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S Tsukagoshi

Publications and source records attributed to S Tsukagoshi.

At least 109 records · Page 6Linked to original sources
PubMed1990

[Antitumor effect of a benzoylphenylurea derivative HO-221].

HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We had interested in various pharmacological actions of benzoylphenylurea compounds. Therefore, many compounds were synthetized and tested in various screening systems. In the process with these tests, we found HO-221 which showed an excellent antitumor activity. The antitumor activity of HO-221 was judged from the survival time and the tumor weight of experimented tumor-bearing animals. HO-221 preparation was orally administered. The compound exhibited significant effects against various animal tumors (P388, L1210, M5076, LLC, C38, S180, W256), and especially effective against the solid tumors. HO-221 was also markedly effective to MX-1 and LX-1 implanted into nude mice. However, the effect against mouse B16 melanoma was moderate. In addition, HO-221 showed a schedule dependency and once every 4 or 7 days treatments were most effective. The antitumor activities of the compound against advanced L1210 and Lewis lung tumors were examined. Tegafur and ara-C were used as reference drug for the study. Three agents showed the antitumor activities against L1210. Against Lewis lung carcinoma, HO-221 showed both the increase of life span and the tumor growth inhibition. On the other hand, tegafur and ara-C were ineffective for the increase of life span.

Animals↗
PubMed1990

[Phase I study of MST-16].

Phase I study with a new oral anticancer agents. MST-16 (Sobuzoxane), was conducted by 3 administration schedules: single, 5 consecutive days and 10-15 consecutive days. No toxicity was observed in the single administration at doses escalated up to 1,500 mg/m2. Dose-dependent leukopenia was observed from 560 mg/m2/day in consecutive 5 day administration, and median days to the nadir and recovery were about 2 and 1 week, respectively. GI-disorders were also observed sporadically from 800 mg/m2/day. One patient with Hodgkin's disease receiving 1,000 mg/m2/day achieved complete response. Consecutive administration for 10-15 days was carried out at a dose of 800 mg/m2/day. Six out of 7 evaluable patients demonstrated leukopenia, and all 2 patients treated for 15 days experienced leukopenia with a nadir corresponding to grade 3. Median days to nadir and recovery were both about 2 weeks. Doses recommended for phase II study were considered to be 1,600 mg/body/day for 5 days and 1,200 mg/body/day for 10-14 days.

Adolescent↗
PubMed1990

[Epirubicin (4'-epi-adriamycin].

Epirubicin (trade name: Falmorubicin) is a stereoisomer, in which the hydroxyl group of doxorubicin is inverted at position 4', and has the similar mechanism of action as that of doxorubicin; namely, this new anthracycline anticancer agent for injection shows a wide antitumor spectrum and strong antitumor activity via the inhibition of DNA and RNA synthesis. In non-clinical experiments, the effect of epirubicin on transplantable murine tumors was similar or superior to that of doxorubicin in rats and mice. As for pharmacodynamics, this drug was found to rapidly penetrate into the tissue from the blood, and to remain there for a long period of time. This drug has been widely used abroad for the treatment of various solid cancers, such as breast cancer, and tumors of hematopoietic organs, such as malignant lymphoma. In Japan, it was proved clinically that the drug was effective on a wide range of tumors, including acute leukemia, malignant lymphoma, breast cancer, ovarian cancer, gastric cancer, hepatic cancer and ureteral epithelioma(bladder cancer, renal cancer and ureteral cancer). In a comparative study of chronic cardiotoxicity, it was noted that epirubicin produced less damage to the myocardium than doxorubicin when every morphological change was examined as an indicator. Electrocardiographic and histopathological findings also disclosed that epirubicin exhibited a smaller effect on the myocardium than that of doxorubicin. In conclusion, epirubicin is a new antitumor agent having an antitumor effect similar or superior to that of doxorubicin with the various toxicities, including cardiotoxicity, which are reduced in this drug in comparison to those of doxorubicin.

Animals↗
PubMed1989

In vivo activity on murine tumors of a novel antitumor compound, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]phenazine-6-carboxamide sodium salt (NC-190).

A novel antitumor compound, N-beta-dimethyl-aminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of greater than 200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1-5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a greater than 280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1-5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1-5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a greater than 300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3-10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1-5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3-10), and a greater than 161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3-10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1-5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.

Animals↗
PubMed1989

Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1.

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.

Animals↗
PubMed1989

Epidermal growth factor receptor-mediated selective cytotoxicity of antitumor agents toward human xenografts and murine syngeneic solid tumors.

Severe toxic side effects of antiproliferative agents limit their clinical usefulness as antitumor drugs. Recently we observed that the antitumor efficacy of various antitumor agents (5-fluorouracil, tegafur, adriamycin, mitomycin C, cyclophosphamide, and cisplatin) against experimental solid tumors was enhanced by prior or simultaneous administration of human epidermal growth factor (EGF). However, coadministration of EGF did not enhance the toxicity of antitumor agents as measured by LD50 and body weight loss. The above selective potentiation of efficacy of the antitumor agents by human EGF can be characterized as follows. In a dose-dependent manner, human EGF enhanced the efficacy of an antitumor agent (5-FU) treatment against human epidermoid carcinoma A431 transplanted sc in athymic nude mice [ED50 = 2.9 (0.2-49.7, 95% confidence interval) microgram/kg, sc]. Various degrees of enhancement were also observed against other experimental tumors transplanted sc. The degrees of enhancement were directly proportional to the numbers of human EGF binding sites present on tumor cell plasma membrane (threshold of binding site density = 1.5 X 10(3) sites/cell) using 5-FU or cisplatin as an antitumor agent, thus suggesting that the binding of EGF to the receptors on tumor cells is an essential process in enhancing the susceptibility of tumor cells to antitumor agents. Normal cells including intestinal epithelial and bone marrow cells are endowed with fewer EGF binding sites (less than 10(3) sites/cell). This may explain partially the absence of EGF-enhanced cytotoxicity by antitumor agents toward normal cells.

Animals↗
PubMed1989

The synergistic effect of human recombinant interferon-alpha 2a in combination with interferon-gamma and the induction of interferon-alpha 2a receptor by interferon-gamma.

An in vitro examination was made of the synergistic antiproliferative effect of recombinant interferon-gamma (IFN-gamma) with interferon-alpha 2a (IFN-alpha 2a) on human tumor cell lines, including lung small cell carcinoma QG-90, amelanotic melanoma HMV-1, renal carcinoma ACHN and Burkitt lymphoma Daudi. Sixty-four percent of HMV-1 cells and 75% of ACHN cells seeded were killed by treatment with 10 pM and 1000 pM of IFN-gamma, respectively. Furthermore, 69% of HMV-1 cells and 59% of ACHN cells were killed by 1000 pM of IFN-alpha 2a. When HMV-1 was treated first with 10 pM of IFN-gamma, and then with 1000 pM of IFN-alpha 2a, 81% of cells seeded were killed (p less than 0.001). Similarly, 89% of ACHN cells were killed by the same sequential treatment with 1000 pM IFN-gamma, and then of IFN-alpha 2a (p less than 0.001). However, adverse sequence of treatment could not produce such a synergistic result. On the surface of these susceptible cells, HMV-1 and ACHN, to both IFNs, the number of receptors for IFN-alpha 2a increased significantly after treatment with IFN-gamma without any serious change of the dissociation constant, suggesting that increase in the number of receptors for IFN-alpha 2a may be the major mechanism of the synergistic effects of IFN-gamma with IFN-alpha 2a.

Cell Division↗
PubMed1988

Specific binding of interferon-gamma and -alpha 2a to tumor cells and their antitumor activities.

Binding activities of a recombinant human interferon-gamma (IFN-gamma) preparation with 5 human tumor cell lines, including lung large cell carcinoma PC-13, lung small cell carcinoma QG-90, amelanotic melanoma HMV-1, renal carcinoma ACHN and Burkitt lymphoma Daudi, were compared with those of IFN-alpha 2a. Three out of five human tumor cell lines, ACHN, HMV-1, and QG-90, were highly susceptible to IFN-gamma: the concentrations required to inhibit 50% of the growth of cells (IC50) of ACHN, HMV-1, and QG-90 were 26, 11 and 7 pM, respectively. IFN-alpha 2a also markedly inhibited the growth of ACHN, HMV-1 and Daudi cells: the values of IC50 for the former and latter cells were 20, 31 and 0.8 pM, respectively. With these susceptible cells, larger amounts of IFN-gamma were bound than with resistant cells. On the other hand, IFN-alpha 2a bound all cell lines, irrespective of the susceptibilities of cells. The values of the apparent dissociation constant (Kd) of binding of both IFNs ranged from 1.3 to 7.3 x 10(-10) M. The competitive binding test revealed that the binding properties of IFN-gamma were different from those of IFN-alpha 2a. Under the present experimental condition, it could be said that, with IFN-gamma, the susceptibilities of cells were linked of the expression of the receptors, but there were some exceptions with IFN-alpha 2a.

Binding, Competitive↗
PubMed1988

[Problems in the development of analogs of anticancer drugs].

Undoubtedly the progress of cancer chemotherapy is supported by the development of new anticancer drugs. In Japan, there is a tendency to develop anticancer drugs by both chemical modification of the known anticancer drugs (analogues) and finding new structures. However, we have to be cautious to develop analogues of the known anticancer drugs. Before we consider to put these drugs into the clinical trials, several points must be clarified: that is, the new compounds would have any merit or superior points compared to the mother compounds. Especially, we should observe whether or not the new compounds possess any reduction of major toxicities of the mother compounds, how about the situation of cross resistance, anticancer efficacies and particularly the results of toxicology studies. We have limited cancer patients for testing new drugs, and also from ethical view, some easy consideration for developing analogues having minor differences from the mother compounds, must be abandoned.

Antineoplastic Agents↗
PubMed1988

[Pirarubicin (THP-adriamycin)].

Pirarubicin (THP-adriamycin or THP-doxorubicin) was found during a search of new anthracycline antibiotics among 4'-O-substituted compounds having less toxicities than other anthracycline anticancer drugs in 1979 by Umezawa et al. In its preclinical studies, this compound possessed almost similar antitumor efficacies to doxorubicin, but was effective against doxorubicin-resistant P388 and other murine tumor cell lines. This compound was rapidly incorporated into tumor cells, inhibiting DNA polymerase alpha and subsequently DNA synthesis. Inhibition of RNA synthesis was also noted. In the clinical studies, clinical responses were established against head and neck cancer, breast cancer, urogenital cancers, ovarian cancer, uterine cancer, acute leukemia, and malignant lymphoma, showing a wide antitumor spectrum clinically. Among the side effects, cardiac toxicity, alopecia and disturbance of the digestive organs were mild. From these results, THP-adriamycin seems to be a useful clinical drug for human solid tumors.

Animals↗
PubMed1988

A two-site solid phase enzyme immunoassay for rat epidermal growth factor.

A sensitive and simple two-site enzyme immunoassay was developed for rat epidermal growth factor (rEGF), which was purified from male rat submaxillary glands. This system is based on the sandwiching of the antigen between anti-rat EGF IgG antibody coated on a polystyrene bead and anti-rat EGF Fab' antibody-linked peroxidase, whose activity was stable at 4 degrees C for 6 months. In this system, the rat EGF was detectable at a concentration of 2 pg/tube. No interference was observed by addition of human plasma. There was no cross-reactivity with mouse EGF, human EGF, or other substances with similar chemical structures.

Animals↗
PubMed1987

Research and development on total artificial heart in University of Tokyo.

The research and development on the total artificial heart (TAH) in the University of Tokyo can be divided chronologically into the three stages, i.e., the first stage (1959-1970); trial and error stage to find appropriate hardwares, the second stage (1970-1985); software stage to find how to control pneumatic TAH and to manage the animals, and the third stage (1985- ); final goal to develop implantable TAH for animal and human. This paper reviews the process of research and development in each stage.

Animals↗
PubMed1987

Synthesis and antitumor activity of tropolone derivatives. 4.

Modifications of monotropolone 2 having poor potency against P388 in mice were studied. The alpha-ethoxy group of 2, prepared from hinokitiol and benzaldehyde diethyl acetal, was replaced with a phenolic or heteroaromatic compound by heating 2 with the appropriate nucleophile. Structure-activity relationships indicated that an acidic hydroxyl and a proton-accepting group situated in the neighboring position, which permits the formation of a chelate with a metal ion, contributed to enhanced activity. Among the compounds studied, the 8-hydroxyquinoline analogue 10f was the most favorable compound.

Animals↗
PubMed1987

Synthesis and antitumor activity of tropolone derivatives. 5.

As part of a study on the structure-activity relationship of antitumor-active tropolone derivatives, a series of bistropone analogues, related to potently active bistropolone 1a, were synthesized and tested for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. The methoxytropones 3 and 5, hydroxytropothione 10, and (N-methylamino)tropones 12 and 13 were inactive in both systems. Methoxytropone 6 exhibited weak activity, whose potency was equal to that of monotropolone 2a.

Animals↗