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Jiro Kikuchi,
Naoya Shibayama,
Satoshi Yamada,
Taeko Wada,
Masaharu Nobuyoshi,
Tohru Izumi, Miyuki Akutsu,
Yasuhiko Kano,
Kanako Sugiyama,
Mio Ohki,
Sam-Yong Park,
Yusuke Furukawa
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ABSTRACT: The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.
PLoS ONE 01/2013; 8(4):e60649. · 4.09 Impact Factor
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ABSTRACT: The definition of primary splenic lymphoma is controversial, but it has been reported to be a rare disease that comprises less than 1% of all malignant lymphomas. Three cases of primary splenic diffuse large B-cell lymphoma treated at our institution are described here. Median follow-up was 34.6 months (range 8.7∼39.2) and median age at diagnosis was 72 years old (range 65∼73). In all three cases, the diagnosis was definitively established not by splenectomy but by ultrasonically guided percutaneous splenic tissue core biopsy. Using the Hans classifier, one of the cases was subclassified as the germinal center B-cell like (GCB) subtype and two as non-GCB subtype. One case was CD5-positive diffuse large B-cell lymphoma. Two patients were in Ann Arbor stage II and one was in stage III. Using the International Prognostic Index, one was categorized as Low/intermediate risk, one as high/intermediate risk, and one as high risk. All patients underwent eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone followed by irradiation therapy. These three patients attained complete response. Although the follow-up period to date has been short, all patients have maintained a complete response and are currently alive. To determine whether our management protocol is valid, further observations are needed.
[Rinshō ketsueki] The Japanese journal of clinical hematology 08/2011; 52(8):703-7.
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Nippon rinsho. Japanese journal of clinical medicine 06/2010; 68 Suppl 6:602-4.
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Jiro Kikuchi,
Taeko Wada,
Rumi Shimizu,
Tohru Izumi, Miyuki Akutsu,
Kanae Mitsunaga,
Kaoru Noborio-Hatano,
Masaharu Nobuyoshi,
Keiya Ozawa,
Yasuhiko Kano,
Yusuke Furukawa
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ABSTRACT: Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-kappaB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8-dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.
Blood 03/2010; 116(3):406-17. · 9.90 Impact Factor
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ABSTRACT: The CD33 antigen is expressed on leukemia cells in most patients with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), and in 20% of patients with acute lymphoblastic leukemia (ALL), while it is absent from pluripotent hematopoietic stem cells and nonhematopoietic cells. Gemtuzumab ozogamicin (GO) is an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, which is a potent cytotoxic agent that causes double-strand DNA breaks, resulting in cell death. GO was developed against CD33 antigen-positive leukemias. The aim of this study was to investigate the cytotoxic effects of this agent in combination with conventional antileukemic agents.
The cytotoxic effects of GO in combination with antileukemic agents were studied against human CD33 antigen-positive leukemia HL-60, U937, TCC-S and NALM20 cells. The leukemia cells were exposed simultaneously to GO and to the other agents for 4 days. Cell growth inhibition was determined using a MTT reduction assay. The isobologram method was used to evaluate the cytotoxic interaction.
GO produced synergistic effects with mitoxantrone, additive effects with cytarabine, daunorubicin, idarubicin, doxorubicin, etoposide and 6-mercaptopurine, and antagonistic effects with methotrexate and vincristine.
Our findings suggest that the simultaneous administration of GO with most agents studied would be advantageous for antileukemic activity. The simultaneous administration of GO with methotrexate or vincristine would have little cytotoxic effect, and this combination may be inappropriate. These findings may be useful in clinical trials of combination chemotherapy including GO or other monoclonal antibodies linked to calicheamicin.
Anticancer research 11/2009; 29(11):4589-96. · 1.73 Impact Factor
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ABSTRACT: Pemetrexed and docetaxel show clinical activities against a variety of solid tumors including lung cancers. To identify the optimal schedule for combination, cytotoxic interactions between pemetrexed and docetaxel were studied at various schedules using three human lung cancer cell lines A-549, Lu-99, and SBC-5 in vitro.
Cells were incubated with pemetrexed and docetaxel simultaneously for 24 or 120 h. Cells were also incubated with pemetrexed for 24 h, followed by a 24 h exposure to docetaxel, and vice versa. Growth inhibition was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis. Cytotoxic interactions were evaluated by the isobologram method.
Simultaneous exposure to pemetrexed and docetaxel for 24 and 120 h produced antagonistic effects in all three cell lines. Pemetrexed (24 h) followed by docetaxel (24 h) produced additive effects in A-549 cells and synergistic effects in Lu-99 and SBC-5 cells. Docetaxel followed by pemetrexed produced additive effects in A-549 and Lu-99 cells and antagonistic effects in SBC-5 cells. The results of cell cycle analysis were fully consistent with those of isobologram analysis, and provide the molecular basis of the sequence-dependent difference in cytotoxic interactions between the two agents.
Sequential administration of pemetrexed followed by docetaxel may provide the greatest anti-tumor effects for this combination in the treatment of lung cancer.
Cancer Chemotherapy and Pharmacology 04/2009; 64(6):1129-37. · 2.83 Impact Factor
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Miyuki Akutsu,
Saburo Tsunoda,
Tohru Izumi,
Masaru Tanaka,
Susumu Katano,
Koichi Inoue,
Seiji Igarashi,
Kaoru Hirabayashi,
Yusuke Furukawa,
Ken Ohmine,
Kazuya Sato,
Hiroyuki Kobayashi,
Keiya Ozawa,
Keita Kirito,
Takahiro Nagashima,
Satoshi Teramukai,
Masanori Fukushima,
Yasuhiko Kano
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ABSTRACT: We evaluated the long-term outcome of very dose-intensive chemotherapy (TCC-NHL-91) for advanced intermediate-grade lymphoma, in which an eight-cycle regimen with 11 drugs was given with granulocyte colony-stimulating factor (G-CSF) support (total 18 weeks). Fifty-nine patients were treated during February 1, 1991 and March 31, 2001 (median age: 48 years). Forty-three patients (73%) were in a high-intermediate risk or high-risk group (HI/H) according to the age-adjusted International Prognostic Index (aa-IPI). Forty-six patients received 7 or 8 cycles of therapy. Ten of 15 patients over age 60 stopped before 7 cycles. Forty-three patients with an initial bulky mass or a residual mass received involved-field radiation. Overall, 56 patients (95%) achieved complete remission (CR). Grade 4 hematotoxicity was observed in all patients. With a median follow-up of 128 months, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 76% and 61%, respectively. Neither aa-IPI risk factors nor the index itself was associated with response, OS, or PFS. One patient died of sepsis during the therapy and one died of secondary leukemia. This retrospective study suggests that the TCC-NHL-91 regimen achieves high CR, OS, and PFS in patients with advanced intermediate-grade lymphoma up to 60 years old and may be a valuable asset in the management of this disease. Further evaluation and prospective studies of the TCC-NHL-91 are warranted.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 02/2008; 17(3):137-49. · 1.30 Impact Factor
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Saburo Tsunoda,
Hiroyuki Kobayashi,
Koichi Inoue,
Tohru Izumi, Miyuki Akutsu,
Susumu Katano,
Tomoki Ueda,
Toshitaka Shirai,
Yoshihiro Masuda,
Kenichi Ohmine,
Takahiro Nagashima,
Masuzu Ueda,
Syojiro Takagi,
Kazuo Muroi,
Keiya Ozawa,
Yasuhiko Kano
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ABSTRACT: We conducted a clinical study of MTX-HOPE (day 1, methotrexate 20 mg per os (po); day 2, hydrocortisone 100 mg intravenous (iv), vincristine 1 mg iv; day 3,4 sobuzoxane 400 mg po; etoposide 25 mg po, repeating every 2 or 3 weeks) in 14 relapsed or refractory patients with non-Hodgkin's lymphoma. Ten responders were obtained 5 CR and 5 PR), and heavily treated patients were included in the responders. The median duration of over all survival which was estimated with Kaplan-Meier curve was 11.1 months (range, 2-18+ months), and the median duration of response was 6.9 months (range, 0.8+ -16.4+ months). Out of the 14 patients,eleven were treated with this regimen in an outpatient setting. Grade 4 neutropenia and thrombocytopenia were observed in 4 and 2 patients,and grade 3 GPT-elevation and stomatitis in two and one, respectively. This newly developed MTX-HOPE therapy may be a promising treatment option for such patients as are intolerable for high-dose chemotherapies with PBSC rescue or wish for outpatient therapy.
Gan to kagaku ryoho. Cancer & chemotherapy 07/2007; 34(6):885-9.
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Leukemia and Lymphoma 04/2007; 48(3):640-2. · 2.58 Impact Factor
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ABSTRACT: FK228 is a novel antitumor depsipeptide that inhibits histone deacetylases and restores the expression of genes aberrantly suppressed in cancer cells. This agent was shown to have broad antitumor activity in preclinical studies, and is currently under phase I/II evaluations. Because of its wide spectrum of actions, it is reasonable to consider the combination with other anticancer drugs in clinical application. We studied the cytotoxic interaction of FK228 in combination with conventional antileukemic agents using human promyelocytic leukemia HL60, Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia KU-812, T-cell lymphoblastic leukemia MOLT3 and Burkitt's lymphoma Raji cell lines. For the combination of FK228 and imatinib, Ph(+) leukemia KU812, K562 and TCC-S cell lines were used. The cells were exposed simultaneously to FK228 and other agents for 4 days. Cell growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We used the isobologram method of Steel and Peckham to evaluate the cytotoxic interaction at the concentration of drugs that produced 80% cell growth inhibition (IC(80)). FK228 showed an additive effect with cytarabine, carboplatin, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, 6-mercaptopurine and SN-38 (active metabolite of irinotecan) in all cell lines studied. FK228 with methotrexate and vincristine showed an antagonistic effect in three and one of the four cell lines, respectively. FK228 was additive with imatinib in all three Ph(+) leukemia cells. Our findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.
Investigational New Drugs 03/2007; 25(1):31-40. · 3.36 Impact Factor
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Yasuhiko Kano, Miyuki Akutsu,
Saburo Tsunoda,
Tohru Izumi,
Hiroyuki Kobayashi,
Koichi Inoue,
Kiyoshi Mori,
Hirofumi Fujii,
Hiroyuki Mano,
Tsogbadrakh Odgerel,
Yusuke Furukawa
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ABSTRACT: The combination of pemetrexed and cisplatin shows good clinical activity against mesothelioma and lung cancer. In order to study the potential cellular basis for this, and provide leads as to how to optimize the combination, we studied the schedule-dependent cytotoxic effects of pemetrexed and cisplatin against four human cancer cell lines in vitro. Tumor cells were incubated with pemetrexed and cisplatin for 24 h at various schedules. The combination effects after 5 days were analyzed by the isobologram method. Both simultaneous exposure to pemetrexed and cisplatin for 24 h and sequential exposure to cisplatin for 24 h followed by pemetrexed for 24 h produced antagonistic effects in human lung cancer A549, breast cancer MCF7, and ovarian cancer PA1 cells and additive effects in colon cancer WiDr cells. Pemetrexed for 24 h followed by cisplatin for 24 h produced synergistic effects in MCF7 cells, additive/synergistic effects in A549 and PA1 cells, and additive effects in WiDr cells. Cell cycle analysis of MCF7 and PA1 cells supported these findings. Our results suggest that the simultaneous clinical administration of pemetrexed and cisplatin may be suboptimal. The optimal schedule of pemetrexed in combination with cisplatin at the cellular level is the sequential administration of pemetrexed followed by cisplatin and this schedule is worthy of clinical investigations.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 02/2006; 16(2):85-95. · 1.30 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 08/2005; 63 Suppl 7:556-8.
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Nippon rinsho. Japanese journal of clinical medicine 08/2005; 63 Suppl 7:559-61.
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ABSTRACT: Pemetrexed is a novel multitargeted antifolate with significant clinical activity against a variety of tumors. We studied the schedule-dependent cytotoxic effects of pemetrexed in combination with paclitaxel in vitro to improve our understanding of how this combination might be used clinically. Human lung cancer A549 cells, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells were exposed to both pemetrexed and paclitaxel in vitro. Cell growth inhibition after 5 days was determined and the effects of drug combinations were analyzed by the isobologram method (Steel and Peckham). Simultaneous exposure to pemetrexed and paclitaxel for 24 h produced antagonistic effects in A549 and PA1 cells, additive/antagonistic effects in MCF7 cells, and additive effects in WiDr cells. Pemetrexed for 24 h followed by paclitaxel for 24 h produced synergistic effects in A549 and MCF7 cells and additive effects in PA1 and WiDr cells, while the reverse sequence produced additive effects in all four cell lines. Cell cycle analysis supported these observations. Our findings suggest that the simultaneous administration of pemetrexed and paclitaxel is suboptimal. The optimal schedule of pemetrexed in combination with paclitaxel is the sequential administration of pemetrexed followed by paclitaxel, and this schedule should be assessed in clinical trials for the treatment of solid tumors.
Cancer Chemotherapy and Pharmacology 01/2005; 54(6):505-13. · 2.83 Impact Factor
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ABSTRACT: Clinical studies of paclitaxel in combination with etoposide against solid tumors have been carried out. The combination
schedules used in these studies are different. We studied the cytotoxic effects of paclitaxel with etoposide against four
human cancer cell lines in vitro to determine the optimal schedule of this combination at the cellular level. Cells were exposed
simultaneously to paclitaxel and to etoposide for 24 h or sequentially to one drug for 24 h followed by the other for 24 h,
after which they were incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was determined
by an MTT reduction assay. The effects of drug combinations at concentrations producing 80% inhibition (IC80) were analyzed by the isobologram method of Steel and Peckham. The cytotoxic effect of paclitaxel and etoposide was cell
line- and schedule-dependent. Simultaneous exposure to paclitaxel and etoposide for 24 h produced additive effects in the
lung cancer cell line A549 and ovarian cancer PA1 cells, and antagonistic effects in the breast cancer cell line MCF7 and
colon cancer WIDr cells. Sequential exposures to paclitaxel followed by etoposide and vice versa produced additive effects
in all four cell lines. These results suggest that maximum cytotoxic effects can be obtained with sequential administration,
but not simultaneous administration, of paclitaxel and etoposide. These findings may have important clinical implications
for this combination.
Cancer Chemotherapy and Pharmacology 08/1999; 44(5):381-388. · 2.83 Impact Factor
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ABSTRACT: The schedule-dependent interaction of paclitaxel and cisplatin was studied in four human carcinoma cell lines: non-small
cell lung cancer, A549; breast cancer, MCF7; ovarian cancer, PA1; and colon cancer, WiDr cells. The cells were exposed simultaneously
to the drugs for 24 h and sequentially to paclitaxel first for 24 h followed by cisplatin for 24 h, or vice versa, and then
incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was then determined by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium
bromide (MTT) reduction assay. The effects of drug combinations at the IC80 level were analyzed by the isobologram method. On simultaneous exposure to paclitaxel and cisplatin, additive and sub-additive
(slight antagonistic) effects were observed in A549, MCF7, and PA1 cells, while sub-additive and protective (antagonistic)
effects were observed in WiDr cells. On sequential exposure to paclitaxel first, followed by cisplatin, additive effects were
observed in all cell lines. On sequential exposure to cisplatin first, followed by paclitaxel, additive effects were observed
in PA1 cells, while additive, sub-additive, and protective effects were observed in A549, MCF7, and WiDr cells.
These findings suggest that the interaction of paclitaxel and cisplatin is schedule- and cell line-dependent. The optimal
schedule of this combination may be paclitaxel first followed by cisplatin.
Cancer Chemotherapy and Pharmacology 02/1996; 37(6):525-530. · 2.83 Impact Factor
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ABSTRACT: In vitro studies with drug combinations of carboplatin and other anticancer agents were carried out in MOLT-3 human lymphoblastic leukemia and HL-60 human promyelocytic leukemia cell lines. Cells were incubated for 3 days in the presence of various concentrations of carboplatin and other drugs and cell growth inhibition was determined by MTT assay. The antitumor effects of the drug combinations at id50 were analyzed using an improved isobologram.In MOLT-3 cells, supra-additive (synergistic) effects were observed for carboplatin in combination with cytosine arabinoside, mitoxantrone and CPT-11. Additive effects were observed for combinations of carboplatin with bleomycin, daunorubicin, doxorubicin, etoposide, 6-mercaptopurine, and vincristine. Sub-additive and protective (antagonistic) effects were observed with methotrexate. Synergistic or antagonistic effects for combinations of carboplatin and CPT-11, cytosine arabinoside, mitoxantrone and methotrexate were also observed in HL-60 cells.These findings suggest that carboplatin has additive or synergistic cytotoxic effects with most of the agents tested. Determination of the usefulness of these drug combinations awaits appropriate in vivo experiments that should assess both tumorcidal effects and possible increased toxicity. The simultaneous administration of carboplatin and methotrexate would be of little effect. To find optimal schedules for this combination, further pre-clinical studies of various combinations schedule would appear to be warranted.
Leukemia Research 03/1993; · 2.92 Impact Factor
