Search

The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A ( 1 ), trichodermamide B ( 2 ), aspergillazine A ( 3 ), DC1149B ( 4 ), ergosterol peroxide ( 5 ), cerebrosides D/C ( 6/7 ), 5-hydroxy-2,3-dimethyl-7-methoxychromone ( 8 ), nafuredin A ( 9 ), and harzianumols E/F ( 10 / 11 ). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5 - 11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2 , 4 , and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC 50 of 22.43 μM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not.

Objective: Novel androgen receptor axis-targeted agents (ARATAs) have been developed for mCRPC and improved overall survival (OS). Here, we aimed to find predictors who will receive the greatest benefits from ARATAs., Methods: We previously performed a multicenter study to identify prognostic factors for metastatic hormone-sensitive prostate cancer (mHSPC, n = 148) and mCRPC (n = 99), and showed that the bone scan index (BSI) was one of the significant prognostic factors for 3-year OS (PROSTAT-BSI study). mHSPC progressed to mCRPC (n = 101), for which 69 patients were treated with (n = 39) or without ARATAs (n = 30, prior to the approval of ARATAs). The 69 patients were divided into two groups according to patient factors, and these cohorts were further divided into two subgroups by usage of ARATAs. OS was compared between subgroups in each group., Results: The predictors were age (<71.4 years), serum levels of C-reactive protein (≥0.16 ng/ml) and alkaline phosphatase (≥548 U/L), time to PSA progression after ADT (<8.9 months), the lowest PSA level (≥1 ng/ml) after ADT, and the rate of PSA decline 3 months after ADT (<0.987), whereas hemoglobin levels, PSA before ADT, Gleason scores, existence of visceral metastases, and BSI were not., Conclusions: The present study identified predictors for the effectiveness of ARATAs. The number of bone metastases (≒BSI), existence of visceral metastases, and Gleason scores, which were identified as high-risk factors in the LATITUDE study and disease volume in CHAARTED criteria, did not appear to be useful for predicting effectiveness from ARATAs., (© 2022 The Japanese Urological Association.)

Background: Sinusoidal obstruction syndrome (SOS) refers to liver injury caused by hematopoietic stem cell transplantation (HSCT) and anticancer drugs including oxaliplatin. Increased splenic volume (SV) on computed tomography (CT) indicates oxaliplatin-induced SOS. Similarly, ultrasonography and liver stiffness measurement (LSM) by shear-wave elastography (SWE) can help diagnose SOS after HSCT; however, their usefulness for diagnosing oxaliplatin-induced SOS remains unclear. We investigated the usefulness of the Hokkaido ultrasonography-based scoring system with 10 ultrasonographic parameters (HokUS-10) and SWE in diagnosing oxaliplatin-induced SOS early., Methods: In this prospective observational study, ultrasonography and SWE were performed before and at 2, 4, and 6 months after oxaliplatin-based chemotherapy. HokUS-10 was used for assessment. CT volumetry of the SV was performed in clinical practice, and an SV increase ≥ 30% was considered the diagnostic indicator of oxaliplatin-induced SOS. We assessed whether HokUS-10 and SWE can lead to an early detection of oxaliplatin-induced SOS before an increased SV on CT., Results: Of the 30 enrolled patients with gastrointestinal cancers, 12 (40.0%) with an SV increase  ≥ 30% on CT were diagnosed with SOS. The HokUS-10 score was not correlated with an SV increase ≥ 30% (r = 0.18). The change in rate of three HokUS-10 parameters were correlated with an SV increase ≥ 30% (r = 0.32-0.41). The change in rate of LSM by SWE was correlated with an SV increase  ≥ 30% (r = 0.40)., Conclusions: The usefulness of HokUS-10 score was not demonstrated; however, some HokUS-10 parameters and SWE could be useful for the early diagnosis of oxaliplatin-induced SOS., (© 2022. The Author(s).)

Purpose: Dysgeusia is an adverse event caused by chemotherapy. Although retrospective studies have shown zinc administration improves dysgeusia, there have been no prospective studies. The present study examined effects of zinc therapy on dysgeusia in patients with gastrointestinal cancer., Methods: This multicenter, prospective, observational study enrolled patients with dysgeusia during chemotherapy treatment. Patients received no intervention (control), polaprezinc p.o., or zinc acetate hydrate p.o., and serum zinc levels were measured at 0 (baseline), 6, and 12 weeks. Dysgeusia was assessed using CTCAE v5.0 and subjective total taste acuity (STTA) criteria using questionnaires at baseline and 12 weeks., Results: From February 2020 to June 2021, 180 patients were enrolled from 17 institutes. There were no differences in mean baseline serum zinc levels among the groups (67.3, 66.6, and 67.5 μg/dL in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. P = 0.846). The changes in mean serum zinc levels after 12 weeks were - 3.8, + 14.3, and + 46.6 μg/dL, and the efficacy rates of dysgeusia were 33.3%, 36.8%, and 34.6% using CTCAE and 33.3%, 52.6%, 32.7% using STTA in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. The STTA scores improved in all groups, with significant improvement observed in the polaprezinc group compared with the no intervention group (P = 0.045)., Conclusion: There was no significant correlation between the degree of serum zinc elevation and improvement in dysgeusia, suggesting that polaprezinc, but not zinc acetate hydrate, was effective in improving chemotherapy-induced dysgeusia., Trial Registration: UMIN000039653. Date of registration: March 2, 2020., (© 2022. The Author(s).)

Background: Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR., Methods: A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint., Results: Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%)., Conclusion: DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051)., (© The Author(s) 2022. Published by Oxford University Press. The data published online to support this summary are the property of the authors. Please contact the authors about reuse rights of the original data.)

The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum-based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum-based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum-based chemotherapy, the SLFN11-positive group (n = 25) showed significantly better overall survival than the SLFN11-negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11-0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum-based chemotherapy, the SLFN11-positive group (n = 29) showed significantly worse overall survival than the SLFN11-negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5-azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11-negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum-based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

What Is Known and Objective: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule)., Methods: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis., Results: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F., What Is New and Conclusion: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib., (© 2021 John Wiley & Sons Ltd.)

Background: TAS-102 is effective against unresectable advanced or recurrent colorectal and gastric cancer. However, its effect on oral squamous cell carcinoma (OSCC) is still unknown. Here, we tried to clarify the possible effect of TAS-102 against angiogenesis and proliferation of human OSCC cells., Materials and Methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration assay and mice xenograft models were used to determine the effect of TAS-102 on growth and migration of OSCC. The activity of phosphorylated nuclear factor kappa light-chain-enhancer of activated B-cells (NF-κB) (p-p65) in cells was detected by immunocytochemistry. The expression of p-AKT serine/threonine kinase 1 (p-AKT), p-p65, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2) and CD31 in mouse tumors were detected by immunohistochemistry., Results: TAS-102 significantly inhibited growth and migration of OSCC both in vitro and in vivo. It suppressed the activity of NF-κB in cells. TAS-102 down-regulated the expression of p-AKT, VEGF, FGF2 and CD31, which was associated with reduced vascularization of HSC2 tumor lesions., Conclusion: These findings suggest that TAS-102 might inhibit angiogenesis and proliferation of OSCC cells., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish., Methods: In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments., Results: We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth., Conclusions: Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background/aim: CBP is a transcriptional coactivator in the Wnt/β-catenin pathway that is related to cell kinetics and differentiation. This study aimed to characterize β-catenin-activated hepatocellular carcinoma (HCC) and evaluate the direct effects of PRI-724 (a selective inhibitor of Wnt/β-catenin/CBP signaling) on HCC., Materials and Methods: Immunohistochemistry for β-catenin was performed in 199 HCC resected samples. Moreover, using cultured HCC cell lines, cell kinetics and its related proteins were analyzed after treatment of cells with C-82 (active form of PRI-724)., Results: Nuclear β-catenin expression was found in 18% of HCC cases and the tumor sizes in these positive samples were larger. In HCC cell lines with a constitutively activated β-catenin, C-82 inhibited cell proliferation. C-82 led to an increase in the percentage of cells in the G 0 /G 1 phase of the cell cycle. The percentage of cells in the sub-G 1 phase also increased. Moreover, C-82 treatment significantly decreased the expression of cell proliferating markers and increased the expression of apoptosis-related proteins., Conclusion: PRI-724(C-82) may be a novel drug for β-catenin-activated HCC therapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cancer treatment has been developing significantly and cancer-related cardiovascular disease treatments such as various anticancer agents and molecular target drugs have been reported often in the era of oncocardiology. Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy. Dasatinib is a novel tyrosine-kinase inhibitor approved for CML with Philadelphia (Ph) chromosome and the most common adverse effects of dasatinib are peripheral edema and pleural effusion, which sometimes impose the interruption or reduction of dosage of dasatinib treatment, accompanied by diuretic and steroid use. The goal of CML treatment is maintaining hematological control in the long term by controlling these side effects. The aim of this study is to clarify the efficacy of tolvaptan in treating dasatinib-induced fluid retention., Methods: We retrospectively analyzed six CML patients who received tolvaptan for dasatinib-induced fluid retention., Results: The mean age of patients was 60.5±11.5 years old, and the mean dosage of dasatinib and tolvaptan were 58.3±20.4mg/day and 5.0±1.9mg/day, respectively. Tolvaptan was introduced 564.5±369.9 days after dasatinib was introduced. Ejection fraction (EF) by echocardiography and brain natriuretic peptide (BNP) levels did not change. However, the diastolic function significantly changed [E/e' of the septal side: from 20.3±2.3 to 16.5±4.2, of the lateral side: from 15.0±2.1 to 12.5±3.8 (p<0.05, respectively)]. New York Heart Association functional class was improved from 3.3±0.5 to 1.5 ± 1.2 (p<0.01) and the grades of fluid retention were also improved. Three patients discontinued dasatinib, and two patients could restart the administration of dasatinib after controlling fluid retention. Five patients could control fluid retention and they could continue with dasatinib therapy without any complications., Conclusions: Tolvaptan may be useful in fluid control in patients with CML treated with dasatinib., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Recent developments of novel targeted therapies are contributing to the increased long-term survival of cancer patients; however, drug-induced cardiotoxicity induced by cancer drugs remains a serious problem in clinical settings. Nevertheless, there are few in vitro cell-based assays available to predict this toxicity, especially from the aspect of morphology. Here, we developed a simple two-dimensional (2D) morphological assessment system, 2DMA, to predict drug-induced cardiotoxicity in cancer patients using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with image-based high-content analysis in a high-throughput manner. To assess the effects of drugs on cardiomyocytes, we treated iPSC-CMs with 28 marketed pharmaceuticals and measured two key parameters: number of cell nuclei and sarcomere morphology. Drugs that significantly perturbed these two parameters at concentrations ≤30 times the human C max value were regarded as positive in the test. Based on these criteria, the sensitivity and specificity of the 2DMA system were 81% and 100%, respectively. Moreover, the translational predictability of 2DMA was comparable with that of a three-dimensional cardiotoxicity assay. RNA sequencing further revealed that the expression levels of several genes related to sarcomere components decreased following treatment with sunitinib, suggesting that inhibition of the synthesis of proteins that comprise the sarcomere contributes to drug-induced sarcomere disruption. Based on these features, the 2DMA system provides mechanistic insight with high predictability of cancer drug-induced cardiotoxicity in humans, and could thus contribute to the reduction of drug attrition rates at early stages of drug development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neo-angiogenesis plays a key role in colorectal cancer, with the vascular endothelial growth factor family proteins and their receptors in particular triggering multiple signaling networks that result in endothelial cell survival, migration, mitogenesis, differentiation, and vascular permeability. Anti-angiogenic therapies have improved colorectal cancer prognosis within the past 15 years. Bevacizumab demonstrated efficacy in combination with chemotherapy under different conditions, including as first- and second-line therapies, and also as a maintenance treatment strategy. Other drugs targeting angiogenesis effectors (e.g., ramucirumab and aflibercept) were approved after bevacizumab failure, confirming the concept of "continuous anti-angiogenic blocking". Recently, a number of new orally available multiple receptor tyrosine kinase inhibitors have been tested in late-stage clinical trials, with modest efficacy. Due to the availability of several anti-angiogenic agents, we need well-designed prospective randomized trials to optimize therapeutic sequencing. The place of biosimilars in the therapeutic armamentarium remains unclear at the moment. Further research is warranted to identify robust predictive biomarkers of efficacy and innovative clinically meaningful anti-angiogenic drugs that are cost-efficient.

Serine/threonine-protein kinase B-Raf (BRAF) inhibitors are very effective in treating melanoma with BRAF mutations. BRAF inhibitors suppress aberrant growth of melanoma cells caused by BRAF mutations. BRAF mutations reportedly result in melanoma cells releasing immunosuppressive factors, and BRAF inhibitors elicit anti-melanoma immune responses by reducing such factors. However, immunological characteristics of tumor cells that acquire resistance to BRAF inhibitors remain unknown. Here, we compared immunological characteristics between a melanoma cell line and its vemurafenib-resistant subline. No differences were observed in the status of BRAF mutations, expression of surface molecules related to antitumor T-cell responses or recognition by human leukocyte antigen-A*0201-matched melanoma-specific cytotoxic T lymphocytes in a short-term co-culture assay. However, resistant tumor cells released high amounts of interleukin-10 depending on aberrant activation of Akt signaling, and dendritic cell functions were considerably suppressed by culture supernatants of the resistant cells. Our findings demonstrated a novel immunological mechanism contributing to tumor growth owing to drug resistance to BRAF inhibitors., (© 2018 Japanese Dermatological Association.)

Background/aim: There is no definitive biomarker that predicts the effectiveness of abiraterone acetate. The objective of this study was to investigate whether dehydroepiandrosterone sulfate (DHEA-S) predicts the effectiveness of abiraterone acetate., Materials and Methods: This study included a total of 28 consecutive patients. The optimal cutoff value of DHEA-S for predicting the PSA response was calculated by receiver operating characteristic (ROC) analysis. The Cox proportional hazards model was performed to determine the predictive factors for the susceptibility to abiraterone acetate., Results: Serum DHEA-S at baseline intercorrelated with the PSA response (correlation coefficient: -0.516). The optimal cutoff value of serum DHEA-S at baseline was 47.4 ug/dl in predicting >50% PSA decline. Serum PSA and serum DHEA-S at baseline were identified as significant factors for predicting PSA progression-free survival (p=0.010 and p=0.003, respectively)., Conclusion: Serum DHEA-S at baseline may be a biomarker for predicting the prognosis of CRPC patients treated with abiraterone acetate., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Acute myelogenous leukemia (AML) is a clinically heterogeneous disease that is frequently associated with relapse and a poor prognosis. Among the various subtypes, AML with the monosomal karyotype (AML-MK) has an extremely unfavorable prognosis. We performed screening to identify antitumor compounds that are capable of inducing apoptosis in primary leukemia cells harboring the AML-MK karyotype and identified a naturally occurring stilbene, Gnetin-C, with potent anti-tumor activities against AML cells from patients with various cytogenetic abnormalities, including patients with the AML-MK karyotype. Gnetin-C simultaneously inhibits the ERK1/2 and the AKT/mTOR pathways, two signals that are essential for the survival of leukemia cells. A combination of Gnetin-C with low doses of chemotherapeutic drugs led to synergistic anti-tumor effects against AML cells. In an immunodeficient mouse model of human leukemia, Gnetin-C attenuated the formation of leukemia, depleted leukemia cells and improved survival. These findings suggest that Gnetin-C has antitumor activities in AML and supports the therapeutic potential of blocking two different pathways in AML., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The objective of this study was to analyze the impact of age on clinical outcomes of metastatic renal cell carcinoma (mRCC) patients receiving axitinib. This study included 144 consecutive mRCC patients who received axitinib for at least 12 weeks as second-line therapy in a routine clinical setting. The efficacy, safety and quality of life (QOL) were compared between patients aged <75 (n = 116) and ≥75 (n = 28) years. No significant differences in the clinicopathological characteristics were noted between younger and older patients. There was no significant difference in the response rate, clinical benefit rate or proportion of patients going on to receive third-line therapy between these two groups. In addition, the progression-free and overall survivals in older patients were similar to those in younger patients. There were no significant differences in the incidences of adverse events between these two groups, except for that of fatigue, which was significantly more frequent in older than younger patients. There was no significant difference in the incidence of the discontinuation of axitinib due to adverse events between the two groups. QOL assessment at 12 weeks after the introduction of axitinib using the Medical Outcomes Study 36-Item Short Form showed no significant differences in any of the eight scale scores between the two groups. Taken together, it might be possible to achieve clinical outcomes in older patients receiving axitinib comparable to those in younger patients, suggesting that advanced age should not be a contraindication to treatment with axitinib as a second-line setting in mRCC patients.

Unlabelled: Several adverse events (AEs) are known to be commonly observed during treatment with different tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) patients. However, no significant correlation appears present in the profiles of such AEs between first- and second-line TKI therapies. Therefore, a second-line targeted agent for patients with mRCC could be selected irrespective of the AE profile during first-line TKI therapy., Background: Several adverse events (AEs) commonly observed during treatment with different tyrosine kinase inhibitors (TKIs). The objective of the present study was to investigate whether the appearance of such AEs during treatment with first-line TKIs significantly affects the occurrence of AEs during second-line TKI therapy for patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: The present study included 154 consecutive patients with mRCC treated with second-line TKIs after the discontinuation of first-line TKIs. The association of AEs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism, between first- and second-line therapies was analyzed in these 154 patients., Results: For all 5 AEs assessed in the present study, the proportion of patients experiencing AEs or those grade ≥ 3 during second-line TKI therapy was not significantly different among the following 3 groups: patients without AEs, those with grade ≤ 2 AEs, and those with grade ≥ 3 AEs during first-line TKI therapy. Furthermore, no significant difference was seen in progression-free or overall survival after the introduction of second-line TKIs between patients with and without grade ≥ 3 AEs during treatment with first-line TKIs., Conclusion: The incidence of AEs or grade ≥ 3 AEs during second-line TKI therapy are not dependent on the profiles of AEs during first-line TKI therapy in patients with mRCC. Therefore, AEs that occur during first-line TKI therapy should not affect the selection of second-line targeted agents for patients with mRCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: To investigate the impact of proteinuria on the renal function of patients with metastatic renal cell carcinoma (mRCC) who received axitinib, a tyrosine kinase inhibitor specifically targeting vascular endothelial growth factor receptors., Methods: This study included 65 consecutive Japanese patients who were diagnosed with mRCC and were subsequently treated with axitinib for at least 12 weeks. The association between the changes in the estimated glomerular filtration rate (eGFR) and proteinuria in these 65 patients was retrospectively assessed., Results: Of the 65 patients, 41 (63.1 %) were judged to be positive for proteinuria. There were no significant differences between the eGFR value before the introduction of axitinib and that at the last clinic visit in either group with or without proteinuria. Furthermore, no significant correlation was noted between the changes in eGFR and the urine protein to creatinine ratio in the group positive for proteinuria, and there was no significant effect of the duration of treatment with axitinib on the changes in eGFR in the proteinuria group. Of several factors examined, univariate analysis identified age, eGFR prior to the introduction of axitinib, and timing of axitinib introduction, but not the presence of proteinuria, as predictors of a decrease in eGFR of >10 %; however, only age appeared to be independently associated with a decrease in eGFR of >10 %., Conclusions: These findings suggest that treatment with axitinib may not have a significant adverse impact on the renal function in patients with mRCC, irrespective of the presence of proteinuria.

The objective of this study was to investigate the significance of changes from the standard dosing schedule of sunitinib, which is 4 weeks of treatment and 2 weeks off (schedule 4/2), to an alternative schedule with 2 weeks of treatment and 1 week off (schedule 2/1), after encountering dose-limiting toxicity in 45 consecutive Japanese patients with metastatic renal cell carcinoma (mRCC). Despite a definitively improved relative dose intensity of sunitinib by changing from schedule 4/2 to 2/1, this difference was not significant. Adverse events (AEs) occurred in all patients on both schedules 4/2 and 2/1; however, the proportion of patients experiencing AEs ≥ grade 3 on schedule 2/1 was significantly lower than that on schedule 4/2. Quality of life (QOL) analysis using SF-36 revealed that all eight scores during schedule 2/1 were more favorable than those during schedule 4/2, and there were significant differences in 2 of the 8 scores between these two schedules. Furthermore, multivariate analyses, which were performed to evaluate the contribution of several AEs on schedule 2/1 to the improvement of each score in SF-36, revealed that fatigue had independent impacts on two scores, despite the lack of an independent association between any scores and the remaining AEs examined. These findings suggest that schedule 2/1 is the optimal dosing schedule of sunitinib against mRCC that balances efficacy and toxicity, since treatment on schedule 2/1 resulted in a markedly improved QOL compared with that on schedule 4/2 by relieving the profile of sunitinib-related AEs.

Purpose: The objective of this study was to investigate the mechanism mediating the acquisition of a resistant phenotype to sorafenib in renal cell carcinoma (RCC)., Methods: A parental mouse RCC cell line, RenCa (RenCa/P), was continuously exposed to increasing doses of sorafenib, and a cell line resistant to sorafenib (RenCa/R), showing an approximately sixfold higher IC(50) than that of RenCa/P, was established. Changes in the expression of several molecules in these cell lines following sorafenib treatment were evaluated by western blotting, and the effects of sorafenib treatment on the in vivo growth patterns were compared., Results: There were no significant differences in sensitivities to potential agents against RCC between RenCa/P and RenCa/R. Among several apoptosis-related proteins, the expression of clusterin in RenCa/R was significantly greater than that in RenCa/P. Following treatment with sorafenib, the expression level of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) in RenCa/P, but not that in RenCa/R, was significantly decreased. Furthermore, additional treatment with a specific inhibitor of the MAPK signaling pathway significantly increased the sensitivity of RenCa/R to sorafenib, but not that of RenCa/P. There was no significant difference between the in vivo growth patterns of RenCa/P and RenCa/R in mice without sorafenib treatment; however, the growth inhibitory effect of sorafenib on the RenCa/P tumor was significantly greater than that on the RenCa/R tumor., Conclusions: These findings suggest that the upregulation of clusterin and continuous activation of the MAPK pathway during sorafenib treatment may be involved in the acquisition of a resistance to sorafenib in RCC.

The objective of this study was to comprehensively analyze the health-related quality of life (HRQOL) in Japanese patients with metastatic renal cell carcinoma (mRCC) during treatment with tyrosine kinase inhibitors (TKIs). This study included 240 Japanese mRCC patients treated with TKIs. We conducted a total of 305 surveys assessing the HRQOL before and 3 months after the introduction of TKIs, including 150, 95 and 60 during treatment with sorafenib, sunitinib and axitinib, respectively, using the Medical Outcomes Study 36-Item Short Form, consisting of eight multi-item scales measuring the health status. There were no significant differences in any of the eight scale scores between these 305 surveys conducted before and 3 months after TKI treatment. Two scores in the surveys during axitinib treatment were significantly superior to those during sorafenib treatment; however, no significant differences were noted in any of the remaining scale scores among the surveys during treatment with the three TKIs. Multivariate analyses, which were performed to evaluate the contribution of several factors to each scale score, revealed that the therapeutic efficacy had independent impacts on two scale scores, despite the lack of an independent association between any scores and the remaining factors, including the age, gender, introduced TKI, timing of TKI introduction and degree of adverse events. Collectively, these findings suggest that treatment with TKIs did not result in a significant impairment of the HRQOL in Japanese patients with mRCC; however, patients with unfavorable disease control appeared to fail to achieve a satisfactory HRQOL during treatment with TKIs.

Objectives: To assess the significance of circulating matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as predictors of disease progression in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib., Materials and Methods: Circulating levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in sera from 52 patients with mRCC treated with sunitinib were measured at the baseline and on the first day of each treatment cycle until progression using enzyme-linked immunosorbent assays., Results: The baseline level of MMP-9 in nonresponders to sunitinib was significantly higher than that in responders, whereas the baseline level of TIMP-2 in nonresponders was significantly lower than that in responders. However, there were no significant differences in the serum levels of MMP-2 and TIMP-1 between responders and nonresponders. The serum MMP-9/TIMP-2 ratio at the baseline in nonresponders was also significantly higher than that in responders. Univariate analysis showed that the MMP-9/TIMP-2 ratio, but not MMP-9 and TIMP-2 levels, was significantly correlated with progression-free survival, and the MMP-9/TIMP-2 ratio, in addition to the Memorial Sloan-Kettering Cancer Center classification and C-reactive protein level, appeared to be independently associated with progression-free survival on multivariate analysis. Furthermore, despite the lack of significant differences in the serum levels of MMP-9 and TIMP-2 between the baseline and the time of progression, the MMP-9/TIMP-2 ratio at the time of progression was significantly elevated compared with the baseline ratio., Conclusions: An imbalance between the serum MMP-9 and TIMP-2 levels could be a novel biomarker to predict disease progression in patients with mRCC under treatment with sunitinib., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To retrospectively review the oncologic outcomes of docetaxel-based chemotherapy in Japanese men with metastatic castration-resistant prostate cancer (mCRPC)., Materials and Methods: This study included 257 consecutive Japanese patients with mCRPC who were treated with docetaxel-based chemotherapy between April 2007 and March 2010. The prognostic significance of several clinicopathologic factors in these patients was analyzed., Results: In these 257 patients, the median age and serum value of prostate-specific antigen (PSA) prior to docetaxel-based chemotherapy were 72 years and 43.0 ng/ml, respectively. Of these patients, 64 (24.9%) and 193 (75.1%) received docetaxel as a weekly (30 mg/m(2)) and 3-weekly (70-75 mg/m(2)) regimen, respectively, and estramustine (EM) was administered in combination with docetaxel in 137 (53.3%). PSA decline was observed in 205 patients (79.8%), including 143 (55.6%) achieving PSA decline ≥ 50%. The median progression-free survival and overall survival (OS) were 4.3 and 25.4 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), PSA value, significant clinical pain, bone metastasis, prior treatment with EM, treatment cycle, and PSA response as significant predictors of OS, of which only PS, significant clinical pain, prior treatment with EM, treatment cycle, and PSA response appeared to be independently related to OS on multivariate analysis. Furthermore, there were significant differences in OS according to positive numbers of these 5 independent risk factors., Conclusions: Oncologic outcomes in Japanese mCRPC patients receiving docetaxel-based chemotherapy is generally favorable, and the risk stratification presented in this study may contribute to precisely predicting the prognosis of such patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC)., Methods: This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed., Results: Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3-4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%)., Conclusion: Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.

Objectives: The objective of this study was to evaluate the significance of docetaxel-based chemotherapy in elderly Japanese men with metastatic castration-resistant prostate cancer (CRPC)., Materials and Methods: This study included a total of 159 consecutive patients aged≥75 years with mCRPC who were treated with docetaxel-based chemotherapy. The efficacy and tolerability of this therapy were retrospectively analyzed., Results: In these 159 patients, the median age and prostate-specific antigen (PSA) level before docetaxel-based chemotherapy were 78 years and 44.0 ng/ml, respectively. Of these patients, 42 (26.4%) and 117 (73.6%) received docetaxel as a weekly (30 mg/m2) and 3-weekly (70 mg/m2) regimen, respectively, and estramustine was administered combining with docetaxel in 77 (48.4%). Following docetaxel-based chemotherapy, PSA declined in 118 patients (74.3%), including 87 (54.6%) achieving a PSA decline≥50%, and the median progression-free survival and overall survival (OS) were 2.9 and 23.2 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), significant clinical pain, bone metastasis, schedule of treatment, treatment cycle, and PSA response as significant predictors of OS, of which only PS, treatment cycle, and PSA response appeared to be independently associated with OS on multivariate analysis. The major grade 3-4 toxicities were myelosuppression, including neutropenia, anemia, and thrombocytopenia in 78 (49.1%), 22 (13.8%), and 14 (8.8%), respectively., Conclusions: These findings suggest that docetaxel-based chemotherapy is clinically feasible in Japanese men aged≥75 years with mCRPC considering the cancer control as well as safety associated with this therapy.

Before the advent of molecular-targeted agents, immunotherapy using cytokines, such as interferon-α (IFN-α) and interleukin-2 (IL-2), had been the mainstay of treatment for patients with metastatic renal cell carcinoma (mRCC), and this therapy may still be occasionally recommended for such patients. In this report, we present two cases of mRCC who were treated with very-low-dose IL-2 therapy and subsequently achieved complete response (CR). Both cases received adjuvant IFN-α therapy following radical nephrectomy; however, multiple lung metastases developed 4 and 12 months after surgery, and low-dose IL-2 (0.7 million U/day) was then administered twice per week for 14 and 35 months, respectively. In both cases, metastatic lesions completely regressed 3 and 20 months after the start of IL-2 therapy, and these responses have persisted for 81 and 67 months, respectively, to date. These findings suggest that immunotherapy with IL-2, even at a very-low-dose setting, may achieve the induction of CR in mRCC; accordingly, IL-2-based immunotherapy should be considered as the initial treatment for appropriately selected patients with mRCC.

We report a case of melanoma that had a marked response to treatment with imatinib mesylate (IM). The patient was a 61-year-old man who presented with a small red nodule on the thumb and destruction of the nail plate. On histological examination, this lesion was diagnosed as a melanoma, and computed tomography revealed lymph-node swelling in the left axilla and nodules in both lung fields. Although the patient received intratumoral injections of interferon-β and systemic administration of dacarbazine, both primary and metastatic lesions increased in size. Immunochemistry detected a KIT mutation, which was confirmed by DNA sequencing analysis, and patient was given IM. Within 2 weeks of starting the IM regimen, the size of the nodule on the nail plate markedly decreased, and the axillary lymph-node swelling and lung-nodule formation regressed. This case suggests that IM may be a promising treatment option for KIT mutation-positive melanoma., (© 2010 The Author(s). Journal compilation © 2010 British Association of Dermatologists.)

Polycomb group protein EZH2, frequently overexpressed in malignant tumors, is the catalytic subunit of polycomb repressive complex 2 (PRC2). PRC2 interacts with HDACs in transcriptional silencing and relates to tumor suppressor loss. We examined the expression of HDAC isoforms (HDAC 1 and 2) and EZH2, and evaluated the possible use of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and EZH2 repressor for gallbladder carcinoma. We used 48 surgically resected gallbladders and cultures of human gallbladder epithelial cells (HGECs), gallbladder carcinoma (TGBC2TKB), and cholangiocarcinoma (HuCCT-1 and TFK-1) cell lines for examination. Immunohistochemically, EZH2 was overexpressed in gallbladder carcinoma, especially poorly differentiated carcinoma, but not in normal epithelium. In contrast, HDAC1/2 were expressed in both carcinoma and normal epithelium in vivo. This pattern was verified in cultured cells; EZH2 was highly expressed only in TGBC2TKB, whereas HDAC1/2 were expressed in HGECs and TGBC2TKB. Interestingly, SAHA treatment caused significant cell number decline in three carcinoma cells, and this effect was synergized with EZH2 siRNA treatment; however, HGECs were resistant to SAHA. In TGBC2TKB cells, the expression of EZH2 and HDAC1/2 were decreased by SAHA treatment, and p16(INK4a), E-cadherin, and p21were simultaneously activated; however, no such findings were obtained in HGECs, suggesting that the effect of SAHA depends on the EZH2-mediated tumor suppressor loss. In conclusion, this study suggests a possible mechanism by which carcinoma cells but not normal cells are sensitive to SAHA and indicates the efficacy of this new anticancer agent in combination with EZH2 repression in gallbladder carcinoma.

We have found that coupling between catharanthine and vindoline occurs non-enzymatically in the presence of flavin mononucleotide and manganese ions with near-ultraviolet light irradiation in vitro. The present study found that the concentrations of catharanthine and vindoline in Catharanthus roseus decreased and those of dimeric indole alkaloids increased under near-ultraviolet light at 4 degrees C. It indicates that this coupling reaction at 4 degrees C occurs non-enzymatically.

The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17beta-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17beta-HSD isoenzymes and nuclear receptors., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Aims: Malignant mesothelioma is an aggressive cancer with no effective treatment options. A redox-silent analogue of alpha-tocotrienol, 6-O-carboxypropyl-alpha-tocotrienol (T3E) is a new potential anti-carcinogenic agent with less toxic effect on non-tumorigenic cells. Here, we evaluated the effect of T3E on killing of chemoresistant mesothelioma cell (H28)., Main Methods: The cytotoxic effect of T3E was evaluated by a WST-1 assay, and cell cycle and apoptosis analysis were done by FACS. Each signal molecule's activity was determined by protein array and immunoblot analysis., Key Findings: T3E effectively inhibited H28 cell growth at practical pharmacological concentrations (10-20 muM) without any effect on non-tumorigenic mesothelial cell (Met-5A). Inhibition of H28 cell growth by T3E mediated through G2/M arrest in cell cycle and induction of apoptosis. Protein array and immunoblot analyses revealed that T3E inhibited the activation of epidermal growth factor receptor (EGFR) via the inactivation of the Src family of protein tyrosine kinases (Src). However, the blockade of the EGFR signaling was not associated with the T3E-dependent H28 cell growth control. In addition to Src inactivation, T3E inhibited signal transduction and activation of transcription Stat3. A combination of an Src inhibitor, PP2, and a Stat3 inhibitor, AG490, induced G2/M arrest and enhanced apoptosis compared with PP2 alone. These results suggest that T3E suppresses H28 cell growth via the inhibition of Src activation and Src-independent Stat3 activation., Significance: T3E can be a new effective therapeutic agent against chemoresistant mesothelioma cells.

Cisplatin is the most common chemotherapeutic agent used in esophageal cancer. However, sensitivity to cisplatin varies greatly between patients. It is important to identify the gene(s) that are related to the sensitivity to cisplatin in esophageal cancer patients. The IC50 for cisplatin was measured for 15 esophageal cancer cell lines (TE1-5, TE8-15, KYSE140, and KYSE150). RNA was extracted from each of these cell lines and a normal esophageal epithelial cell line, namely, Het1A, and gene expression profiles were analyzed using an oligonucleotide microarray consisting of 34 594 genes. TE4 was highly resistant and TE12, 14, and 15 were sensitive to cisplatin. Thirty-seven genes were differentially expressed in the cisplatin-resistant esophageal cancer cell line. Our investigation provides a list of candidate genes that may be associated with resistance to cisplatin in esophageal cancer cells, which may serve as a basis for additional functional studies.

The aim of this study was to investigate the efficacy and safety of an oral fluoropyrimidine anticancer agent, S-1, in patients with oral squamous cell carcinoma. Patients with pathologically confirmed squamous cell carcinoma and at least one measurable lesion were enrolled. Oral administration of S-1 (40 mg/m2 twice daily) for 28 days was followed by a 14-day rest period. A total of 41 consecutive eligible patients were enrolled in the study between October 2002 and August 2004. The sites of the primary tumor were the gingiva (n=18), the tongue (n=12), the palate (n=5), the oral floor (n=4), the buccal mucosa (n=1), and the labial mucosa (n=1). A median of two cycles of treatment (range, 1-5) was administered. A complete response was achieved in nine patients and a partial response in eight patients, for an overall response rate of 41.5% (95% confidence interval, 26.4-56.5%). The 3-year survival rate was 76.4% (95% confidence interval, 62.8-90.0%). Although grade 3 anemia and anorexia occurred in two patients each (4.9%), and grade 3 neutropenia, thrombocytopenia, nausea, vomiting, stomatitis, and diarrhea in one patient each (2.4%), no grade 4 toxicities were observed. S-1 exhibits definite antitumor activity in patients with oral squamous cell carcinoma and is well tolerated.

Gefitinib (ZD1839), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, is an anticancer agent for patients with non-small cell lung carcinoma. Recently, however, as a result of accumulating evidence, it has been recognized that gefitinib can give rise to lethal lung toxicity. The authors report a case of interstitial lung disease (ILD) induced by gefitinib, which improved promptly following cessation of the administration of the agent. Clinical signs suggesting a good prognosis were noted, namely, findings similar to acute eosinophilic pneumonia on CT and a disassociation in the elevation of specific serum markers of ILD. At the time of onset of ILD, serum concentrations of surfactant protein (SP)-A and SP-D were significantly increased, whereas that of KL-6 was not increased. A previous study of three cases of lethal lung toxicity resulting from gefitinib administration revealed a significant and almost equal increase in KL-6, SP-A and SP-D. These results suggest that SP-A and SP-D may be indicators of gefitinib-induced ILD and that KL-6 is a predictor of outcome. Using a combination of these markers may help to establish a differential prognosis in patients with gefitinib-induced ILD.

To examine the effect of an oral fluoropyrimidine anti-cancer agent (S-1) on the radiosensitivity of a human oral cancer cell line with focusing on inhibition of survival signal, Akt/PKB. A human oral cell cancer cell line B88 was used. Activation of Akt/PKB in vivo was examined by immunohistochemistry, and apoptotic cells were detected by TUNEL method. Activation of Akt/PKB in vitro was investigated by Western blot and ELISA, and apoptotic cells were detected by Hoechst 33258 staining. S-1 (10 mg/kg/day or 50 microg/ml) greatly enhanced radiosensitivity in B88 cells by suppressing the activation of Akt/PKB. Significant increase in the percentage of apoptotic cells was observed in S-1 treated B88 cells. Survival signals Akt/PKB may be involved in determining radiosensitivity. S-1, an oral fluoropyrimidine anti-cancer agent can exert the enhancing effect on radiation by suppressing the activation of Akt/PKB.

The glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, which is refractory to chemotherapy in most cases. The lack of chemotherapeutic success is correlated with overexpression of the product P-glycoprotein (PGP) coded by the multidrug resistance 1 (MDR1) gene and a subsequent release of drugs from the tumor cells. For the chemotherapeutical treatment of glioblastomas, the endothel cell is of special importance since due to its manifold metabolic and protective tasks within the blood-brain barrier, it already has a relatively high PGP expression under physiological conditions. The aim of the present study was to analyze the uptake of the antimitotic drug Doxorubicin (DOX) and the expression of PGP in human and rat glioblastoma cell lines and in a human endothelial cell line at different time points. In the following in vivo approach DOX enriched glioblastoma cells were transplanted into rats and the developed tumor was investigated histologically. The results showed an increased uptake and an enhanced expression of PGP at certain time points in every cell line. In the tissue a DOX release was mainly observed in perivascular surroundings. It was concluded that DOX enhanced the constitutive PGP expression which led to a subsequent exclusion of DOX in tumor cells but also in the endothelial cells of the tumor vasculature. Since the vascularization is a prerequisite for tumor growth, the inhibition of the PGP expression in tumor endothelial cells might be a clinical approach to make the DOX treatment more effective.

Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic action is exerted by the induction of apoptosis. However, activation of the transcription factor NF-kappaB results in protection against apoptosis. We examined the molecular mechanisms involved in the induction of apoptosis by CDDP as regards both suppression of NF-kappaB and activation of caspases. Human oral squamous carcinoma cells (B88) were employed in this study. We found that CDDP treatment affected neither NF-kappaB activity nor the expression levels of antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase-9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis, were detected after treatment with CDDP. Finally, apoptosis was also clearly observed, as evidenced by cleavage of PARP through the activation of caspase-3. These findings suggest that CDDP exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-kappaB activity that follows the suppression of antiapoptotic proteins.

Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. The drug has been widely used for the treatment of many acute and chronic diseases and can exert antitumor effects on several human cancer cells. In this study, we examined the mechanism of the antitumor effects by cepharanthine on a human oral squamous cell carcinoma (SCC) cell line. Treatment of oral SCC cells with cepharanthine (10-20 micrograms/ml) resulted in a significant suppression of cell growth. Cepharanthine preferentially suppressed the growth of B88 cells when compared with other human oral SCC cells. Moreover, it was found, by flow cytometry analysis and Hoechst 33258 staining, that G1 arrest and DNA fragmentation occurred in cepharanthine-treated B88 cells. Furthermore, induction of p27Kip1 and reduction of cyclin E and Skp2 were detected by Western blotting. B88 tumor-bearing nude mice were treated with cepharanthine, which was administered subcutaneously (40 mg/kg/day). The cepharanthine treatment results in a significant suppression of tumor growth. Overall these results indicate that cepharanthine may inhibit the growth of human oral SCC cells by down-regulating cyclin E to induce G1 arrest through a pathway of p27Kip1 induction.

Background: Surgeons sometimes encounter hyperbilirubinemia without mechanical obstruction of the biliary tree postoperatively. Many of these patients have bacterial infections and endotoxemia. Kupffer's cells stimulated by endotoxin secrete inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. We hypothesized that TNF-alpha and IL-6 might be involved in the pathogenesis of hyperbilirubinemia., Methods: Effects of TNF-alpha and IL-6 on the contractions of bile canaliculi (BC) of rat hepatocyte couplets were examined and time-lapse images using phase-contrast microscopy were taken. Bile was collected from rats treated with or without the cytokines. The livers, perfused with lanthanum after the injection of cytokines, were examined ultrastructurally using electron microscopy., Results: The number of BC contractions decreased in the couplets treated with both cytokines. The rapid movement of a droplet from BC was observed at the intercellular space of the hepatocyte couplet treated with TNF-alpha. Systolic blood pressure and hepatic tissue blood flow of rats injected with TNF-alpha were not changed, whereas the hepatic tissue blood flow of rats treated with IL-6 decreased (Dunnett test, P <.05). Bile secretion was reduced in both groups of rats (Dunnett test, P <.05). In rats treated with TNF-alpha the total serum bile acid concentration increased and lanthanum temporarily accumulated in BC., Conclusions: These results suggest that TNF-alpha and IL-6 may reduce BC contractions and thereby decrease bile flow.

Background: Antimicrotubule drugs (AMDs), such as taxol and vincristine, are the most important addition to the chemotherapeutic armamentarium against human cancers. It has been shown that prolonged AMD treatment induces hyperploidy in G1-checkpoint-defective cancer cells and that these hyperploid cells subsequently undergo apoptosis. However, a fraction of these hyperploid cells are able to survive the prolonged mitotic stress and resume cell-cycle progression., Results: We established hyperploid clones that escaped from cell death after AMD treatment from two glioma cell lines, U251MG and U87MG. Subtractive comparative genomic hybridization (CGH) analysis revealed that clones derived from U87MG mainly had chromosome number changes, but that those from U251MG showed both numerical and structural chromosomal changes. Furthermore, numerous aberrations identified in U251MG clones were remarkably chromosome-specific, which may have been due to clonal selection for cells that have an advantage in growth and/or survival. All clones derived from both cell lines had abnormalities in chromosome segregation, and karyotypes of clones were more heterogeneous than those of parental cells, suggesting that cells having a higher chromosome number are subject to asymmetric chromosome segregation, resulting in a heterogeneous karyotype. All clones derived from U87MG and U251MG increased both centric and acentromeric micronuclei, suggesting the presence of chromosome structural abnormality., Conclusions: AMD treatment induces hyperploid formation and chromosome instability in checkpoint-deficient cancer cells.

Purpose: To evaluate the utility of an interventional CT system for intraarterial chemotherapy or chemoembolization for locally advanced and/or recurrent hepatic tumors., Methods: Thirty-eight patients with locally advanced or recurrent hepatic tumors underwent 73 intraarterial contrast-enhanced CT (IA-CECT) examinations immediately before chemotherapy or chemoembolization. The degree of tumor vascularity on angiography and enhancement on IA-CECT was classified into three grades: no, mild, or marked vascularity. The IA-CECT grades were compared with the angiographic grades., Results: Twenty-nine (69%) of 42 examinations that were interpreted as having no or mild vascularity on angiography were classified as marked enhancement on IA-CECT. Based on IA-CECT findings, the position of the catheter was changed in 14 (19%) of 73 CT examinations. The reasons for the reposition were as follows: weak or no enhancement of the tumor (n = 11) or strong enhancement of the gallbladder wall (n = 3). The treatment strategy was changed in three patients (8%). No major complications relating to the interventional procedures were observed., Conclusions: IA-CECT is a reliable method when evaluating the perfusion of the tumor and adjacent normal tissues. The interventional CT system is useful for performing safe and effective intraarterial chemotherapy or chemoembolization in patients with locally advanced and/or recurrent hepatic tumors.

We examined the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on carboplatin-induced thrombocytopenia in rats. The focus was on whether myelofibrosis is associated with the PEG-rHuMGDF treatment in this chemotherapy model. After a single injection of carboplatin, rats received subcutaneous PEG-rHuMGDF at pharmacologic doses (1,3, or 30 micrograms/kg) or a vehicle daily for 7 days. PEG-rHuMGDF at more than 3 micrograms/kg ameliorated the thrombocytopenia at day 10. Histologically, no myelofibrosis was detected in the rats treated with PEG-rHuMGDF or vehicle. Subsequently, PEG-rHuMGDF at a suprapharmacologic dose (100 micrograms/kg) was subcutaneously administered to normal and to carboplatin-treated rats daily for 7 days. Histological analysis revealed that the treatment with PEG-rHuMGDF induced myelofibrosis in the normal rats but not in the carboplatin-treated rats. Additionally, the transforming growth factor-beta 1 (TGF-beta 1) levels in the extracellular fluid and the whole extract of the bone marrow were increased to a much lesser degree in the carboplatin-treated rats compared to the normal rats. These findings suggest that PEG-rHuMGDF is effective for carboplatin-induced thrombocytopenia. Proper control of platelet counts and TGF-beta 1 levels is essential so that myelofibrosis is not induced in clinical use.

Indolo[3,2-b]quinoline derivatives (1) having various amine moieties were prepared and their antitumor activities against P388 leukemia in mice were evaluated, for the purpose of gaining an insight into the role of the amine moiety in the antitumor activity and searching for an effective amine moiety. Introduction of a methylene group between the phenyl group and amino or methanesulfonamido group resulted in decrease or loss of activity.