Akira Kawashima
Chugai Pharmaceutical Co.
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Featured researches published by Akira Kawashima.
Bioorganic & Medicinal Chemistry Letters | 2009
Jun Ohwada; Sawako Ozawa; Masami Kohchi; Hiroshi Fukuda; Chikako Murasaki; Hitomi Suda; Takeshi Murata; Satoshi Niizuma; Masao Tsukazaki; Kazutomo Ori; Kiyoshi Yoshinari; Yoshiko Itezono; Mika Endo; Masako Ura; Hiromi Tanimura; Yoko Miyazaki; Akira Kawashima; Shunsuke Nagao; Eitarou Namba; Koutarou Ogawa; Kazuko Kobayashi; Hisafumi Okabe; Isao Imperial Higashihak Umeda; Nobuo Shimma
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.
Drug and Chemical Toxicology | 2004
Yongke Lu; Akira Kawashima; Ikuo Horii; Laifu Zhong
The effects of DL‐buthionine‐(S,R)‐sulfoximine(BSO) and L‐cysteine(CYS) on cytotoxicity induced by cisplatin(CP) and diclofenac(DIC) in primary cell cultures of hepatocytes and renal tubular epithelial cells(RTEC) isolated from rats or monkeys were studied. Hepatocytes and RTEC were inoculated into collagen coated 96‐well culture plates. After preincubation, a series of concentrations of CP or DIC were added, and 16 h and 4 h prior to CP and DIC, 40 µM BSO and 5 mM CYS were added, respectively. MTT assays were performed to evaluate cytotoxicity(concentrations of drug that inhibited 50% cell growth, IC50). CYS made IC50s of CP in rat and monkey RTEC increase up to more than 5 mM, but BSO made IC50s of CP in rat RTEC lower down with bigger magnitude than that in monkey RTEC; similarly, CYS made IC50s of CP in rat hepatocytes increase up to more than 5 mM, but BSO made IC50s lower down with bigger magnitude than that in rat RTEC. However, neither CYS nor BSO had significant effects on all IC50s of DIC in all examined cells. These results suggested that during CP‐induced stress state, rat hepatocytes were more susceptible to changes of GSH level than rat RTEC, and rat RTEC were more dependent on intracellular GSH status than monkey RTEC. DIC‐induced cytotoxicity in RTEC and hepatocytes are independent of GSH level.
Bioorganic & Medicinal Chemistry Letters | 2009
Satoshi Niizuma; Masao Tsukazaki; Hitomi Suda; Takeshi Murata; Jun Ohwada; Sawako Ozawa; Hiroshi Fukuda; Chikako Murasaki; Masami Kohchi; Kenji Morikami; Kiyoshi Yoshinari; Mika Endo; Masako Ura; Hiromi Tanimura; Yoko Miyazaki; Tsuyoshi Takasuka; Akira Kawashima; Eitaro Nanba; Kounosuke Nakano; Kotaro Ogawa; Kazuko Kobayashi; Hisafumi Okabe; Isao Imperial Higashihak Umeda; Nobuo Shimma
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
Renal Failure | 2005
Yongke Lu; Akira Kawashima; Ikuo Horii; Laifu Zhong
Background. Cisplatin (CP)-induced kidney damage and effects of DL-buthionine-(S,R)-sulfoximine (BSO) on it are species- and age-different. It remains unclear whether CP-induced cytotoxicity in renal proximal tubular epithelial cells (RTEC), the main target cells of CP, is also species- and age-different; and whether CP-induced cytotoxicity varies with the difference in age and species, if any, is one of the questions. In the present study, the effects of BSO on CP-induced cytotoxicity in primary cultures of RTEC isolated from monkeys and different age and sex rats were studied. Methods. The RTEC were isolated from 3-week-old, 2-month-old, or 5-month-old rats, and 6-8 year-old monkeys. After subculturing, RTEC was inoculated into type I collagen-coated 96-well culture plates; after preincubation, 40 µM BSO was added, 16 hours later, varying concentrations of CP were added. At that time, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were performed to test cell viability. Results. The concentrations of CP that inhibited 50% cell growth (IC50) of RTEC from rats and monkeys were 1.11 and 3.03 mM at 8 hours, and 0.51 and 1.24 mM at 24 hours, respectively. The BSO made the IC50s of RTEC from rats and monkeys lower, down to 0.07 and 0.48 mM at 8 hours, and 0.02 and 0.11 mM at 24 hours, respectively. The IC50s of RTEC from different sex and age rats were almost same. Conclusion. These results suggested that CP-induced cytotoxicity was concentration- and time-dependent, with species-dependent differences, rat RTEC were more susceptible to CP than monkey RTEC, rat RTEC were more dependent on glutathione (GSH) during the stress state were than monkey cells; CP-induced cytotoxicity was without sex- and age-dependent differences in rat RTEC.
Journal of Toxicological Sciences | 2006
Hidetoshi Shindoh; Akira Kawashima; Nobuyuki Shishido; Kounosuke Nakano; Kazuko Kobayashi; Ikuo Horii
Journal of Toxicological Sciences | 2007
Hidetoshi Shindoh; Akira Kawashima; Nobuyuki Shishido; Kounosuke Nakano; Kazuko Kobayashi; Ikuo Horii
Journal of Toxicological Sciences | 1999
Akira Kawashima; Akira Inomata; Kazuko Kobayashi; Ikuo Horii
Journal of Toxicological Sciences | 1998
Ikuo Horii; Akira Kawashima
Journal of Toxicological Sciences | 1995
Akira Kawashima; Kazuko Kobayashi; Takashi Abo; Izuru Imamura; Ikuo Horii
Journal of Toxicological Sciences | 1995
Hidetoshi Shindoh; Akira Kawashima; T. Tahara; Ikuo Horii