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Biomedical subjects

S Tsukagoshi

Publications and source records attributed to S Tsukagoshi.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Advance in cancer chemotherapy].

From the middle of the 20th Century, many anticancer drugs have been developed, and about 40 kinds of anticancer drugs are currently have been used for cancer treatment. From the past pre-clinical and clinical studies, it was found that combination of two or more drugs was sometimes more effective than the single use, resulting the increase of cure-rates in some-type of human malignancies. Recently, new treatment regimens based on the concept of biochemical modulation have been used for the treatment of cancer of the digestive organs. Also, currently, supportive therapies against the adverse-drug reactions (side effects) became available, and sometimes improvement of QOL of the cancer patients has been expected with the use of these therapies. In facing to the 21st Century, studies of new type of drugs such as those to novel molecular targets have been progressing.

Antineoplastic Agents↗
PubMed1998

[Phase I clinical study of oxaliplatin].

Oxaliplatin is a new platinum derivative. A multicentric phase I study was conducted with a monotherapy of Oxaliplatin. A total of 20 patients were enrolled who had histologically proven 6 ovarian cancers, 5 uterine cervix cancers, 3 lung cancers, 3 breast cancers, 1 endometrial cancer, 1 gastric cancer, and 1 colorectal cancer. Oxaliplatin was administered as a 2-hour infusion at doses of 20, 40, 80, 130, and 180 mg/m2 every 3 weeks, for a total of 30 cycles. A dose-related and reversible peripheral sensory neuropathy was the dose-limiting toxicity with minimal hematotoxicity and no nephrotoxicity. No hydration was needed. The plasma platinum concentration was biphasically decreased. Cmax and AUC were dose-dependent. T1/2 beta was 31.3 hours. The recommended dose for further studies was 130 mg/m2. A partial response was observed in endometrial cancer.

Adult↗
PubMed1998

[Phase I study of raltitrexed (ZD-1694)].

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.

Adult↗
PubMed1998

[A phase II study with high-dose cytarabine (NS-075) in adult patients with relapsed and refractory acute leukemia].

A multi-center phase II clinical study with high dose cytarabine (NS-075) was conducted in adult patients with relapsed and/or refractory acute leukemia. 2 g/m2 cytarabine was given 12 times by 3-hour intravenous infusion every 12 hrs. 46 patients were registered, and 44 were evaluable: 35 with acute myeloid leukemia (AML) and 9 with acute lymphoblastic leukemia (ALL). There were 28 males and 16 females, with a median age of 37.5 years (range 15-68), including 6 of more than 60 years. Among 35 patients with AML, there were 16 (45.7%) complete and 2 (5.7%) partial remissions. Among 9 patients with ALL, there were 2 (22.2%) complete and 1 (11.1%) partial remissions. The major non-hematologic toxicities were gastrointestinal symptoms such as nausea/vomiting, anorexia and diarrhea, as well as fever, infection, conjunctivitis, alopecia, hepatic and renal dysfunctions. Central nervous system (CNS) toxicity was mild and reversible. Therapy-related death occurred in 5 patients resulting from prolonged pancytopenia, which suggests the necessity of strict countermeasures for infections as well as good patient care. These results indicate that high-dose cytarabine is a promising therapy for treatment of relapsed and/or refractory acute leukemia.

Adolescent↗
PubMed1997

Antitumor activity of TZT-1027, a novel dolastatin 10 derivative.

Dolastatin 10, a pentapeptide isolated from the marine mollusk Dolabella auricularia, has antitumor activity. TZT-1027, a dolastatin 10 derivative, is a newly synthesized antitumor compound. We evaluated its antitumor activity against a variety of transplantable tumors in mice. Intermittent injections of TZT-1027 were more effective than single or repeated injections in mice with P388 leukemia and B16 melanoma. Consequently, TZT-1027 shows schedule dependency. TZT-1027 was effective against P388 leukemia not only when administered i.p., but also when given i.v. However, although TZT-1027 given i.v. was active against murine solid tumors, TZT-1027 administered i.p. was ineffective against all the tumors tested with the exception of colon 26 adenocarcinoma. The i.v. injection of TZT-1027 at a dose of 2.0 mg/kg remarkably inhibited the growth of three murine solid tumors; colon 26 adenocarcinoma, B16 melanoma and M5076 sarcoma, with T/C values of less than 6%. The antitumor activities of TZT-1027 against these tumors were superior or comparable to those of the reference agents; dolastatin 10, cisplatin, vincristine, 5-fluorouracil (5-FU) and E7010. In experiments with drug-resistant P388 leukemia, TZT-1027 showed good activity against cisplatin-resistant P388 and moderate activity against vincristine- and 5-fluorouracil-resistant P388, but no activity against adriamycin-resistant P388. TZT-1027 was also effective against human xenografts, that is, tumor regression was observed in mice bearing MX-1 breast and LX-1 lung carcinomas. TZT-1027 at 10 microM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to be, at least in part, ascribable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT-1027 has been entered into phase I clinical trials.

Animals↗
PubMed1997

[Development of new anticancer drugs--the historical background and current status in Japan].

Historically the development of new anticancer drugs in Japan was initiated in 1950s by M. Ishidate et al. for alkylating agents and by H. Umezawa, T. Hata et al. for antitumor antibiotics. In current cancer chemotherapy, appreciable clinical responses have been reported against some types of hematological and childhood malignancies and solid cancers such as chorionic, ovarian, testicular cancers. However, solid cancers such as many GI-tract, lung, breast and other cancers are still drug-refractory. Since many of these cancers have been discovered at their advanced forms, the drug treatment has been a very important modality. From these reasons, efforts have been placed on the search of new anticancer drugs. Recently, new anticancer drugs relating to taxanes, camptothecins, platinum compounds have exhibited excellent clinical activities against some solid cancers. From these experiences, searches of novel anticancer drugs including those against molecular targets have been continued. The author is greatly indebted to the late Professor Morizo Ishidate for the initiation of his career in cancer research.

Antineoplastic Agents↗
PubMed1997

[A new antiemetic ramosetron hydrochloride].

Ramosetron hydrochloride as a 5-HT3 receptor antagonist-type antiemetic, which was developed in Japan. It has an indole ring which is the mother nucleus of serotonin (5-HT) and a tetrahydrobenzimidazol radical. These components are linked by a carbonyl radical. It was reported in non-clinical studies that ramosetron hydrochloride exhibited more potent and sustained antagonistic activities against 5-HT3 receptors than existing 5-HT3 receptor antagonist-type antiemetics. It was also reported that ramosetron hydrochloride inhibited vomiting by anticancer drugs in a potent and sustained manner. The phase I trial was initiated in May, 1991. Phase II and phase III trials were then conducted in a total of 357 patients at 121 institutions in Japan. The symptoms targeted in these trials were nausea and vomiting induced by anticancer drugs, such as cisplatin. Based on the results of the phase II trial, it was recommended that ramosetron hydrochloride be infected once daily at a dose of 0.3 mg. In phase III trial, a placebo-controlled double-blind study and an open trial was performed. The utility of the drug seemed to be confirmed by the results of these studies. Ramosetron hydrochloride shown an efficacy rate of 79.8% (178/223 patients) against nausea and vomiting induced by anticancer drugs, such as cisplatin when administered at a dose of 0.3 mg. The efficacy rate was 85.1% (40/47 patients) when given at a dose of 0.3 mg before the administration of anticancer drugs, such as cisplatin. The incidence of adverse effects was 2.0% (7/352 patients). Main adverse effects reported were feeling of heat, headache, and heavy feeling in the head. These adverse effects were of no clinical importance.

Animals↗
PubMed1997

[Recent development of antitumor antimetabolites in Japan--cytosine arabinoside analogues].

Since there have been relatively high incidence of cancer of the digestive organs in Japan, many 5-fluorouracil analogues have been studied as the drugs to treat such cancers. Beside these fluoropyrimine compounds, cytosine arabinoside (ara-C) analogues have also been studied, and some of them have shown appreciable clinical activities against human malignancies. In this paper, as such analogues, experimental and clinical studies of gemcitabine (dFdC). DMDC and cytarabine ocfosfate were reviewed. Among these drugs, gemcitabine (Eli Lilly, Japan) showed more than 20% response rate against non-small cell lung cancer in the late phase II study in Japan. Unfortunately, clinical study of DMDC (Yoshitomi) is currently suspended because of the lack of the hint of clinical activity, but the author believes that this might show some clinical activities by changing the treatment regimens in the future. Cytarabine ocfosfate (Nippon Kayaku) has already put on market as the first drug to be active against ANLL and MDS by giving orally.

Animals↗
PubMed1997

[Development of a new tubulin-interacting agent, docetaxel (taxotere) in Japan].

A new semi-synthetic taxoid, docetaxel (taxotere) was recently developed in Japan. The phase I study was initiated in 1991, and the MTD was determined as 70-90 mg/m2, dose-limiting factor as leukopenia, and recommended dose for the phase II study as 60 mg/m2, every 3-4 weeks. The early and late phase II studies were conducted based on above dose schedule. After the late phase II studies, appreciable responses were obtained against advanced recurrent breast (50.4%) and inoperable lung (22.4%) cancers, and the results were accepted by MHW of the Japanese Government. Docetaxel possesses an unique tubulin-interacting activity (promotion of assembly of stable microtubules) and currently combination studies with other anticancer drugs or radiotherapy are ongoing.

Antineoplastic Agents, Phytogenic↗
PubMed1997

[Fundamental studies on the surgical adjuvant chemotherapy to support the clinical efficacies].

There have been many evidences for the usefulness of surgical adjuvant therapy of human advanced solid malignancies. Experimentally, many studies to support efficacies of such adjuvant therapy were reported. In this paper, such studies carried out abroard and in Japan were reviewed. Especially, several experimental studies in Japan using UFT as the drug used in adjuvant settings were introduced. In these reports, UFT was reported as a drug effective experimentally in adjuvant treatment. This fact seemed to support the clinical efficacies of UFT in surgical adjuvant chemotherapy.

Animals↗
PubMed1997

[TUT-7 early phase II clinical study for various solid tumors and hematologic malignancies].

An early Phase II study with TUT-7 (menogaril), a new anthracycline antitumor antibiotic, was conducted in patients with various malignant tumors at 81 departments of 65 institutions nationwide. One course of TUT-7 treatment consisted of seven (7) or fourteen (14) consecutive days of administration at 75 or 100 mg/body/day with two-week drug withdrawal; at least two courses of treatment were given in principle. Among the 165 patients registered, 145 patients were eligible and 128 patients were evaluable for antitumor efficacy. In 11 patients with malignant lymphoma, one (1) had CR and five (5) had PR (54.5%); in three (3) patients with prostate cancer, one (1) had PR (33.3%); and in 12 patients with uterine cervical cancer, two (2) had PR (16.7%). Adverse drug reactions frequently observed were digestive organ disorders (anorexia and nausea/vomiting) and malaise. The abnormality in laboratory tests observed frequently was myelosuppression (leukopenia and neutropenia).

Adult↗
PubMed1997

[Phase I study of S-1. S-1 Study Group].

We have conducted Phase I study of a novel oral antitumor agent of fluorinated pyrimidines, S-1, in which tegafur (FT) is combined with two classes of modulator, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1 as a multi-center study with 16 institutions nationwide. Two administration methods, once and twice daily administrations, were evaluated. As a result, MAD was determined as 150 mg/body/day approximately 200 mg/body/day and 75 mg/body x2/day approximately 100 mg/body x2/day, respectively. DLF was myelosuppression, mainly consisting of leukopenia in the two administrations. Most adverse reactions observed, including myelosuppression, disappeared by discontinuation of administration, and recovery was in about 2 weeks. Adverse reactions other than myelosuppression which induced the discontinuation were rash and vomiting. Other adverse reactions observed were anorexia, malaise, diarrhea and stomatitis. Diarrhea and stomatitis were mild (Grade 1), except those observed at a dose of 200 mg/body/day, and did not induce discontinuation of administration. Based on these findings and pharmacokinetic evaluation, the recommended dose and administration for Early Phase II studies were determined as twice daily administration of 75 mg/body for 28 consecutive days with 14 days rest (1 course).

Administration, Oral↗
PubMed1996

[LY188011 phase I study. Research Group of Gemcitabine (LY188011)].

LY188011 (Gemcitabine hydrochloride) is a new derivative of deoxycytidine. Phase I study was carried out by a cooperative study group. LY188011 was administered weekly for 3 consecutive weeks starting with an initial dose of 60 mg/m2 (1n) and then increasing the dosage to 1,000 mg/m2 (16.7n). Dose limiting factor was found to be myelosuppression (decreases of WBC, neutrophils and platelet), and MTD was considered to be 1,000 mg/m2. The nadir of WBC and platelet were observed after about 1-3 weeks. It took 1-2 weeks for their recovery. Other adverse reactions included fever, fatigue, anorexia, nausea/vomiting, anemia and transient elevations of GOT and GPT. However, those adverse reactions were mild. T1/2 rho of plasma concentration was about 19 min and the C5min was dependent on the dose. Anti-cancer effects were observed in one gastric cancer and two colon cancer patients. It is recommended that the dosing schedule for an early phase II study is 800 mg/m2 weekly for 3 weeks with 1 week of rest as one cycle, in multiple cycles.

Adult↗
PubMed1996

[Phase I study of bicalutamide (Casodex), a nonsteroidal antiandrogen in patients with prostatic cancer].

A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.

Administration, Oral↗
PubMed1996

[Clinical early phase II study of bicalutamide (Casodex) in patients with prostatic cancer].

To investigate the efficacy and safety of bicalutamide (Casodex) with its clinically recommended dose, the randomized early phase II study was performed in 124 patients with prostatic cancer (stage C, D). The patients were given 50, 80 or 100 mg of bicalutamide orally once a day in fixed doses for 12 weeks; 122 patients were eligible for evaluation. The overall response rate was 50.0% (20/40), 61.0% (25/41) and 53.7% (22/41) in the 50 mg, 80 mg and 100 mg groups, respectively. The response rate in prostate lesion, bone and lymph node metastases was slightly higher in the 80 mg group than in the 50 mg and 100 mg groups. The proportion of patients showing a response with regard to serum PSA (CR and PR) was 84.2, 92.7 and 97.6% in the 50, 80 and 100 mg groups, respectively. The incidence of adverse reactions was 65.0, 61.0 and 61.0% in the 50, 80 and 100 mg groups, respectively, and there was no significant difference in overall safety rating in the three groups. Frequent adverse reactions were gynecomastia and breast pain. Only one patient in the 80 mg group was withdrawn due to shortness of breath. Serum concentrations of LH, testosterone and estradiol increased significantly after treatment. Bicalutamide was concluded to be effective and well tolerated in patients with prostatic cancer, and its recommended dose was 80 mg once daily.

Administration, Oral↗
PubMed1996

[Phase I study on DMDC].

Phase I study on antimetabolic carcinostatic DMDC was conducted at 16 medical institutions nationwide for patients with various types of malignant tumors. DMDC was administered by intravenous infusion as per the following three schedules: single administration, single repeated administration, and 5-consecutive-day administration. The safety of the compound was examined single administration in 16 patients, by the single repeated administration in 5 patients, and by the 5 consecutive-day administration in 7 patients, for a total of 28 patients. In the single administration trial, 200 mg/m2 (1 n) was given as an initial dose, then increased stepwise to 450 mg/m2 (2.25 n). The single repeated administration trial was conducted at a single dose of 300 mg/m2. One treatment course lasts until recovery from side effects and abnormalities in laboratory test values. As a general rule, the administration was repeated for 2 treatment courses or more. In the 5-consecutive-day administration trial, an initial dose was 30 mg/m2/day (1 n), and increased to 40 mg/m2/day (1.3 n). The dose-limiting factors for both the single and 5-consecutive-day administration trials were decreases in the numbers of leukocytes and neutrophils. The maximum tolerated dose for single administration trial was over 400 mg/m2 (2 n), and for the 5-consecutive-day administration trial 40 mg/m2 (1.3 n). The decrease in the number of leukocytes and neutrophils for both the single administration and 5-consecutive-day administration trial reached its nadir one to two weeks after administration, and recovered in about one week. In the single repeated administration trial, the administration interval for patients who had completed 2 courses was 2 approximately 3 weeks. The plasma half-life of DMDC in the final phase of elimination in the single administration trial was 5.2 approximately 6.3 hours, and no differences were seen among dose levels. The urinary excretion rate was between 32.0 approximately 61.5% until 48 hours after administration. No accumulation was seen in the 5-consecutive-day administration trial. There were no findings to suggest an antitumor effect in the present study. Given the recovery pattern for suppression of marrow, the above mentioned results led us to decide that an recommended method of administration and dosage in an early phase II trial would be 300 mg/m2 per administration by an intravenous infusion every 2 approximately 3 weeks.

Aged↗
PubMed1995

Antimicrotubule effects of the novel antitumor benzoylphenylurea derivative HO-221.

The antitumor action of HO-221, a novel benzoylphenylurea derivative, was studied. The in vitro cytotoxic strength of HO-221 was investigated, as measured by IC50 values, compared with those of other drugs with different action mechanisms, using Chinese hamster lung (CHL) cells, mouse leukemia L1210 cells and human promyelocytic leukemia HL-60 cells. Morphological alterations following treatment were observed under a phase contrast microscope, and the mitotic index was determined at regular intervals to check for accumulation of metaphase cells. HO-221 was found to have a very strong toxic effect on all cell types, equal to that of the spindle poisons used as controls. HO-221 also produced the same specific morphological changes as the spindle poisons, with a significant accumulation of metaphase cells. A chromosome analysis of treated cells showed that HO-221 frequently induced polyploid and aneuploid cells, but without accompanying chromosome-breaking activity. An in vivo mouse bone marrow micronucleus assay was also carried out. The assay allowed the in vivo identification of a chromosome breaker or a spindle poison through the measurement of the relative sizes of micronuclei produced and erythrocytes. HO-221 was found frequently to induce relatively large micronuclei, an action regarded as specific to spindle poisons. It was thus demonstrated that HO-221 acts as a spindle poison both in vitro and in vivo. In order to investigate the mechanism of this action, a study of tubulin assembly using purified calf brain tubulin was carried out, which demonstrated clearly that HO-221 inhibits microtubule assembly. A detailed investigation of the action mechanism of HO-221 as a spindle poison is now called for.

Animals↗