP alone did not affect tumor growth, the growth inhibition by antitumor drugs was augmented by DP. DP enhanced the antitumor effect of UFT significantly (P less than 0.05), and combination treatment with UFT and DP proved to be the most effective regimen for inhibiting growth of B16 melanoma. Combination treatment with UFT and DP shows promise for clinical cancer.

Animals↗

PubMedDate not supplied

Hyperthermia potentiates the cytotoxic activity of 1-hexylcarbamoyl-5-fluorouracil in sarcoma-180 cells and human malignant tumor cells.

The sunergic effects on sarcoma-180 (S-180) cells and on human malignant tumor cells between 1-hexylcarbamoyl-5-fluorouracil (HCFU), a lipophilic masked compound of 5-fluorouracil (5-FU), and hyperthermia were investigated. After the S-180 cells had been exposed to 77 microM of the drug for 3 days, with or without heat (43 degrees C) treatment for 2 hr, the succinate dehydrogenase (SD) activity was assayed to determine cell viability. The SD activity of S-180 cells treated with HCFU combined with heat decreased to about 7.8% of findings in the control cells. When the S-180 cells were implanted in a pad of the left posterior inferior foot of a mouse, the size of the tumor markedly decreased in case of exposure to HCFU and heat, compared with findings in other groups. Body weight of the mice remained stable after these procedures. Decrease in the SD activity of 6 human gastric cancers and 7 colorectal cancers exposed to HCFU combined with heat was compared with findings in the other groups. The SD activity markedly decreased when the cells were exposed to HCFU combined with heat. These results suggest that HCFU plus hyperthermia treatment is effective in the host with a malignancy and that the toxicity is minimal.

Animals↗

PubMedDate not supplied

Modulation of cytotoxic effect of anticancer drugs by dipyridamole in HeLa cells in vitro.

Exponentially growing HeLa cells were treated with various antitumor drugs and dipyridamole (DP), and the cell growth inhibition ratio was determined. Enhanced growth inhibition was found in combined treatment with DP and 5-fluorouracil, 1-hexylcarbamoyl-5-fluorouracil, methotrexate, adriamycin, daunomycin, 4'-0-tetrahydropyranyl-adriamycin, actinomycin D and vincristine. In contrast, reduction of the cytotoxic effect of cytosine arabinoside and enocitabine was found when these were combined with DP.

Antineoplastic Agents↗

PubMedDate not supplied

5-Fluorouracil is converted to F-nucleotides more extensively and is more cytotoxic in poorly differentiated than in well differentiated human gastric carcinoma.

The sensitivity to 5-fluorouracil (5-FU) was examined in 40 well differentiated and 50 poorly differentiated gastric cancer tissues and 15 normal tissues, using the in vitro succinate dehydrogenase inhibition (SDI) test. The tissue phosphorylating and degrading activities of 5-FU were compared in each type of tumor and in the normal tissues. Decreases in succinate dehydrogenase (SD) activity were more apparent in the poorly differentiated cancer tissues than in the well differentiated cancer tissues (p less than 0.005), and than in the normal tissues (p less than 0.001), exposed to 5-FU. The rate of sensitivity to 5-FU was higher in the poorly differentiated than in the well differentiated tissues and than in the normal tissues. The phosphorylating activities of 5-FU, in pathways involving uridine (Urd) phosphorylase and Urd Kinase, and thymidine (dThd) phosphorylase and dThd Kinase, were 1.7 fold higher in the poorly differentiated than in the well differentiated tissues and several fold higher than in the normal tissues (p less than 0.05-p less than 0.001). The degrading activity of 5-FU was similar in both types of tumor and in the normal tissues. Our findings show that 5-FU is actively metabolized to 5-FU-nucleotides in poorly differentiated tissues after incorporation into the tumor cells. 5-FU seems to have an increased susceptibility in cases of poorly differentiated gastric carcinoma.

Culture Techniques↗

PubMedDate not supplied

Cytotoxicity of N4-behenoyl-1-beta-D-arabinofuranosylcytosine through gradual conversion to 1-beta-D-arabinofuranosylcytosine in HeLa cells.

The metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) and N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) was studied in Hela cells. After the cells were exposed to ara-C at a concentration of 20 micrograms/ml or BH-AC at 46.5 micrograms/ml for 1, 3, 6, 12 or 24 hr, the level of ara-C was determined using the radioimmunoassay method, and the level of BH-AC and 1-beta-D-arabinofuranosyluracil (ara-U), using high-performance liquid chromatography. In the ara-C-treated cells, the intracellular ara-C increased to 1.26 micrograms/g cells after exposure for 6 hr, and ara-C was rapidly changed to ara-U in the cells and in the medium. In the BH-AC-treated cells, the intracellular BH-AC increased after exposure for 24 hr and BH-AC was gradually converted to ara-C in the cells: the intracellular level of ara-C was only 15% of that of BH-AC after exposure for 24 hr. BH-AC level in the medium persisted for 24 hr, at the initial concentration. Our findings show that BH-AC is stable compared to ara-C and gradually converts to ara-C. This conversion is presumably a critical step in the antineoplastic effect of BH-AC.

Antineoplastic Agents↗

PubMedDate not supplied

4'-O-tetrahydropyranyladriamycin has greater antineoplastic activity than adriamycin in various human tumours in vitro.

The sensitivities of 84 human tumor tissues (23 gastric, 8 colorectal cancers, 34 hepatomas, 6 breast, 6 lung cancers and 7 malignant lymphomas) to adriamycin (ADM) and 4'-0-tetrahydropyranyladriamycin (THP-ADM), a semisynthetic anthracycline glycoside, were determined using the in vitro succinate dehydrogenase inhibition (SDI) test. The succinate dehydrogenase (SD) activity of the tumor tissues was assayed following exposure to 6.9 microM of the drug for 3 days; sensitivity was considered positive when the SD activity decreased to below 50% of that of the control cells. In the case of exposure to THP-ADM, the SD activity in the tissue decreased and the decrease was more extensive in the gastric, colorectal cancers, hepatomas, lung cancers, with a statistically significant difference (P less than 0.001-P less than 0.05), but not in the breast cancers and malignant lymphomas. The rate of sensitivity was 70.2% for THP-ADM and 51.2% for ADM in the 84 tumor tissues. The percentage of tissues with a higher sensitivity to THP-ADM, compared to ADM, was 79.8%. As THP-ADM proved to be more cytotoxic than ADM to human tumors in vitro, this drug should be kept in mind when anti-cancer chemotherapy is designed.

Antineoplastic Agents↗

PubMedDate not supplied

Potentiation of 5-fluorouracil cytotoxicity by combining hyperthermia and dipyridamole in vitro.

Evidence was obtained for the augmentation of cytotoxic effects of 5-fluorouracil (5-FU) when hyperthermia and dipyridamole (DP) were combined in vitro. Nontoxic levels of DP enhanced the combined cytotoxicity of 5-FU and heat against HeLa and B16 melanoma cells, and the 50% effective concentration of 5-FU decreased 7.3 fold for HeLa cells and 3.0 fold for B16 melanoma cells, when exposed to heat plus DP. This combined effect did not depend on intracellular increases in the concentrations of 5-FU. Thus hyperthermia together with DP seems to improve the sensitivity of tumor cells to 5-FU. As the sensitivity of colorectal cancer tissue to drugs is low, 5-FU plus hyperthermia and DP shows promise for the treatment of such patients.

Cell Survival↗

PubMedDate not supplied

Clinicopathological features of patients who died with second primary cancer after curative resection for gastric cancer.

The appearance of a second cancer in patients who had undergone curative operation for the first gastric cancer is one of the crucial problems for the clinician. We analysed data on 910 patients with gastric cancer treated with curative resection, with respect to the risk factors for second primary cancer and the prognosis. Of 910 patients, 69 (7.6%) died with a second primary cancer. In patients with a second primary cancer, there were more men and age was more advanced, compared to the survivors. The gastric tumor was larger, the serosal invasion was more prominent and lymphatic involvement was more frequent. The postoperative 5-year survival for patients with a second primary cancer was 60.9%, the 10-year rate was 31.9% and the 15-year was 19.6%. Multivariate analysis revealed that risk factors for a second primary cancer was advanced age, male sex and a larger tumor. Our findings suggest that during the follow-up of patients with gastric cancer treated by curative resection and risk factors, a second primary cancer may occur in other organs, in addition to a recurrence of the first cancer.

Age Factors↗

PubMedDate not supplied

Lymphatic advancement to peritoneal dissemination and liver metastasis in gastric cancer patients.

Lymph node metastasis is a risk factor for the occurrence of peritoneal dissemination and liver metastasis in patients with gastric cancer. We analysed data on 893 Japanese patients with serosally invasive gastric cancer, with respect to the relation between lymph node metastasis and peritoneal dissemination or liver metastasis. All these patients were treated in our clinics. Lymph node metastasis was evident in 746 patients, and in these patients the tumors were larger, lymphatic and vascular involvement were prominent and rates of peritoneal dissemination and liver metastasis were higher. In 147 patients with no evidence of lymph node metastasis, peritoneal dissemination was seen in 3.4% of cases and there was no liver metastasis. In cases of peritoneal dissemination and in those with liver metastasis, the rate of lymphatic involvement was higher than when there was vascular involvement. Peritoneal dissemination and liver metastasis are likely to be concomitant with lymph node metastasis in cases of serosally invasive gastric cancer. It seems apparent that lymphatic spread leads to peritoneal dissemination and liver metastasis in patients with gastric cancer.

Female↗

PubMedDate not supplied

Apoptosis in normal tissues induced by 5-fluorouracil: comparison between bolus injection and prolonged infusion.

The induction of apoptosis in normal tissues was histopathologically examined in rats treated with 5-fluorouracil (5-FU). 5-FU was administered by either bolus intravenous injection or 72-hr prolonged intravenous infusion (PIF). Bolus injection and PIF of 5-FU induced different kinetic profiles of apoptosis in the thymus, spleen and ileum. The bolus injections of 5-FU induced a greater extent of apoptosis in these tissues, compared to PIF 5-FU. These data indicate that the kinetics and extent of apoptosis induced by 5-FU depends on the schedule of the 5-FU administration, and that 5-FU-induced toxicity may be related to 5-FU-induced apoptosis in normal tissues.

Animals↗

PubMedDate not supplied

Surgical treatment for gastric carcinomas with concomitant hepatic metastasis.

BACKGROUND/AIMS: We have reviewed our experience with gastric cancer patients having synchronous liver metastasis in an attempt to clarify how to treat such patients. PATIENTS AND METHODS: In 116 patients with gastric cancer metastatic to the liver, evaluations were executed to find an effective treatment. Fourteen received gastrectomy plus hepatic resection (Group A), 68 gastrectomy alone (Group B), and 34 non-resected (Group C). RESULTS: The average survival time was 15.0 months in Group A, 7.2 months in Group B and 3.6 months in Group C, with a statistical difference between Group B and Group C (p < 0.05). In Group A patients, the mean survival time was 21.5 months in those undergoing potentially curative surgery for the carcinoma without incurable factors other than liver metastasis. The survival time was 6.3 months in those undergoing noncurative gastrectomy and hepatectomy because of evidence of incurable metastatic spread, the value being similar to that following gastrectomy alone in Group B patients. In Group B, adjuvant chemotherapy led to a significant increase in survival (p < 0.05). CONCLUSIONS: Hepatectomy combined with gastrectomy seems to be effective as an active measure to lengthen survival for patients of gastric carcinoma and concomitant liver metastasis only when other incurable factors were not evident at operation. Noncurative gastrectomy followed by adjuvant chemotherapy is recommended in the presence of various incurable factors.

Case-Control Studies↗

PubMedDate not supplied

Overexpression of p53 is associated with growth pattern and prognosis in advanced gastric cancer.

BACKGROUND/AIMS: The growth pattern of advanced gastric carcinoma, based on volumetric analysis, is closely associated with the biological characteristics of tumors, including DNA ploidy, and is an important prognostic factor. Abnormality of the p53 tumor suppressor gene plays an important role in alteration of cells and possibly leads to cancer development. MATERIALS AND METHODS: Expression of tumor suppressor gene p53 was investigated immunohistochemically in the primary lesion of 196 patients with advanced gastric cancers, and the relationship of p53 immunopositivity with the growth pattern and prognosis was analyzed. RESULTS: Positive p53 staining was found in 94 (48%) of the 196 primary carcinomas. Vessel invasions were more frequent and lymph node metastasis was more extensive in p53-positive tumors (p < 0.05), whereas p53 immunopositivity was not associated with depth of cancer invasion nor with the stage of cancer. In the column and mountain type tumors, characterized by vertical or penetrative growth, positive p53 staining was found in 53.8% and 52.9%, respectively. In the funnel type tumor, characterized by superficially spreading growth, positive p53 staining was found in significantly lower incidence (28.9%, p < 0.05). The 5-year survival rates were 44.2% and 25.4% for patients with p53 negative and positive gastric carcinomas, respectively (p < 0.01). Multivariate analysis showed that p53 overexpression was an independent prognostic factor of patients with advanced gastric cancer. CONCLUSIONS: These findings suggest that p53 gene alteration is associated with less favorable prognosis of advanced gastric cancer, possibly by providing tumors with a potential of vertical growth into the gastric wall.

Carcinoma↗

PubMedDate not supplied

Optimal duration of whole body hyperthermia when combined with cis-diaminne-1,1-cychlobutane dicarboxylate platinum (II) (carboplatin).

Minimizing normal tissue toxicity can enhance the therapeutic gain of thermochemotherapy. For this purpose, we investigated the optimal duration of whole body hyperthermia (WBH) (41.5 degrees C) when administered simultaneously with carboplatin (CBDCA). Using a transplantable fibrosarcoma in Fischer 344 rats, we measured tumor growth delay (TGD) as well as normal tissue toxicities (body weight loss, thrombocytopenia) induced by various durations of WBH (0.5, 1.0, 1.5, 2.0 or 2.5 hours) when combined with CBDCA (30 mg/kg, i.v.). When combined with CBDCA, 1.0 hour WBH increased the TGD compared to 0.5 hour of WBH, but with WBH durations greater than 1.0 hour, the TGD did not further significantly increase. Measuring CBDCA-induced myelosuppression, the platelet count on day 6 post-treatment decreased from a control mean of 6.8 x 10(8)/ml to 1.8 x 10(8)/ml after 2.5 hour WBH exposure in a duration-dependent manner (p < 0.001). To estimate the specific therapeutic efficacy (STE), we calculated a ratio of TGD to myelosuppression (thrombocytopenia). Compared to other WBH exposure times, 1.0 hour duration of WBH combined with CBDCA produced the highest STE (2.8) and over 1.5 hour duration of WBH did not result in any additional increase in STE. We conclude that 1.0 hour WBH exposure is optimal when combined with CBDCA in order to maximize the therapeutic gain.

Animals↗