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T Yoshinari

Publications and source records attributed to T Yoshinari.

At least 19 recordsLinked to original sources
PubMed2001

Metallic behavior and periodical valence ordering in a MMX chain compound, Pt(2)(EtCS(2))(4)I.

A new one-dimensional (1-D) halogen-bridged mixed-valence diplatinum(II,III) compound, Pt(2)(EtCS(2))(4)I (3), has been successfully synthesized from [Pt(2)(EtCS(2))(4)] (1) and [Pt(2)(EtCS(2))(4)I(2)] (2). These three compounds have been examined using UV-visible-near-IR, IR, polarized Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and X-ray crystal structure analyses (except for 1). Compound 3 was further characterized through electrical transport measurements, determination of the temperature dependence of lattice parameters, X-ray diffuse scattering, and SQUID magnetometry. 3 crystallizes in the monoclinic space group C2/c and exhibits a crystal structure consisting of neutral 1-D chains with a repeating -Pt-Pt-I- unit lying on the crystallographic 2-fold axis parallel to the b axis. The Pt-Pt distance at 293 K is 2.684 (1) A in the dinuclear unit, while the Pt-I distances are essentially equal (2.982 (1) and 2.978 (1) A). 3 shows relatively high electrical conductivity (5-30 S cm(-1)) at room temperature and undergoes a metal-semiconductor transition at T(M-S) = 205 K. The XPS spectrum in the metallic state reveals a Pt(2+) and Pt(3+) mixed-valence state on the time scale of XPS spectroscopy ( approximately 10(-17) s). In accordance with the metal-semiconductor transition, anomalies are observed in the temperature dependence of the crystal structure, lattice parameters, X-ray diffuse scattering, and polarized Raman spectra near T(M-S). In variable-temperature crystal structure analyses, a sudden and drastic increase in the Pt-I distance near the transition temperature is observed. Furthermore, a steep increase in U(22) of iodine atoms in the 1-D chain direction has been observed. The lattice parameters exhibit significant temperature dependence with drastic change in slope at about 205-240 K. This was especially evident in the unit cell parameter b (1-D chain direction) as it was found to lengthen rapidly with increasing temperature. X-ray diffraction photographs taken utilizing the fixed-film and fixed-crystal method for the metallic state revealed the presence of diffuse scattering with line shapes parallel to the a* axis indexed as (-, n + 0.5, l) (n; integer). Diffuse scattering with k = n + 0.5 is considered to originate from the 2-fold periodical ordering corresponding to -Pt(2+)-Pt(2+)-I-Pt(3+)-Pt(3+)-I- or -Pt(2+)-Pt(3+)-I-Pt(3+)-Pt(2+)-I- in an extremely short time scale. Diffuse lines corresponding to 2-D ordering progressively decrease in intensity below 252 K and are converted to the diffuse planes corresponding to 1-D ordering near T(M-S). Furthermore, diffuse planes condensed into superlattice reflections below T(M-S). Polarized Raman spectra show temperature dependence through a drastic low-energy shift of the Pt-I stretching mode and also through broadening of bands above T(M-S).

Journal Article↗
PubMed2001

Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxyl) ethylamino-12,13-dihydro-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]] against pediatric and adult central nervous system tumor xenografts.

PURPOSE: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts. METHODS: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)]. RESULTS: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001). CONCLUSION: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent.

Adult↗
PubMed1999

Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

Animals↗
PubMed1999

Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.

J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.

Animals↗
PubMed1999

Substitution at the F-ring N-imide of the indolocarbazole antitumor drug NB-506 increases the cytotoxicity, DNA binding, and topoisomerase I inhibition activities.

The antitumor drug NB-506, which is currently undergoing phase I/II clinical trials, contains a DNA-intercalating indolocarbazole chromophore substituted with a glucose residue. In addition to interacting with DNA, the drug stabilizes the topoisomerase I-DNA covalent complex. To reinforce the DNA binding and anti-topoisomerase I activities of NB-506, an analogue containing a new substituent on the naphthalimide ring F was synthesized. The N-formylamino group of NB-506 has been replaced with a more hydrophilic group, N-bis(hydroxymethyl)methylamino. In this study we show that the incorporation of a longer substituent on the N6 position effectively reinforces both the interaction with DNA and the capacity of the drug to maintain the integrity of the topoisomerase I-DNA covalent complexes. The strength and the mode of binding of the drugs to DNA were studied by complementary biophysical techniques including absorption, fluorescence, and circular and linear dichroism. Various biochemical procedures were applied to investigate the effects on human topoisomerase I using plasmid DNA as well as restriction fragments. The drug binding sites and the positions of the topoisomerase I-mediated cleavage sites were mapped with nucleotide resolution using footprinting and sequencing techniques. Cytotoxicity measurements performed with various human cancer cell lines (HCT-116, DLD-1, MKN-45) indicate that the newly designed drug is 3 to 4 times more toxic to colon and gastric cancer cells than NB-506. Therefore, the results suggest that the antitumor activity of indolocarbazole-based drugs can be enhanced by incorporating DNA and/or topoisomerase I reactive groups. They also support the hypothesis that the substituent on the imide nitrogen on the F ring of NB-506 has direct interaction with the molecular target. The study helps to define the structure-activity relationships in the indolocarbazole series of antitumor agents targeting topoisomerase I.

Animals↗
PubMed1999

Intercalation into DNA is not required for inhibition of topoisomerase I by indolocarbazole antitumor agents.

The DNA-intercalating antitumor drug NB-506 is a potent topoisomerase poison currently undergoing phase I/II clinical trials. It contains a planar indolocarbazole chromophore substituted with a glucose residue. Up until now, it was thought that intercalation of the drug into DNA was essential for the stabilization of topoisomerase I-DNA covalent complexes. But, in the present study, we show that a regio-isomeric form of NB-506 has lost its capacity to intercalate into DNA, but remains an extremely potent topoisomerase I poison. The new analogue contains two hydroxyl groups at positions 2,10 instead of positions 1,11 in NB-506. The relocation of the two OH groups reduces considerably the strength of binding to DNA and prevents the drug from intercalating into the DNA double helix. However, the topoisomerase I inhibition capacity of the new analogue remains very high. The two drug isomers are equally potent at maintaining the integrity of the topoisomerase I-DNA covalent complexes, but stimulate cleavage at different sites on DNA. NB-506 stabilizes topoisomerase I preferentially at sites having a pyrimidine (T or C) and a G on the 5' and 3' sides of the cleaved bond, respectively. The 2,10-isomer induces topoisomerase I-mediated cleavage only at TG sites and, thus, behaves exactly as the reference topoisomerase I poison camptothecin. Finally, cytotoxicity measurements performed with a panel of murine and human cancer cell lines reveal that the newly designed drug is considerably (up to 100-fold) more toxic to tumor cells than the parent drug NB-506. We conclude that the DNA-binding and topoisomerase I poisoning activities of NB-506 can be viewed as two separate mechanisms.

Animals↗
PubMed1999

A new mechanism of acquisition of drug resistance by partial duplication of topoisomerase I.

Topoisomerase (topo)-I targeting antitumor agents are very effective in vivo against various human cancers. The indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl)- 5H-indolo[2,3-alpha]pyrrolo-[3,4-c]carbazole-5,7(6H)-dione (NB-506) is a potent inhibitor of the religation step of topo I reaction, like camptothecin (CPT). We established a NB-506-resistant cell line from murine leukemia cell line P388. This resistant cell line, P388/F11, exhibited 73-fold higher resistance to NB-506 and 3.5-fold higher cross-resistance to CPT than the parental cell line. No induction of cleavable complex formations induced by NB-506 and CPT were detected by K-SDS precipitation assays in P388/F11 cells. Analysis of nuclear extracts from P388/F11 cells revealed that the relaxation activity of topo I was one-quarter of that of the parental cells, and that the activity was resistant to induction of DNA cleavage by these drugs. Furthermore, Western blot and Northern blot analyses showed the expression of an abnormal-sized 170-kDa topo I protein and its 6.0-kb transcript and the absence of the normal topo I protein and transcript in P388/F11 cells. Analyses of the structure of the abnormal topo I transcript by reverse transcription-PCR and direct sequencing methods revealed that a large portion of the gene from codon 21 to codon 609 was duplicated in its coding region. This internal duplication resulted in in-frame fusion and, thus, production of a partially duplicated protein of 1357 amino acids. Finally, we expressed and purified the recombinant P388/F11 topo I in a baculovirus system. P388/F11 topo I showed similar catalytic activity to wild-type topo I, but reduced sensitivities to NB-506 and CPT. These results show that the altered sensitivity of duplicated topo I is involved in the NB-506 resistance of P388/F11 cells and indicate a novel resistant mechanism which involves duplication of the topo I gene.

Animals↗
PubMed1999

Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506.

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.

Animals↗
PubMed1999

A clinicopathological study of postoperative pulmonary metastasis of uterine cervical carcinomas.

OBJECTIVE: To investigate the clinicopathological backgrounds and prognostic factors of uterine cervical carcinomas metastatic to the lung. METHODS: A total of 519 patients with invasive cervical carcinoma (Stage pTIb-IIb) treated by abdominal radical hysterectomy at the Saitama Cancer Center from January 1, 1976 to December 31, 1989 were analyzed clinicopathologically. RESULTS: The frequencies of pulmonary metastasis were 6.4% (24/377) and 11.3% (16/142) in patients with negative and positive pelvic lymph nodes, respectively. Among 24 negative lymph node patients, 15 had pulmonary metastasis only. The overall 5-year survival rate of these 15 patients was 36% after relapse. Of the 15, the prognosis of 12 patients with 1-3 pulmonary metastases only was better, that is, 46% after surgical resection (mean size of resectable tumor = 2.8 cm) and/or chemotherapy. But the other patients died within 3.3 years after relapse. CONCLUSIONS: The occurrence of pulmonary metastasis only, its number (1-3) and size (mean size = 2.8 cm), and no lymph node metastasis are important prognostic factors. For these patients, active surgical resection of the pulmonary lesion(s) and further chemotherapy are recommended in order to improve their prognosis.

Adenocarcinoma↗
PubMed1999

A DNA binding indolocarbazole disaccharide derivative remains highly cytotoxic without inhibiting topoisomerase I.

NB-506 is a glucosylated indolocarbazole related to the antibiotic rebeccamycin and is currently under clinical trials as an anticancer drug. This compound is a DNA intercalating agent and a potent topoisomerase I poison. The glucose residue attached to the planar indolocarbazole chromophore plays a significant role in the interaction of the drug with nucleic acids and contributes positively to the stabilization of topoisomerase I-DNA covalent complexes. To investigate further the influence of the carbohydrate moiety, we studied the DNA binding and topoisomerase I inhibition properties of an analogue of NB-506 bearing a disaccharide side chain. Fluorescence and footprinting studies indicate that the replacement of the glucose chain of NB-506 with a maltose residue does not hinder the capacity of the drug to bind to DNA and to recognize GC-rich sequences. The addition of the second sugar residue does not reinforce the interaction with DNA but abolishes the capacity of the drug to inhibit topoisomerase I. Unexpectedly, the disaccharide analogue of NB-506 has totally lost its capacity to stimulate DNA cleavage by topoisomerase I. In addition, like NB-506, the new analogue is not an inhibitor of topoisomerase II. However, despite the absence of topoisomerase poisoning activity, the cytotoxic activity is fully maintained. The maltosyl-indolocarbazole drug proved to be as potent as NB-506 at inhibiting the growth of various human and murine tumour cell lines. The study raises the question as to whether topoisomerase I poisoning is important for the antitumour activity of rebeccamycin analogues.

Animals↗
PubMed1998

Sequence-selective DNA cleavage by a topoisomerase I poison, NB-506.

An indolocarbazole compound, NB-506, inhibits the activity of topoisomerase I by stabilizing the DNA-topoisomerase I complex (cleavable complex). NB-506 inhibited the religation step of topoisomerase I activity more potently than camptothecin or its derivative, topotecan. A cleavage assay using an end-labeled fragment of DNA revealed that the pattern of cleavage induced by NB-506 was different from that induced by camptothecin. The preferred cleavage sites of NB-506 were found to be not only T but also A or C at the 3'-terminus of the cleaved DNA (position -1), while the DNA cleavage sites of camptothecin always had T at position -1. At the 5'-terminus of the cleaved DNA (position +1), NB-506 showed a preference for G, which is a feature shared in common with camptothecin. Therefore, the difference in cleavage patterns was most likely due mainly to the preferred base at position -1. Moreover, the re-ligation rate was significantly slower at NB-506-selective sites, which had C at position-1, than at camptothecin-selective sites or at sites cleaved by both NB-506 and camptothecin. Our data suggest that NB-506 is an unique topoisomerase I poison and that its potent inhibition of topoisomerase I is partly dependent on retardation of re-ligation at sites selectively induced by NB-506.

Animals↗
PubMed1996

Potent antitumor activity of quinolone compounds with an unsaturated aminoazabicyclo group at the C-7 position of the quinolone ring.

Relationships between the substituents on the quinolone nucleus of 2 and related compounds and their biological activities were studied. 2, 3 and 1 carrying a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl group at the C-7 position increased the rate of formation of DNA-protein complexes in cells, and inhibited the growth of tumor cells more strongly than the compounds with other substituents. The introduction of a fluorine atom or a methoxy group at the 8-position and an amino group at the 5-position increased the activity still further. The three compounds listed were all effective against P388 leukemia in mice. Subcutaneous injection of 2 at 2 mg/kg strongly suppressed the growth of human MX-1 breast cancer cells in nude mice. 1 has various functional groups that increase the cytotoxic potential of quinolone derivatives: a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl moiety at C-7, a cyclopropyl group at the 1-position, fluorine atoms at the 6- and 8-positions, and an amino group at the 5-position of the quinoline carboxylic acid. These data suggest that this series of compounds provide good models for the further design of potent antitumor quinolones.

Animals↗
PubMed1995

Novel antitumor indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11- dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4- c]carbazole-5,7(6H)-dione (NB-506): induction of topoisomerase I-mediated DNA cleavage and mechanisms of cell line-selective cytotoxicity.

A new indolocarbazole antitumor agent, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H- indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione], enhanced the DNA cleavage catalyzed by HeLa S3 topoisomerase I at 0.01 microM but not the cleavage by topoisomerase II at 300 microM. It also caused single-strand DNA breakage in intact cells at 0.08 microM and more. Unlike the known topoisomerase I inhibitor camptothecin, NB-506 intercalated with DNA. However, the binding affinity to DNA and the inhibition against DNA polymerase alpha and RNA polymerase II were marginal compared with those of Adriamycin or actinomycin D. NB-506 inhibited the growth of various tumor cell lines at two micromoles or less, and its cytotoxicity was found to be cell line selective. This selective cytotoxicity of NB-506 was not fully explained by the differences in topoisomerase I activity in these cell lines, but there was some relationship between the amount of NB-506 accumulated in these cell lines and its cytotoxicity toward them. In conclusion, NB-506 is a potent topoisomerase I poison, acting selectively on tumor cell lines accumulating NB-506.

Animals↗
PubMed1995

Novel indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole- 5,7(6H)-dione (NB-506): its potent antitumor activities in mice.

NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D- glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-di one d is a new antitumor indolocarbazole compound. The growths of murine M5076 and Ehrlich solid tumors were inhibited 76 and 96%, respectively, by i.v. injection at doses of 300 mg/m2. Furthermore, NB-506 caused regression of nodules of human PC-13 lung cancer and MKN-45 stomach cancer cells at i.v. doses of 90 mg/m2. Human HCT 116 and LS 180 colon cancers also regressed with injections of NB-506. Repeated injections of NB-506 had a stronger antitumor effect than intermittent injections in mice with MKN-45. The cumulative toxicity of NB-506 was low in terms of lethality in mice, i.e., the LD50s on single and 10 repeated i.v. injections into CDF1 mice were 990 and 810 mg/m2/injection, respectively. In conclusion, NB-506 is considered to be an interesting possible candidate as an anticancer drug for treatment of solid tumors in humans.

Animals↗
PubMed1994

Inhibition of topoisomerase II by a novel antitumor cyclic depsipeptide, BE-22179.

BE-22179, a novel cyclic depsipeptide antibiotic having two 3-hydroxyquinoline moieties, inhibited the DNA-relaxing activity of L1210 topoisomerase II completely at 0.08 microM. This effect was far stronger than that of VP-16. However, it did not show any marked effect on topoisomerase II-mediated DNA cleavage. BE-22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 microM, but showed DNA-intercalating ability (DNA unwinding) at 30 microM. The structure of BE-22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE-22179, interfered with DNA relaxation by topoisomerase II, though the effect was not due to inhibition of the catalytic activity of topoisomerase II but to conformational change of DNA based on its intercalation into DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might rather be specific to BE-22179. BE-22179 prevented DNA synthesis as well as RNA synthesis in L1210 cells and inhibited the growth of the cells. However, it remains unclear to what extent the topoisomerase II inhibition was responsible for the cytotoxicity of BE-22179.

Animals↗
PubMed1994

A new topoisomerase II inhibitor, BE-22179, produced by a streptomycete. I. Producing strain, fermentation, isolation and biological activity.

A new topoisomerase II inhibitor, designated BE-22179, was isolated from the culture broth of Streptomyces sp. A22179, which resembles "Streptomyces gangtokensis". The inhibitor was extracted from the mycelial cake of the culture broth with organic solvent and successively purified by silica gel chromatography. BE-22179 inhibited topoisomerase II strongly but not topoisomerase I and showed potent antitumor activity against various tumor cell lines both in vitro and in vivo.

Animals↗
PubMed1993

Induction of topoisomerase I-mediated DNA cleavage by a new indolocarbazole, ED-110.

ED-110 is a new semisynthetic antitumor agent derived from a novel indolocarbazole antibiotic, BE-13793C, produced by an actinomycete. ED-110 induced topoisomerase I-mediated DNA cleavage in vitro as strongly as camptothecin, whereas topoisomerase II-mediated DNA cleavage was not induced by this agent. Exposure of P388 cells to ED-110 caused a typical topoisomerase toxicity, i.e.: formation of cleavable complexes; inhibition of nucleotide synthesis rather than protein synthesis; and cell cycle arrest in G2. ED-110 inhibited the growth of P388 cells, with a 50% growth-inhibitory concentration of 44 nM. ED-110 is distinguished from camptothecin by its very different structure and its ability to intercalate into double-stranded DNA. These results suggest that ED-110 has potential as a novel antitumor agent targeting topoisomerase I.

Animals↗