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Yasuhiko Kano

Publications and source records attributed to Yasuhiko Kano.

At least 19 recordsLinked to original sources
PubMed2007

Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines.

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.

Antineoplastic Agents↗
PubMed2006

Phase II study of weekly chemotherapy with paclitaxel and gemcitabine as second-line treatment for advanced non-small cell lung cancer after treatment with platinum-based chemotherapy.

PURPOSE: We evaluated the tolerability and activity of the combination of weekly paclitaxel (PTX) and gemcitabine (GEM) in second-line treatment of advanced non-small cell lung cancer (NSCLC) after treatment with platinum-based chemotherapy. PATIENTS AND METHODS: PTX (100 mg/m(2)) and GEM (1,000 mg/m(2)) were administered to patients with previous treated NSCLC on days 1 and 8 every 3 weeks. RESULTS: A total of 40 patients (performance status 0/1/2, 7/27/6 pts) were enrolled. The response rate was 32.5% (95% confidence interval: 18.0-47.0%). The median survival time was 41.7 weeks (95% confidence interval: 28.5-54.7 weeks). The median time to disease progression was 19 weeks. Hematological toxicities (grade 3 or 4) observed included neutropenia in 60%, anemia in 15%, and thrombocytopenia in 12.5% of patients. Non-hematological toxicities were mild, with the exception of grade 3 diarrhea, pneumonitis, and rash in one patient each. There were no deaths due to toxicity. CONCLUSION: The combination of weekly PTX and GEM is a feasible, well-tolerated, and active means of second-line treatment of advanced NSCLC.

Adult↗
PubMed2006

Pilot phase II study of weekly chemotherapy with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer.

PURPOSE: The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory or relapsed small-cell lung cancer (SCLC) were evaluated. PATIENTS AND METHODS: Paclitaxel (100 mg/m(2)) and carboplatin (with a target area under the concentration versus time curve of 2 mg min/ml using the Calvert formula) were administered to patients with previously- treated SCLC on days 1 and 8 at every 3-4 weeks. RESULTS: A total of 29 patients (pts) [male/female, 26/3 pts; median age 62.7 years (43-74); performance status 0/1/2, 9/10/10 pts] were enrolled between March 2000 and June 2002. The mean number of cycles administered per pt was 3 (1-7). The overall response rate was 69% (95% confidence interval 52-86%), and 83% (15/18) in sensitive pts and 45% (5/11) in refractory pts (P<0.01). The overall median survival time was 29.6 weeks with a 1-year survival rate of 37% [34.1 weeks in sensitive pts and 23.1 weeks in refractory pts (P=0.085), 46.9 weeks in PS 0-1 and 16.3 weeks in PS 2 (P<0.001)]. The median time to progressive disease was 16.4 weeks [21.7 weeks in sensitive pts and 15.3 weeks in refractory pts (P=0.32)]. Hematologic toxicities observed included grade >or=3 neutropenia in 55%, grade >or=3 anemia in 36%, and grade >or=3 thrombocytopenia in 3%. Non-hematologic toxicities were mild except for grade 3 diarrhea in three pts and grade 3 pneumonitis in one pt. CONCLUSION: Weekly chemotherapy with paclitaxel and carboplatin was well- tolerated and gave a high-response rate in pts with refractory or relapsed small-cell lung cancer.

Adult↗
PubMed2006

Histone deacetylase inhibitor depsipeptide (FK228) induces apoptosis in leukemic cells by facilitating mitochondrial translocation of Bax, which is enhanced by the proteasome inhibitor bortezomib.

Histone deacetylase (HDAC) inhibitors are promising candidates for molecular-targeted therapy for leukemia. In this study, we investigated the mechanisms of cytotoxic effects of depsipeptide (FK228), one of the most effective HDAC inhibitors against leukemia, using human myeloid leukemic cell lines HL-60 and K562. We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to release cytochrome c, which was almost completely blocked by overexpression of Bcl-2. The mitochondrial damage was caused by the translocation of Bax but not other pro-apoptotic Bcl-2 family proteins to the mitochondria. FK228 did not affect the interaction between Bax and Bax adaptor proteins such as 14-3-3theta and Ku70. FK228-induced apoptosis and mitochondrial translocation of Bax were markedly enhanced by the proteasome inhibitor bortezomib. The synergistic action of FK228 and bortezomib was at least partly mediated through conformational changes in Bax, which facilitate its translocation to the mitochondria. These results suggest that the combination of HDAC inhibitors and proteasome inhibitors is useful in the treatment of leukemia especially in the context of molecular-targeted therapy. The status of Bcl-2 and Bax may influence the sensitivity of tumors to this combination and thus can be a target of further therapeutic intervention.

14-3-3 Proteins↗
PubMed2006

Schedule-dependent interactions between pemetrexed and cisplatin in human carcinoma cell lines in vitro.

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.

Carcinoma↗
PubMed2005

Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile.

Depsipeptide (FK228), a histone deacetylase inhibitor, is a promising new anticancer agent. The mechanism of resistance to this agent was studied using KU812 cells. Depsipeptide-resistant KU812 cells expressed P-glycoprotein (P-gp) and their resistance was abolished by co-treatment with verapamil. P-gp expression returned to the parental cell level when resistant cells were cultured in depsipeptide-free medium, while resistant cells cultured in the medium containing 16 nM depsipeptide still showed hyper-acetylation of histones. Moreover, resistant cells showed erythroid differentiation. Microarray analysis revealed that 28 genes showed increased expression and three genes showed decreased expression in resistant cells compared with parental cells. These 31 genes had various functions relating to signal transduction, cell cycle, apoptosis, and control of cell morphology and differentiation. Among the 28 genes that were upregulated, 15 genes also showed an increased expression in parental cells treated with 4 nM depsipeptide for 48 h, while the other 13 genes including P-gp were different. Among the three genes with decreased expression, HEP27 was most dramatically downregulated. These findings suggest that continuous exposure to depsipeptide reversibly induces P-gp, which contributes to the onset of resistance, but the altered gene expression profile of resistant cells may also play a role.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

A phase II study of docetaxel and infusional cisplatin in advanced non-small-cell lung cancer.

BACKGROUND: To evaluate the efficacy and safety of combination chemotherapy of cisplatin (5-day continuous infusion) and docetaxel for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients had an ECOG performance status of 0-2 with measurable NSCLC. Patients received continuous infusion cisplatin 20 mg/m2/day on 5 days and bolus docetaxel 60 mg/m2/day (day 1; PiD therapy) at a 4-week interval. RESULTS: Forty-three patients were enrolled. The mean number of cycles administered per patient was 2, and ranged from 1 to 4. The response rate was 49% (95% confidence interval, 33.9-63.8%). The median survival time was 47 weeks and the 1-year survival rate was 47%. The major toxic effects were grade 3 or 4, neutropenia (88%), leukopenia (81%), thrombocytopenia (14%) and anemia (42%). There were no treatment-related deaths. CONCLUSION: PiD therapy was a well-tolerated and active regimen for patients with advanced NSCLC. The major toxicity was neutropenia.

Adult↗
PubMed2005

Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines.

The combination of imatinib and a farnesyltransferase inhibitor might be effective for reducing the number of BCR/ABL-positive leukemia cells. In this study, we examined the differences in the mechanisms of the growth inhibitory effect of the combination of imatinib and R115777 (Zarnestra) among BCR/ABL-positive cell lines. Steel and Peckham isobologram analysis indicated that this combination had a strong synergistic inhibitory effect on growth in all imatinib-resistant cell lines and their parental cell lines. Levels of cleaved caspase 3 were increased by the combination treatment in all cell lines. However, both the level of cleaved PARP and the number of annexin-V-positive cells were much less increased in KCL22 and KCL22/SR cells than in K562, KU812, K562/SR and KU812/SR cells. The combination treatment promoted p27(KIP1) accumulation and induced a significant increase in the percentage of G0/G1 KCL22 and KCL22/SR cells. In other cell lines, the percentage of G0/G1 cells was not increased but rather decreased. The results indicate that induction of apoptosis and blockage of the cell cycle were major mechanisms of the synergistic inhibitory effect of the combination treatment, but the relative importance of these mechanisms differed among cell types. Additional treatment for overriding the G1 checkpoint may be required to eradicate leukemia cells, in which the combination induces cell cycle arrest.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228).

Inhibition of histone deacetylase (HDAC) is a novel strategy for the treatment of leukemias via restoration of aberrantly silenced genes. In this study, we conducted a detailed analysis of anti-leukemic effects of an HDAC inhibitor (HDI), depsipeptide (FK228), using myeloid leukemia cell lines HL-60 and K562. DNA chip analysis revealed upregulation of TNF-alpha mRNA and a number of molecules involved in TNF-signaling such as TRAF-6, caspases-10, and -7 in depsipeptide-treated HL-60 cells, which prompted us to examine the involvement of the TNF/TNF receptor system in the anti-leukemic effects of the drug. Upregulation of TNF-alpha was induced by depsipeptide in HL-60 and K562 cells, which expressed type I TNF receptors (TNF-RI). Depsipeptide activated caspases-8 and -10, which in turn cleave caspases-3 and -7, leading to apoptotic cell death in both cell lines. Anti-TNF-alpha neutralizing antibody and short interfering RNA (siRNA) against TNF-RI alleviated the activation of the caspase cascade and the induction of apoptosis, indicating the presence of an autocrine loop. Finally, we demonstrated that the enhanced production of TNF-alpha by depsipeptide was due to transcriptional activation of the TNF-alpha gene through hyperacetylation of histones H3 and H4 in its promoter region (-208 to +35). These results suggest that autocrine production of TNF-alpha plays a role in the cytotoxicity of depsipeptide against a subset of leukemias.

Acetylation↗
PubMed2005

Establishment and characterization of A novel Philadelphia-chromosome positive chronic myeloid leukemia cell line, TCC-S, expressing P210 and P190 BCR/ABL transcripts but missing normal ABL gene.

A novel Philadelphia-chromosome positive (Ph+) cell line, TCC-S, has been established from a patient with Ph+ chronic myeloid leukemia (CML) in the blastic crisis. TCC-S cells were shown to express both P210 and P190 BCR/ABL transcripts by reverse transcriptase-polymerase chain reaction (PCR), although quantitative-PCR revealed that TCC-S cells mainly expressed P210 BCR/ABL transcript. Karyotype analysis revealed several triploid clones which constantly harbored two der(9)del(9) (p12)t(9;22) (q34;qll)s and two del(9) (q21)s. The der(9)del(9) (p12)t(9;22) (q34;q11) is rarely found in other CML cell lines. Moreover, to the best of our knowledge, del(9) (q21) resulting in missing of a restrict region including normal ABL gene has not been found among CML cell lines previously described. Thus, TCC-S cells with only BCR/ABL gene and no normal ABL gene may be a useful tool for functional study of ABL in Ph+ CML.

Blast Crisis↗
PubMed2004

Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro.

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Ectopic cyclin D1 expression blocks STI571-induced erythroid differentiation of K562 cells.

Bcr-Abl tyrosine kinase inhibitor induces apoptosis and erythroid differentiation of K562 cells. During this erythroid differentiation, c-Myc and cyclin D1 transcripts are transiently downregulated. Accordingly, we studied the effect of cyclin D1 overexpression on erythroid differentiation. After treatment with 250 nM STI571, 90% of K562 and 25% of K562/D1 cells underwent erythroid differentiation. The basal expression of glycophorin A in K562/D1 cells was markedly diminished compared with that by parental cells. STI571 treatment failed to induce glycophorin A expression in K562/D1 cells. During STI571 treatment, ERK activity was downregulated in parental cells, while it was constantly activated in K562/D1 cells. These results suggest that ectopic expression of cyclin D1 causes the resistance of K562 cells to erythroid differentiation by modulating ERK regulation.

Benzamides↗
PubMed2004

Inactivation of ERK accelerates erythroid differentiation of K562 cells induced by herbimycin A and STI571 while activation of MEK1 interferes with it.

K562 cells contain a Bcr-Abl chimeric gene and differentiate into various lineages in response to different inducers. We studied the role of the mitogen-activated protein kinase (MAPK) kinase 1 (MEK1)/extracellular signal-regulated kinase (ERK) pathway during the erythroid differentiation of K562 cells induced by tyrosine kinase inhibitors (herbimycin A or STI571), using genetically modified cells (constitutively MEK1-activated K562: K562/MEK1, and inducible ERK-inactivated K562: K562/CL100). Basal expression of glycophorin A was markedly reduced in K562/MEK1 cells compared with that in parental cells, while it was augmented in K562/CL100 cells. Herbimycin A and STI571 differentiated K562 cells accompanying with the transient down-regulated ERK. Moreover, the erythroid differentiation was markedly suppressed in K562/MEK1 cells, and early down-regulation of ERK activity was not observed in these cells. In contrast, the induction of ERK-specific phosphatase in K562/CL100 cells potentiated erythroid differentiation. Once the phosphatase was induced, the initial ERK activity became repressed and its early down-regulation by the inhibition of Bcr-Abl was marked and prolonged. These results demonstrate that the erythroid differentiation of K562 cells induced by herbimycin A or STI571 requires the down-regulation of MEK1/ ERK pathway.

Benzamides↗
PubMed2003

Phase II study of the combination of vinorelbine and cisplatin in advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of combination chemotherapy with cisplatin and vinorelbine for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were those with measurable NSCLC. They were treated with two or more cycles of a regimen consisting of vinorelbine 25 mg/m(2) on days 1 and 8 and cisplatin 80 mg/m(2) on day 1 every 3 weeks. RESULTS: A total of 45 patients were enrolled. The response rate was 51.1% (23/45; 95% CI 35.8% to 66.3%). The median survival was 286 days with a 1-year survival rate of 40%. The median number of treatment cycles was 2. The major toxic effect was neutropenia of grade 3 or higher (84%). Nonhematological toxicities, including vomiting (62%), were mild (grade 2 or less). There were no treatment-related deaths. CONCLUSION: The high response rate and good tolerability proved this combination therapy to be a safe and effective treatment for advanced NSCLC.

Adult↗
PubMed2003

Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c.

ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6 (ETS translocation variant 6). In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARG-expressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12). STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC(50) of 200 nM. The growth inhibition was primarily because of cell cycle arrest at G1 phase when cells were treated with 100 nM STI571 for 48 h, and apoptosis was induced after longer exposure (72 h) or by a higher dose (1000 nM). STI571 increased the amount of p18/INK4c after 2 h of culture, when the cell cycle pattern was not yet affected, but not that of other CDK inhibitors (CKI). p18/INK4c was more abundant in G1-enriched fractions than in S- and G2/M-enriched fractions of STI571-treated HT93A cells, suggesting that the upregulation of p18/INK4c expression correlates with the cell cycle arrest. Treatment of HT93A cells with antisense oligonucleotides against the Ink4c gene abrogated the growth inhibition by STI571. These results suggest that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/INK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.

Antineoplastic Agents↗
PubMed2003

Preventive effect of Kampo medicine (Hangeshashin-to) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer.

PURPOSE: Kampo medicine Hangeshashin-to (TJ-14) which contains baicalin, a beta-glucuronidase inhibitor, alleviates diarrhea induced by irinotecan (CPT-11). We conducted a randomized comparative trial to investigate whether support with TJ-14 would prevent and control CPT-11-induced diarrhea. METHODS: Of 44 previously untreated patients with advanced non-small-cell lung cancer randomized, 41 (18 TJ-14 group, 23 control group) were available for evaluation. The chemotherapy regimen consisted of a combination of cisplatin and CPT-11. TJ-14 (7.5 g/day) was administered orally. RESULTS: Of the 41 patients, 39 experienced diarrhea. Compared with the control group, the TJ-14 group showed a significant improvement in diarrhea grades ( P=0.044) as well as a reduced frequency of diarrhea grades 3 and 4 (one patient versus ten patients; P=0.018). However, the two groups showed no differences in the frequency of diarrhea or the number of days the symptoms continued. This study was stopped at an interim evaluation. CONCLUSION: TJ-14 was effective in preventing and controlling CPT-11-induced diarrhea.

Adult↗