Satoshi Kayukawa

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

Recent reports showing successful inhibition of cancer and leukemia cell growth using histone deacetylase inhibitor (HDACi) compounds have highlighted the potential use of HDACi as anti-cancer agents. However, high incidence of toxicity and low stability in vivo were observed with hydroxamic acid-based HDACi such as suberoylanilide hydroxamic acid (SAHA), thus limiting its clinical applicability. In this study, we found that a novel non-hydroxamate HDACi NCH-51 could inhibit the cell growth of a variety of lymphoid malignant cells through apoptosis induction, more effectively than SAHA. Activation of caspase-3, -8 and -9, but not -7 was detected after the treatment with NCH-51. Gene expression profiles showed that NCH-51 and SAHA similarly upregulated p21 and downregulated anti-apoptotic molecules including survivin, bcl-w and c-FLIP. Proteome analysis using two-dimensional electrophoresis revealed that NCH-51 upregulated anti-oxidant molecules including peroxiredoxin 1 and 2 and glutathione S-transferase at the protein level. Interestingly, NCH-51 induced reactive oxygen species (ROS) after 8 h whereas SAHA continuously declined ROS. Pretreatment with an antioxidant, N-acetyl-L-cysteine, abolished the cytotoxicity of NCH-51. These findings suggest that NCH-51 exhibits cytotoxicity by sustaining ROS at the higher level greater than SAHA. This study indicates the therapeutic efficacy of NCH-51 and novel insights for anti-HDAC therapy.

Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy.

AIM To examine whether administration of lentinan, purified β-1, 3-glucan, can prolong survival in advanced gastric cancer patients receiving S-1-based chemotherapy. METHODS Since 2004, 78 patients with metastatic or recurrent gastric cancer have received S-1-based chemotherapy as first-line treatment. Survival, side effects, and the ratio of granulocytes/lymphocytes (G/L ratio) were compared between 2 groups of patients who received chemo-immunotherapy using lentinan and chemotherapy alone. RESULTS Median overall survival was significantly longer in the former group than in the latter group [689 d (95% CI: 431-2339 d) vs 565 d (95% CI: 323-662 d), P = 0.0406]. In addition, the G/L ratio in patients who received lentinan was maintained around or below 2, which was significantly lower than that in patients who received chemotherapy alone (P < 0.001). CONCLUSION Chemo-immunotherapy with lentinan offers a significant advantage over S-1-based chemotherapy alone in terms of survival in patients with advanced gastric cancer.

Overexpression of carboxylesterase‐2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT‐11), for multiple myeloma

Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN‐38, an active metabolite of irinotecan (CPT‐11), have been reported, we investigated the therapeutic potential of CPT‐11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 µg/mL for CPT‐11 and less than 2 ng/mL for SN‐38. This efficacy was partly explained by the high expression level of human carboxylesterase‐2 (hCE‐2) in MM cells. Interestingly, high expression of hCE‐2 represented the nature of normal plasma cells, suggesting that hCE‐2 could efficiently generate SN‐38 within the plasma cells. As expected, higher sensitivity to CPT‐11 was observed in hCE‐2‐overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE‐1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT‐11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT‐11 alone significantly reduced the tumor volume. When a combination of CPT‐11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT‐11 in patients with relapsed or refractory MM are warranted. (Cancer Sci 2008; 99: 2309–2314)

Chemo-Immunotherapy Using Lentinan for the Treatment of Gastric Cancer with Liver Metastases

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Systemic chemotherapy is the main treatment option for advanced gastric cancer when the tumor is inoperable. Despite recent advances in chemotherapeutic agents, the prognosis of unresectable or recurrent gastric cancer remains extremely poor. In Japan, combination therapy including S-1 and cisplatin is the standard first-line treatment for advanced gastric cancer; however, the five-year survival rate remains very low. Lentinan, the backbone of beta-(1,3)-glucan with beta-(1,6) branches, an active ingredient purified from Shiitake mushrooms, has been approved as a biological response modifier for the treatment of gastric cancer. This agent has been used in combination with oral fluoropyrimidines to improve the overall survival of gastric cancer patients. A retrospective chart review on 138 metastatic gastric cancer patients receiving chemotherapy was performed in Nagoya Memorial Hospital from 1 September 2010 to 31 August 2015. 12 patients with liver metastases were treated by lentinan in combination with S-1-based chemotherapy. The rate of objective response was 42% (5/12) and the disease control rate was 83% (10/12) in response to chemo-immunotherapy using lentinan, with a median overall survival of 407 days (95% CI: 207–700 days).

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Primary Cutaneous Diffuse Large B-Cell Lymphoma with TongueInvolvement

We report a case of diffuse large B-cell lymphoma involving the thigh skin and tongue in an 85-year-old woman. No systemic symptoms or other lesions were observed at diagnosis. Local radiotherapy was effective, but cutaneous recurrence occurred 6 months after the treatment. The patient died of old age with no macroscopically distinguishable nodal or systemic lesions. A postmortem examination revealed intravascular invasion into the tongue, lung, and lymph nodes around the pancreas. To our knowledge, this is the first report of primary cutaneous diffuse large B-cell lymphoma with tongue involvement.

Effects of Oral Rinse using Lemon-Flavored Water with or without Rebamipide on Fluoropyrimidine-Induced Stomatitis

Aim: To examine the efficacy of oral rinsing against chemotherapy-induced stomatitis. Methods: Consecutive fluoropyrimidine-treated patients with stomach and colorectal cancer were enrolled from April 2009 to March 2011 (n=43; Group 1) and from January 2012 to December 2012 (n=45; Group 2). The incidence and severity of stomatitis were compared between Group 1 patients, who were instructed to gargle with lemonflavored water 6 times daily, and Group 2 patients, who did not receive any specific guidance. Among patients in the gargle group, we determined the rate of gargling compliance as well as quality of life (QOL) scores, and evaluated the impact of rebamipide use on patient outcomes. Results: The incidence of stomatitis was significantly reduced in Group 1 (14.0%) compared to that in Group 2 (33.3%) and its severity in the former group was milder. Among patients using lemon-flavored water, concomitant rebamipide use had no statistically significant impact on stomatitis incidence (with versus without rebamipide, 19.0% versus 9.0%), the rate of gargling compliance (96.4% versus 94.2%), or QOL scores. Conclusions: Oral rinse with lemon-flavored water is useful for the symptomatic control of fluoropyrimidineinduced stomatitis, regardless of the presence or absence of rebamipide.

Bladder squamous cell cancer accompanied by Trousseau's syndrome: a case report

The association between thrombosis and cancer has been recognized since Trousseaus report in 1865. We present a case of bladder squamous cell carcinoma associated with multiple cerebral infarctions. This patient was diagnosed as having Trousseaus syndrome and received radiotherapy for bladder cancer treatment, along with anticoagulation therapy.

Adverse Effects of Bevacizumab During Treatment for Metastatic Colorectal Cancer

Objective : Bevacizumab has been increasingly used in combination chemotherapy for the treatment of metastatic or recurrent colorectal cancer. The aim of this report is to underline the possible risks associated with bevacizumab use. Methods : Between July 2005 and March 2013, a total of 130 patients with metastatic colorectal cancer who received oxaliplatin as first-line chemotherapy were divided into 2 groups those treated with bevacizumab (group A) and those without (group B), and compared. The primary endpoint was to clarify the profile of bevacizumab - induced adverse effects. Secondary endpoints examined therapeutic effects, including overall survival (OS). Results : The incidence of major side effects was almost equivalent, except for bleeding, between the 2 groups. With regard to the therapeutic effects, 1 patient in group A showed complete disappearance of multiple lung metastases without any evidence of recurrence. The median OS was 926 days (95% confidence interval [CI], 756 - 1257) in group A and 534 days (95% CI, 421 – 621) in group B ( p < 0.01). Conclusion : The results demonstrate that bevacizumab prolonged survival in these patients although there was an increased risk of clinically significant bleeding.

Pathological Complete Response Induced by the Combination Therapy of Gemcitabine and 24-h Infusion of Cisplatin in Two Cases Initially Diagnosed as Node-Positive Advanced Urothelial Carcinomas

We report on two patients, successfully treated by the combination therapy of gemcitabine and 24-h intravenous infusion of cisplatin, who were initially diagnosed with node-positive advanced urothelial cancer. Each patient had a very good clinical response and underwent curative radical surgery after gemcitabine/cisplatin chemotherapy. A microscopically detailed examination of surgically obtained specimens showed the complete disappearance of malignant cells in the two cases. As a pilot study, we have used the regimen of gemcitabine plus 24-h continuous infusion of cisplatin, instead of bolus injection, for the treatment of 20 patients with node-positive or metastatic urothelial cancer. The clinical response rate in this regimen was 75% (complete response 7/20; 35%, partial response 8/20; 40%). The median overall survival was 665 days. As for the adverse effects, the incidences of severe neutropenia and thrombocytopenia (grade 3-4) were 20% and 15%, which might be less toxic than conventional gemcitabine plus cisplatin therapy. The 24-h infusion of cisplatin combined with gemcitabine can be highly recommended as neoadjuvant chemotherapy for locally advanced urothelial cancer.