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Biomedical subjects

A Wakui

Publications and source records attributed to A Wakui.

At least 19 recordsLinked to original sources
PubMed1992

Histopathological evaluation on the effect of induced hypertension chemotherapy presurgically performed in patients with advanced carcinoma of the stomach.

Stomachs resected from 13 patients with an advanced gastric carcinoma were examined histopathologically to evaluate the effect of induced hypertension chemotherapy (IHC) using angiotensin II. Eight of the 13 patients, randomly chosen, were treated presurgically by IHC with a regimen of 5-fluorouracil, adriamycin and mitomycin C; the same regimen was used in the remaining five patients but without inducing hypertension. Clinical evaluation of the effect gave rise to the confirmation, presurgically, of complete response in three and partial response (PR) in two patients in the IHC group, whereas in the non-IHC group, the highest rating was PR, which was attained in only one patient. Also in the histopathological assessment based on a five-step grading, the IHC group earned in average a higher score than the non-IHC group, with a difference proved significant by Wilcoxon's test. A histological rating of Grade 3, the highest effectiveness, was given to three patients in the IHC group, in one of whom the resected stomach disclosed no viable carcinoma cells but only fibrotic areas replacing carcinoma. There was also a correlation between the clinical and histological ratings as proved to be significant by Spearman's test. We conclude that in gastric carcinoma, the effect of chemotherapy is enhanced by angiotensin II-IHC.

Adenocarcinoma↗
PubMed1992

[Pharmacokinetic studies on fluorinated pyrimidine in cancer cell and tissue].

A number of the studies on pharmacokinetics of fluorinated pyrimidines have been precisely reported. In mice bearing Ehrlich ascites carcinoma, 5-FU showed highest concentration in the lung and kidney immediately after i.v. administration of 5-FU, and in the liver, it showed rather lower concentration but for a longer period. 5-FU in blood was transferred into ascites fluid rapidly, and thus, the level of 5-FU in ascites fluid became higher than that in blood. FT is a masked compound of 5-FU, having a tetrahydrofuryl group. Drug metabolizing enzyme, natural degradation, and thymidine phosphorylase are considered to be responsible for the molecular conversion of FT into 5-FU. In order to increase the level of drug metabolizing enzyme, P450 in the liver of tumor bearers, of which P450 level was extremely lower as compared to normal individuals, phenobarbital was very effective from our previous experiment. Clinically, phenobarbital 200mg/day for 3 successive days was administered in prior to FT, and a better response was obtained than FT alone. Prevention from degradation of 5-FU in the liver by uracil kept higher level of 5-FU in blood. HCFU and 5'DFUR are also masked form of 5-FU and are converted to 5-FU in the liver.

Animals↗
PubMed1992

[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for gastrointestinal cancers. 254-S Gastrointestinal Cancer Study Group].

A phase II clinical study of 254-S, a new anticancer platinum complex for gastrointestinal cancers, was conducted by the 254-S Gastrointestinal Cancer Study Group consisting of 16 institutions. 254-S was administered at 100 mg/m2 by intravenous drip infusion. This administration was repeated at 4-week intervals. The cases in which 254-S could be administered at least two times were regarded as complete cases evaluable for tumor response; of 75 cases registered, 53 were complete cases (29 cases with esophageal cancer, 12 with stomach cancer and 12 with colon cancer). As a result, 15 partial responses (PR) were obtained in the 29 patients with esophageal cancer and 1 PR from the 12 patients with stomach cancer, for a 51.7% and 8.3% response rate, respectively. 5 PR (55.6%) were obtained in 9 esophageal cancer patients with prior chemotherapy, including 2 PR in 4 patients previously treated with cisplatin. Major toxic effects observed were hematotoxicity including thrombocytopenia (59.0%), leukopenia (68.9%) and anemia (57.4%) and gastrointestinal toxicity such as nausea and vomiting (63.9%) and anorexia (41.0%); since grade 3 or 4 thrombocytopenia was observed with an incidence of 27.9%, careful monitoring seems to be required during the treatment with this product. Abnormal parameter changes on renal function included elevations of BUN (18.0%) and serum creatinine (9.8%). Based on these results, it was concluded that 254-S is a useful anticancer agent for the treatment of esophageal cancer.

Antineoplastic Agents↗
PubMed1992

[A phase I study of DWA2114R].

Phase I study of DWA2114R, a new platinum analogue, was conducted in 39 patients with various tumor types by a group of 13 institutions. Of the 39 patients entered in this study, 35 were evaluable. The starting dose was 40 mg/m2 (1N) and the drug was administered i.v. for 20-30 min, escalating stepwisely up to 1,000 mg/m2 (25 N). The dose limiting factor (DLF) was leukocytopenia, especially neutrocytopenia, and the maximum tolerated dose (MTD) was more than 1,000 mg/m2. Major clinical toxicity was gastrointestinal. Hepatotoxicity and nephrotoxicity were mild. Following administration of the drug, plasma concentrations of total and filterable platinum (Pt) showed a triphasic and biphasic decays. Excretion into urine within 24 hours was in the range of 54.2% to 92.2% of the administered platinum. The recommended dose of phase II study was 800-1,000 mg/m2, repeating every 3-4 weeks.

Adult↗
PubMed1992

[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum (II)].

A new platinum complex 254-S had a superior preclinical therapeutic indices compared to cisplatin, showing decreased renal and gastrointestinal toxicities. Phase I clinical study with a single dose schedule was conducted to investigate the safety, toxicity, pharmacokinetics and possible efficacy against various advanced cancers by a cooperative study of 10 institutions. The drug was administered by i.v. infusion for 60 min dissolved in 250 ml of 5% xylitol solution, without the use of hydration and antiemetics. At least 3 patients at each dose level of 10, 20, 40, 80, 100 and 120 mg/m2 were tested and 28 patients were entered into this study. Myelosuppression, especially thrombocytopenia, appeared strongly at dose level of 80 mg/m2 and dose limiting thrombocytopenia was found in 2 of 5 patients. Leukocytopenia was also dose-related but moderate. Platelet and WBC nadirs occurred around 3 weeks after administration with recovery in about one week. Although slight elevation of BUN and creatinine were temporarily observed in a few cases, no significant renal toxicity was observed. Anorexia, nausea and vomiting were observed in the majority of patients, but milder than cisplatin. In conclusion, 254-S has demonstrated reduced non-hematologic toxicities as compared to cisplatin. This drug appears to be well tolerated and 120 mg/m2 was maximum tolerated dose. The recommended dose for phase II studies was thought to be 100 mg/m2 by i.v. infusion every 4 weeks.

Adult↗
PubMed1992

[Preoperative role of angiotensin II induced hypertension chemotherapy (IHC) in advanced gastric carcinoma].

To investigate the role of preoperative IHC in advanced gastric carcinoma, clinical, surgical and pathological stagings of 13 patients were analysed retrospectively. These patients were treated with a 3-drug combination of adriamycin, 5-fluorouracil and mitomycin C under angiotensin II induced hypertensive state. The response rate was 69.2% and mean survival time was 850.2 days. "Down staging" in surgical stage was observed in 5 out of 13 cases (38.3%), and in pathological stage 7 cases (53.8%) "down staging" was achieved. Mean survival time of "pathological down-staging" cases was significantly longer than that of "non-down-staging" cases (1039.6 vs 322.1 days, p less than 0.01, generalized Wilcoxon test). IHC brings selective increase of drug delivery to tumor tissue, and will be useful as preoperative chemotherapy in advanced gastric carcinoma in terms of "down staging".

Adult↗
PubMed1991

Mutations of the P53 gene, including an intronic point mutation, in colorectal tumors.

In this study, analysis of structural changes of the p53 gene in colorectal tumors revealed point mutations detected in 8 of 14 carcinomas and 2 of 2 adenomas. Of these 10 cases with point mutations, eight had one or more missense mutations, one had a nonsense mutation, and the remaining one had, interestingly, an intronic point mutation with subsequent activation of a cryptic splice donor site in the flanking exon. This report contains the first identification of an intronic point mutation of the p53 gene in a colorectal cancer case.

Amino Acid Sequence↗
PubMed1991

Expression of glutathione S-transferase-pi messenger RNA in human esophageal cancers.

The expression of human glutathione S-transferase-pi (GST-pi) in resected primary esophageal tumors and in matching normal esophageal mucosa from 25 patients undergoing radical surgery was measured by RNA blot hybridization. The RNA transcript levels of GST-pi in the tumor tissues were higher than those in normal tissues in 20 of 25 cases (80%). The mean GST-pi mRNA value in the tumor tissues (n = 25) was significantly (P less than 0.01) elevated as compared with that in background mucosa (n = 29), and in ten of 25 tumors (40%) the level of GST-pi mRNA exceeded the mean normal tissue value by two standard deviations (normal mean value + 2 X SD). The results obtained from the current experiment thus suggests that GST-pi might be a useful marker for human esophageal cancer. No correlation between GST-pi mRNA level and clinical stage or histologic characteristics was apparent.

Adult↗
PubMed1991

Association between restriction fragment length polymorphism of the human cytochrome P450IIE1 gene and susceptibility to lung cancer.

Cytochrome P450IIE1 (P450IIE1) is involved in metabolic activation of carcinogenic nitrosamines, aniline and benzene. We detected a restriction fragment length polymorphism of the human P450IIE1 gene with the restriction endonuclease DraI. The population was thus divided into three genotypes, namely, heterozygotes (CD) and two forms of homozygotes (CC and DD). The distribution of these genotypes among lung cancer patients differed from that among controls with statistical significance of P less than 0.05 (chi 2 = 7.01 with 2 degrees of freedom). This result strongly suggests that host susceptibility to lung cancer is associated with the DraI polymorphism of the P450IIE1 gene.

Adenocarcinoma↗
PubMed1991

Induction of natural killer (NK) activity in mice by injection of chromomycin A3.

Intravenously or intraperitoneally administered Chromomycin A3 (CHRM), an anticancer drug, augmented natural killer (NK) activity of both spleen cells and peritoneal exudate cells in BALB/c mice. When CHRM was administered intravenously, NK activity increased to about five fold that in nontreated mice on the 3rd to the 5th day, then rapidly decreased by the 7th day. On the other hand, when CHRM was administered by the intraperitoneal route, a peak of increased NK activity was observed on 5th to 7th day followed by a more gentle decrease. Augmentation of NK activity by CHRM was enhanced by additional administration of Interferon- gamma (IFN-gamma). Experimental evidence that NK activity could be augmented by CHRM in various strains of mice, independent of H-2 haplotype, suggested that involvement of genetic control within class I region of major histocompatibility complex could be excluded. When BALB/c mice inoculated subcutaneously with Meth A cells were treated with i.p. injection of CHRM, or CHRM in combination with IFN-gamma, the growth of the tumor cells was inhibited, indicating in vivo significance for the increased NK activity. Since this inhibitory effect was decreased by the injection of anti Asialo GM1 antibody (alpha-ASGM1), the effector cells presumably exerting killing activity against Meth A cells were concluded to be Asialo GM1 antigen positive.

Animals↗
PubMed1991

[Phase I clinical study of zinostatin stimalamer (YM 881) by intravenous injection].

A phase I clinical study by intravenous injection of zinostatin stimalamer (YM 881), a protein anti-cancer drug, was conducted in 50 patients with malignant tumors. The initial dose was 0.5 mg/m2 (n) in the single dose test, and 0.2 mg/m2/day in the repeated dose test for 5 successive days. Doses were increased up to 12n according to the modified Fibonacci's method in both the single and repeated dose tests. The dose limiting factor was thrombopenia in both the single and repeated dose tests. The maximum tolerated dose was 6.0 mg/m2 (12n) in the single dose test, and the subtoxic dose was 2.4 mg/m2/day in the five day repeated dose study. These results indicate that dose of 1.0 to 1.4 mg/m2/day (5 n to 7 n) are appropriate for the phase II repeated dose study.

Adult↗
PubMed1991

[Early phase II study of YM 881 (zinostatin stimalamer) by intravenous injection. Research group for intravenous YM 881].

An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.

Adult↗
PubMed1991

[Phase I trials--clinical studies of antineoplastic agents].

The establishment of the starting dose and the dose escalation are the principal issues of the Phase I trials of anticancer agents. We report the procedures and results of the Phase I studies we participated in Japan in the 1980's concerning 17 intravenous anticancer agents. The drugs indicated a correlation between the mouse LD10 and the man MTD (maximum tolerated dose) in mg/m2. Median mouse LD10 (135 mg/m2) approximated to median man MTD (137 mg/m2) in mg/m2. One fifth of the mouse LD10 was lower than the man MTD. Therefore, as recognized at the 23rd Annual Congress, Japan Society for Cancer Therapy, the lower one of either 1/5 the mouse LD10 or 1/3 the dog TDL (toxic dose low) in mg/m2 has to be determined as safe starting dose. The modified Fibonacci search scheme has been generally adopted for the dose escalation. 14 applicable drugs were examined including 7 drugs in the early 1980's and 7 drugs in the late 1980's. The real number of steps that reached the man MTD was compared to the number of the steps taken in the dose escalation by the Fibonacci's method. The real steps were more than the Fibonacci's ones in the late 1980's. It showed the tendency of a more careful and safer dose escalation, however, to put it critically, the dose escalation was not efficient enough. It is expected that the contradictory problem between safety and efficacy in the Phase I studies will be solved by developing methods like pharmacokinetic study in animals and man.

Antineoplastic Agents↗
PubMed1991

[Randomized controlled trial of induced hypertension chemotherapy (IHC) using angiotensin II human (TY-10721) in advanced gastric carcinoma (TY-10721 IHC Study Group Report)].

A randomized controlled trial was carried out to elucidate the enhancement of chemotherapeutic effect of induced hypertension chemotherapy (IHC) using newly synthesized angiotensin II human (TY-10721) in advanced gastric carcinoma under multi-institutional cooperation. In IHC, the drugs were administered under the hypertensive state induced and maintained by the continuous infusion of TY-10721. The regimen for the trial was as follows: adriamycin (33 mg/m2, day 3), 5-fluorouracil (330 mg/m2/day through day 1 to 3, 8 to 10) and mitomycin C (5 mg/m2, day 8). It was repeated every 4 weeks. Of 67 registered cases, 62 eligible patients were randomized to either IHC arm or control arm (non-IHC) in which the drugs were administered by an ordinary i.v. injection. According to the Criteria of Japanese Society for Cancer Treatment, the response rate of IHC group was 31.3% and that of non-IHC was 6.7% with statistically significant difference (p less than 0.05; chi 2c). There were 4 CR and 6 PR in 32 eligible cases of IHC and 2 PR in 30 of non-IHC. Clinical characteristics of patients and toxicities were not different in both groups. Clinical advantage of IHC was confirmed by increase of the response rate in this trial.

Adult↗
PubMed1991

Undifferentiated sarcoma of the liver in a 21-year-old woman: case report.

A successful surgical case of malignant undifferentiated (embryonal) sarcoma of the liver (USL), a rare tumor normally found in children, is reported. The patient was a 21-year-old woman, complaining of epigastric pain and abdominal fullness. Chemical analyses of the blood and urine and complete blood counts revealed no significant changes, and serum alpha-fetoprotein levels were within normal limits. A physical examination demonstrated a film, slightly tender lesion at the liver's edge palpable 10 cm below the xiphoid process. CT scan and ultrasonography showed an oval mass, confined to the left lobe of the liver, which proved to be hypovascular on angiography. At laparotomy, a large, 18 x 15 x 13 cm tumor, found in the left hepatic lobe was resected. The lesion was dark red in color, encapsulated, smooth surfaced and of an elastic firm consistency. No metastasis was apparent. Histological examination resulted in a diagnosis of undifferentiated sarcoma of the liver. Three courses of adjuvant chemotherapy, including adriamycin, cis-diaminodichloroplatinum, vincristine and dacarbazine were administered following the surgery with no serious adverse effects. The patient remains well with no evidence of recurrence 12 months after her operation.

Adult↗
PubMed1991

[The effect of induced hypertension chemotherapy using angiotensin II human in patients with advanced gastric carcinoma--a histopathological evaluation on the excised stomachs].

In an attempt to evaluate the effect of induced hypertension chemotherapy (IHC) using angiotensin II human, histopathological analysis was performed on stomachs excised from thirteen patients who had advanced gastric carcinoma and were submitted to presurgical cancer chemotherapy. IHC was introduced in randomly chosen eight patients and, in the remaining five patients, chemotherapy was designed under conventional conditions. A common regimen comprising 5-fluorouracil, adriamycin, mitomycin C was applied in both the IHC and non-IHC groups. The clinical effect in these patients, assessed prior to surgery, gave rise to the confirmation of three CR patients in the IHC group, while in the non-IHC, PR was the highest score. Histological examination illuminated a patient in the IHC group in whom no viable carcinoma cell proved to remain in the excised stomach, a state meeting the requirements for the highest (Grade 3) effectiveness according to the standard given by the Japanese Research Society for Gastric Cancer. In another two patients of the same group, the effect was Grade 2, i.e., the degeneration and loss of carcinoma cells in the major part of tumor. In contrast, the effect in the non-IHC group was Grade 1b at the highest, where chemotherapy-associated degeneration and necrosis did not predominate over one third of tumor area. Thus, the mean histological score was apparently higher in the IHC than in the non-IHC group, with a difference significant at p less than 0.05 by Wilcoxon's test. Patients clinically evaluated as effective tended to be so pathologically as well, as shown by Spearman's rank correlation test which gave a significant correlation between the clinical and pathological scores.

Adenocarcinoma↗
PubMed1991

[Evaluation of cardiotoxicity in new anthracycline analog ME 2303. ME 2303 Study Group].

ME 2303 is a new anthracycline analog which differs from adriamycin in the sugar moiety. ME 2303 displays a higher antitumor activity against L 1210 and P 388 Leukemia than adriamycin. To evaluate the cardiotoxicity of ME 2303, ECG tracings (21 patients) and Holter ECGs (9 patients) were recorded before and after the administration of ME 2303 for various malignancies (mean dose 123.8 mg/m2), and some of the electrocardiographic parameters were analyzed. Control ECGs were normal in 17 patients, in 4 patients minor ECG findings like sinus tachycardia (2 patients), low voltage (1 patient) and flattening of the T wave (1 patient) were observed. After treatment, no relevant ECG changes were observed except one case who showed a flat T in pretreatment ECG. In this patient developed ST-T changes were seen after treatment. The basic rhythm was sinus rhythm in all of the cases, and the heart rate showed no significant changes. ME 2303 had no effects on the specialized conduction system. With regard to arrhythmia, no increase in number and severity was observed. In Holter ECG no development of ST-T changes was seen after treatment.

Adult↗