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Biomedical subjects

T Taguchi

Publications and source records attributed to T Taguchi.

At least 127 records · Page 7Linked to original sources
PubMed1991

Time course of changes in brain energy metabolism of the rat after microsphere-induced cerebral embolism.

The present study was designed to elucidate pathophysiological changes in the brain energy metabolism after cerebral ischemia. Cerebral ischemia was induced in rats by administering microspheres into the right carotid canal, and the time course of changes in cerebral energy metabolism was examined up to the 7th day after the operation. Approximately 50% of the operated rats revealed typical symptoms of stroke. In the right hemisphere, cerebral ATP and creatine phosphate of the rat on the 1st to 7th day were greatly reduced by the microsphere-induced cerebral embolism (maximally 52 and 61%, respectively), whereas the tissue lactate level was increased on the 1st, 3rd and 5th day after the embolism (maximally 125%), suggesting an induction of microsphere-induced cerebral ischemia. These changes in the tissue metabolites were accompanied by a decrease in the mitochondrial oxidative phosphorylation measured in the presence of succinate. A similar trend in the changes of biochemical markers was observed in the left hemisphere, but to a lesser degree or to an insignificant degree. The pathophysiological alterations in behavior and cerebral metabolism of microsphere-injected rats tended to return toward the normal levels on the 7th day after the operation. The results provided information on a useful model for therapeutic studies of anti-ischemic agents in the brain.

Adenosine Triphosphate↗
PubMed1991

[DNA topoisomerase inhibitor as chemotherapeutic drug--clinical point of view].

CPT-11 is a semisynthesized derivative of camptothecin that has a potent antitumor activity by inhibiting DNA topoisomerase I. Leukopenia (mainly neutropenia) is DLF (dose limiting factor) and MTD (maximum tolerated dose) is higher than 250 mg/m2 in CPT-11 from the results of clinical phase I study. Now we are going on phase II study of CPT-11. We are seeing the cases responded to the drug in cancer of the lung, ovary, uterus, stomach, colorectum, pancreas, breast, malignant lymphoma etc.

Animals↗
PubMed1991

[Phase I study of YM881 (zinostatin stimalamer) suspension by hepatic arterial infusion. Research Group for Intra-arterial Infusion Therapy with YM881].

A phase I study of YM-881 (zinostatin stimalamer), neocarzinostatin combined with butylesterified styrene maleate, suspended in iodized poppy oil ethyl ester, was conducted in patients with hepatocellular carcinoma by giving single intra-arterial infusions via catheters inserted by Seldinger's method. Four dose levels, 2, 4, 6, and 8 mg, were tested. Major adverse reactions were fever, anorexia, nausea, vomiting, and abnormal hepatic function. Both the incidence and severity of adverse reactions tended to increase with the 8 mg dose. Tumor regression of 50% or more occurred in one receiving 2 mg and one receiving 4 mg. The results of the study suggest that doses of 6 mg or less may be appropriate for the phase II studies.

Adult↗
PubMed1991

[New interesting chemotherapeutic regimens in advanced gastric cancer].

We have made over view of new chemotherapeutic regimen for treatment of advanced gastric cancer 5-FU + MMC, FT + MMC and UFT + MMC therapy have been used widely for treatment of advanced gastric cancer as chemotherapeutic regimens in Japan. These regimens did not shown made than 25% in response rate as antitumor effect. Since development of CDDP, FP (5-FU + CDDP), FAP (5-FU + ADM + CDDP) and EAP (Etoposide + ADM + CDDP) is becoming gradually very important regimen for treatment of advanced stomach cancer patients. Recently, we have studied EAP therapy on 50 cases of advanced gastric cancer from January 1988 to September 1989. ADM 20 mg/m2, CDDP 40 mg/m2 and Etoposide 100 mg/m2 were administered on day 1 and 7, 2 and 8, and 4, 5 and 6, respectively, with not less than 2 courses every 3 to 4 weeks. The rate of effectiveness were obtained 43.8% with a confidence interval 95% of 30-58%. Median survival time was only 5.1 months for EAP therapy, which was highly effective but led to no prolonged survival period. Thus it is thought that good control of leukopenia, a dose-limiting factor remains to be examined. Biochemical modulation of 5-FU using such as MTX + LV and CDDP + LV (leucovorin) now under studying in the nation wide in Japan, so far it is getting better results.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

[Early changes of postpneumonectomy lung growth in premature rats].

Following pneumonectomy in animals, the contralateral lung increases in volume, weight, collagen content, protein, and cell number, reaching levels approximate to those of both lungs of control animals. The volume and weight response in quicker and more complete in young animals compared to old animals. The increase in the amount of DNA was found to be greater in young rats compared to old ones. However, little is known about the effects of pneumonectomy in immature animals, in which combined effects of normal and the compensatory lung growth may be expected. The present studies were aimed at elucidating early changes in terms of morphology and biochemistry in the contralateral lung following pneumonectomy in premature rats. Male Sprague-Dawley rats (2 week-old) were subdivided into 3 groups. Group P, underwent left pneumonectomy, group S was sham operated, which group C was matched by age, sex, and weight with group P. Morphological studies consisted of light microscopic morphometry and immunohistochemistry using anti-bromodeoxyuridine (BrdU) were performed. Biochemical studies included measurement of DNA polymerase activity, DNA and RNA content, collagen and elastin content. The wet lung weight in group P after one week reached approximately the same as that of bilateral lungs of groups S and C. The fixed lung volume of group P reached that of group S or group C at three weeks. The activity of DNA polymerase and BrdU positive alveoli were increased only during the early period following pneumonectomy. DNA content in group P reached the same range as group S and C at 4 weeks, suggesting the occurrence of cellular hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Phase II study of YM881 (zinostatin stimalamer) suspension injected into the hepatic artery. Research Group for Intra-arterial Injection Therapy with YM881].

A phase II study of YM 881 (zinostatin stimalamer) to determine the response and safety was conducted in patients with hepatocellular carcinoma by injecting a suspension of the drug into the hepatic artery. Repeated doses of 4 to 6 mg of the drug were given every 4 weeks so that the tumor tissues were filled with the suspension. Of the 195 registered patients, 15 were ineligible for the study, 8 dropped out, and data were missing for 5. A total of 167 patients completed the study. Response was assessed in the 167 patients who completed the study. CR was found in one, PR in 59, MR in 25, NC in 67, and PD in 15, with a response rate of 35.9. The safety of the drug was assessed in 177, excluding ineligible patients and 3 who dropped out because of the concurrent use of other drugs. Adverse reactions were found in 93.2% of the patients, and abnormal values in clinical laboratory tests in 60.5%. Major unwanted symptoms included fever, nausea, vomiting, and anorexia. Major abnormal changes in laboratory tests were elevated total bilirubin and LDH and abnormal hepatic function. About half the patients had malaise and pain related to the intra-arterial infusion therapy. The one year survival rate was 56.9%, and the duration of survival of 50% of the patients was 407 days.

Adult↗
PubMed1991

Efficacy of internal mammary node dissection in the treatment of breast cancer.

The present study compares clinical and pathological findings and survival data from 410 patients who have undergone extended radical mastectomies in our hospital during the 20 years from 1967 with those derived from 261 who underwent mastectomies without dissections of the internal mammary nodes, in order to determine the value of additional internal mammary node dissection following standard radical mastectomy. Extended radical mastectomy was used in 289 of 361 (80.1%) patients with medial tumors, and in 121 of 310 (39.0%) with lateral tumors. Metastases to the internal mammary nodes were found in 18.5% (76) of all patients, in 20.4% (59) of the patients with medial tumors and in 14.0% (17) of those with lateral tumors. Of the patients with medial tumors, internal mammary node metastases were found in seven of 44 (15.9%) at TNM Stage I, and the rate of metastases rose with advances in stage. Internal mammary node metastases alone, without those to the axillary nodes, were found in 14 patients (4.8%) with medial tumors and in two with lateral tumors. The 10-year survival rate in patients with medial tumors and metastases to the internal mammary nodes only was 67.0%, which was as good as that in patients with metastases to the axillary nodes only. In conclusion, extended radical mastectomy was valuable in the treatment of relatively early medial breast cancer at TNM Stages I and II.

Adult↗
PubMed1991

[Phase I study of CI-898. CI-898 Study Group].

We conducted a phase I study of CI-898 (trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).

Adult↗
PubMed1991

[Predictability of preclinical evaluation of anticancer drugs by human gastrointestinal cancer--nude mouse panel].

We evaluated the predictability to clinical response of experimental effects of various anticancer agents on human cancer--nude mouse panel established in our department. The human cancer lines used were 12 gastric, 4 colorectal, 3 breast, 2 pancreatic cancers and 1 melanoma xenografted into BALB/c athymic nude mice under SPF conditions. Seven mice each with equivalent mean volume of sc inoculated tumor (about 100 mm3) were subjected to the treatment and control groups. Experimental treatment was conducted daily 25 times for antimetabolites, and intermittently 5 times once or twice a week for other drugs. Dosage of each drug adopted was maximal tolerated dose predetermined for the treatment schedule. Four weeks after the initiation of treatment, the therapeutic effect of each experiment was evaluated by the tumor growth inhibition rate (IR) based on the comparison of mean tumor weight between the 2 groups. When the IR was greater than 58%, the drug was evaluated as effective. The clinical response rate of each drug was referred from the result of the phase II study. Direct comparison of effects on 16 experimental chemotherapies in xenografts with responses to the corresponding clinical therapy of each donor patient revealed a fairly high accordance rate (94%). To elucidate the value of human cancer--nude mouse panel as the preclinical secondary screening, the response rates of 8 anticancer drugs treated to 15 cancer xenografts were compared with the cumulative clinical data available in each drug. Generally, the response rates of the human cancer xenografts to the drugs showed fairly good correlations with the cumulative clinical response rates of the corresponding drugs to the same organs. Using this panel, preclinical examinations of 6 new agents under development, including 254 S and other 2 CDDP derivatives, were performed in expectation the positive correlation with further clinical data.

Animals↗
PubMed1991

[Nuclear DNA content in breast cancer in relation to postoperative recurrence].

Nuclear DNA content in breast cancer patients who underwent extended radical mastectomy was investigated to evaluate its possible relation to postoperative recurrence. The most frequent site of the first recurrence in diploid type (D type) cases was the bone and the frequency was significantly higher than that in non-diploid type (N type) cases. On the other hand, the ploidy pattern in all cases associated with local or local lymph node recurrence was N type and the lung was the next frequent site of recurrence in N type case. The frequency of over 4c cells was the highest in the cases of local or local lymph node recurrence being significantly higher than in all cases of distant recurrence or of the bone recurrence. The cumulative disease-free survival rate in patients with D type breast cancer was significantly higher than that in patients with N type. These results suggest that nuclear DNA content provides important information for deciding therapy and the schedule of postoperative follow-up study based on the mode of recurrence.

Breast Neoplasms↗
PubMed1991

[Combination chemotherapy with orally administered UFT and leucovorin (LV)].

We evaluated the efficacy of the combination therapy of UFT with Leucovorin (LV) against mouse colon adenocarcinomas and human colon adenocarcinoma. In vitro studies, it was shown that LV potentiated the cytotoxicity of FUra against 7 out of 9 cell lines used in this experiment. In vivo studies, the antitumor activity of UFT against mice bearing colon 38 adenocarcinoma was increased following administration of LV either before, after or at the time of treatment with UFT. Further studies were performed on the combination effect of UFT and LV against mouse colon 26 adenocarcinoma and human colon adenocarcinoma KM20C. Consequently, the combined treatment of UFT with LV was more effective than UFT alone against two cell lines. Our studies suggest that combination chemotherapy of UFT with LV is a promising approach for the treatment of a human colon cancer in clinical practice.

Adenocarcinoma↗
PubMed1991

[Cross-resistance of HO-221 and various antitumor agents in sublines of mouse leukemia].

HO-221, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2- nitrobenzoyl) urea is a new benzoylphenylurea derivative. The compound exhibits significant antitumor effects against various animal tumors, and was especially effective against the solid tumors implanted subcutaneously. HO-221 inhibits DNA polymerase alpha activity strongly in vitro. In this study, we examined the cross-resistance of HO-221 to various antitumor agents using sublines of mouse leukemia. HO-221 showed antitumor effects in mice bearing L 1210 or P 388 leukemia resistant to 10 antitumor agents, DM (daunomycin), MMC (mitomycin C), CDDP (cisplatin), 5-FU (5-fluorouracil), Ara-C (cytosine arabinoside), MTX (methotrexate), CPA (cyclophosphamide), CQ (carboquone), ADM (adriamycin) and VCR (vincristine), respectively. These antitumor agents were also effective in P 388 leukemia resistant to HO-221 (P 388/HO-221). Furthermore, CDDP- and MMC-resistant sublines showed a collateral sensitivity to HO-221 in vivo. The grow the inhibitory effects were also noted in vitro in ADM-, CDDP- and MMC-resistant cells by HO-221. However, the in vitro experiments didn't show such collateral sensitivity on the resistant sublines. These results suggest that there is no cross-resistance between HO-221 and other known antitumor agents, and that HO-221 seemed to be worth for evaluating clinical usefulness.

Animals↗
PubMed1991

[Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five-year results. Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan].

A randomized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer. The schedules for drug administration were different in four districts: ACNU + Futraful (FT) group and FT alone group in the Hokkaido-Shikoku district; the same schedule groups plus untreated group in the Chubu-Kinki district; MMC+FT group, FT alone group in the Tohoku-Kanto district; and ADM+FT group and FT alone group in the Chugoku-Kyushu district. The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study. The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer, but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies. In n2 (+) or a2(s) rectal cancer in particular, combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate, and the rate of local recurrence was significantly lower with ADM+FT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Preparation, metabolic stability and biological properties of omega-trifluorinated analog of 12-hydroxyeicosatetraenoic acid.

12-Hydroxyeicosatetraenoic acid (HETE) is associated with a variety of inflammatory conditions. For studies on pathophysiological function of 12-HETE, metabolically more stable analogs of 12-HETE would be useful. We biologically synthesized 20,20,20-trifluoro-12-HETE (20-F3-12-HETE) by incubating enantioselectively synthesized 20,20,20-trifluoro-arachidonic acid with human platelets. The product was identified by UV absorption spectrophotometry and gas chromatography-mass spectrometry. When 1 microgram 20-F3-12-HETE was incubated with 5 X 10(6) human neutrophils for 45 min, only 5% of the analog was metabolized while 66% of 12-HETE was metabolized in the same incubation condition. With 2 X 10(7) neutrophils, 37% of the analog was metabolized at the same incubation condition while 87% of 12-HETE was metabolized. Thus, by blocking omega-oxidation of 12-HETE with fluorine atoms, the stability of 12-HETE was greatly increased. This result indicates that the omega-oxidation is a major pathway for 12-HETE metabolism. The analog demonstrated as much chemotactic activity on human neutrophils as 12-HETE, and binding affinity of the analog for 12-HETE receptor in human epidermal cell was equal to that of 12-HETE. An analog of 12-HETE, which has extended metabolic stability without alteration of neutrophil chemotactic activity and binding affinity, would be a useful tool for studies on pathophysiological role of 12-HETE in inflammatory conditions.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

[Antitumor activity of HO-221, a derivative of benzoylphenylurea against human cancer xenografts in nude mice].

HO-221, a derivative of benzoylphenylurea, is a newly developed anticancer drug which was found to show an excellent antitumor effect against transplantable murine tumors by the novel mechanism of action. This study was designed to evaluate the antitumor effect of HO-221 and to establish the optimum regimen, using seven human gastrointestinal and breast cancers xenografted in nude mice. Better antitumor effect of HO-221 by oral administration was observed when it was suspended in larger volume of the vehicle. Moreover, the effect increased by the multiple intermittent administration compared to the single treatment. Best antitumor effect was observed by oral administration of 75 mg/kg (0.1 ml/10 g mouse body weight) repeated twice weekly for a total of eight times or 300 mg/kg (0.2 ml/10 g mouse body weight) repeated once weekly for a total of four times. The antitumor effects of these two regimens were approximately equal except against H-31, the former regimen being more effective. When the tumor growth inhibition rate (IR) over 58% was rated as "effective", the above two regimens were equally effective against 4 of 7 cancers, H-111, H-154, H-143 and H-31. While HO-221 was not effective to a gastric cancer line, H-81, which was most susceptible to the variety of existing anticancer agents, but effective to another gastric cancer line, H-111, which was relatively resistant to conventional cytocidal agents. From the aspect of chemosensitivity spectrum, this drug revealed a rather different pattern compared to other antimetabolites. Although oral administration volume is limited in small animal model, enhancing its antitumor effect may be possible in clinical application by contriving the method of administration. HO-221 is, thus, considered to be a promising drug for further study.

Administration, Oral↗
PubMed1991

[Combination chemotherapy of HO-221, a derivative of benzoylphenylurea with various anticancer agents against human cancer xenografts in nude mice].

Antitumor effect of HO-221, a derivative of benzoylphenylurea, has been previously studied against seven human cancer xenografts in nude mice established and maintained in our laboratory. In this study, the effect of combination chemotherapy was examined with six of the above seven human cancer cell lines. These consisted of four gastric cancers (H-55, H-111, H-81 and H-154), one breast cancer (H-31) and one pancreatic cancer (H-48). HO-221 was used in combination with one of the following widely used anticancer drugs; mitomycin (MMC), adriamycin (ADM), CDDP, VP-16 and 5-fluorouracil (5-FU). When the tumor growth inhibition rate (IR) by combination of two drugs (at 1/2 MTD for each drug) exceeded both of IR obtained separately with single drug at 1/2 MTD, the combination regimen was rated as showing an additive effect. When IR by combination of two drugs at the same dose level exceeded both of IR obtained separately by MTD of each single drug, the regimen was rated as showing a synergistic effect. Histological changes and side-effects were also taken into consideration for the evaluation of the drug. Combination of HO-221 and MMC produced an additive effect against H-55 and H-111, a synergistic effect against H-81. In the treatment of H-31 which was highly susceptible to these drugs, a remarkable effect was shown in both IR and cellular changes even by combination using 1/2 MTD and 1/4 MTD doses. Combination with ADM at 1/2 MTD for both produced an additive effect against H-111 and H-48. Combination at MTD produced a marked antitumor effect against H-111 and a strikingly remarkable combination effect was confirmed. Combination with CDDP produced an additive effect against H-81 and a synergistic effect against H-154. Moreover, the weight loss by this combination regimen was far less than that by single administration of CDDP at MTD. An additive effect was demonstrated by combination with VP-16. Combination with 5-FU produced minimal combination effect. HO-221 was thus found to have a high antitumor effect by combination with various anticancer agents that are at present widely used clinically. HO-221 is expected to be a promising anticancer drug in its clinical application.

Animals↗