[Show abstract][Hide abstract] ABSTRACT: Neurotoxicity is one of the most frequent side-effects of oxaliplatin. Oxaliplatin-induced cumulative and dose-limiting neurotoxicity either results in dose reduction or decreases the patients' quality of life. However, the symptoms of neurotoxicity often vary among patients. The current study presents the case of a male with rectal cancer, who was administered a cumulative oxaliplatin dose of >5,000 mg/m(2) without developing neurotoxicity or allergic reactions. Consequently, this patient continued therapy with modified 5-fluorouracil, leucovorin and oxaliplatin treatment for four years, with stabilization of the disease. This case indicates that if oxaliplatin-containing chemotherapy shows efficacy with no toxicity, the long-term administration of oxaliplatin would be effective and tolerable. Previously, the analysis of genomic polymorphisms in drug target genes has been important for explaining interindividual variations in the efficacy and toxicity of anti-cancer drugs. In the present patient, the glutathione S-transferase P1 (GSTP1) gene polymorphism, which is involved in the detoxification of platinum drugs, was analyzed. The genotype of the present case has been revealed as wild type (Ile/Ile) genotype. In addition, the associations between oxaliplatin-induced neurotoxicity and the GSTP1 polymorphism were also assessed. Certain studies have demonstrated that oxaliplatin-induced neurotoxicity occurs more frequently in patients with the Ile/Ile genotype, while others have demonstrated that those patients with the Val/Val or Ile/Val genotypes are more likely to develop neurotoxicity. Therefore, correlation between the GSTP1 polymorphism and oxaliplatin-induced neurotoxicity remains controversial. Overall, further development of individualized chemotherapy with an analysis of genomic polymorphisms in the drug target genes is required for the prophylaxis oxaliplatin-induced neurotoxicity.
[Show abstract][Hide abstract] ABSTRACT: Toll‑like receptor activation intitially recruits the myeloid differentiation primary response gene (88) (MyD88) protein. A polymorphism *1244 A>G (rs7744) in the 3'‑untranslated region of MyD88 has been identified. In the present study, the association of this polymorphism with ulcerative colitis (UC) was investigated. The population studied comprised 922 individuals, including patients with UC (UC cases) and without (controls). Genotyping of rs7744 was performed by PCR single-strand conformation polymorphism and the rs7744 G allele frequencies in the controls and UC cases were 32.8 and 43.5%, respectively (P<0.0001). The results showed that the genotype frequency of the AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls (P=0.0012 for both groups). The rs7744 minor allele variants were significantly associated with susceptibility to UC as indicated by dominant and recessive genetic models. The minor allele variants were associated with an increased risk for UC in the male individuals but not the female individuals. The rs7744 was also associated with a non‑continuous phenotype of UC and steroid unused/independent UC. This minor allele homozygote was associated with the disease severity of UC, hospitalization and response to steroid treatment. The results of the present study provided evidence that MyD88 polymorphism rs7744 was significantly associated with the development of UC and that this polymorphism may be associated with the response to treatment therapies for UC.
Molecular Medicine Reports 11/2013; · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.
[Show abstract][Hide abstract] ABSTRACT: RBM8A (Y14) contains an RNA-binding motif and forms a tight heterodimer with Magoh. The heterodimer is known to be a member of the exon junction complex that forms on mRNA before export and it is required for mRNA metabolism processes such as splicing, mRNA export and nonsense-mediated mRNA decay. Recently, deficient cellular proliferation has been observed in RBM8A- or Magoh-depleted cells. These results prompted us to study the role of RBM8A in cell cycle progression of human tumour cells. The depletion of RBM8A in A549 cells resulted in poor cell survival and the accumulation of mitotic cells. After release from G1/S arrest induced by a double thymidine block, the RBM8A-silenced cells could not proceed to the next G1 phase beyond G2/M phase. Finally, the sub-G1 population increased and the apoptosis markers caspases 3/7 were activated. Silenced cells exhibited an increased frequency of multipolar or monopolar centrosomes, which may have caused the observed deficiency in cell cycle progression. Finally, silencing of either RBM8A or Magoh resulted in mutual downregulation of the other protein. These results illustrate that the RBM8A-Magoh mRNA binding complex is required for M phase progression and both proteins may be novel targets for anticancer therapy.
Experimental Biology and Medicine 08/2013; 238(8):889-97. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer.
Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined.
Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts.
The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.
PLoS ONE 01/2013; 8(2):e55289. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stress proteins of the pancreas, such as tumor protein 53-induced nuclear protein 1 (TP53INP1), are important factors in the invasion and metastasis of pancreatic cancer. TP53INP1 is a pro-apoptotic factor and is transcriptionally regulated in p53-dependent and -independent manners. A previous study proved that gemcitabine induces TP53INP1 expression in pancreatic cancer cells and the pancreatic cancer cell line (PANC-1). The present study aimed to clarify the association between TP53INP1 and gemcitabine sensitivity. The expression of TP53INP1 and its related factors, such as cell growth and cell cycle status in TP53INP1-knockout mouse embryonic fibroblasts [TP53INP1(-/-)-mouse embryonic fibroblasts (MEFs)] to those in wild-type counterparts (TP53INP1(+/+)-MEFs) were compared. Flow cytometric analysis demonstrated no difference of the checkpoint function in TP53INP1(-/-)-MEFs and TP53INP1(+/+)-MEFs when exposed to 10 ng/ml of gemcitabine. No significant difference was found in the level of p53 expression in the cell types, although the base level and gemcitabine-induced expression of p21 were significantly decreased in TP53INP1(-/-)-MEFs, compared to those in wild-type counterparts. Results showed that gemcitabine induced the p21 expression in TP53INP1(+/+)-MEFs, although not in TP53INP1(-/-)-MEFs. However, their respective cell-cycle checkpoints were not different. Therefore, TP53INP1 was found to be associated with drug sensitivity through control of the cell cycle.
Molecular and clinical oncology. 01/2013; 1(1):100-104.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is one of the most lethal cancers, with an incidence equaling mortality. It is a heterogeneous group of neoplasms in which pancreatic ductal adenocarcinoma is most common. Pancreatic cancer cannot be cured even if detected early. When treatment is initiated, a suitable method of administration of anticancer drugs must be chosen. Anticancer drugs kill tumor cells. However, side effects including initiation are problematic in anticancer drug therapy. Improved methods for the diagnosis of side effects of pancreatic cancer by using sensitive and specific tumor markers are highly desirable. Therefore, efficient strategies for biomarker discovery are urgently needed. Here, we present an approach based on direct experimental access to proteins released by PANC-1 human pancreatic cancer cells in vitro. A two-dimensional (2-D) map and catalog of this subproteome, herein termed the secretome, were established comprising more than 1,000 proteins observed by '2-D difference in-gel electrophoresis analysis using cyanine dye'. We investigated 22 spots that were 1.20-fold upregulated and 31 spots that were 0.66-fold downregulated by gemcitabine chloride treatment. Proteins in these spots were identified by nano-high-performance liquid chromatography electrospray ionization time of flight mass spectrometry/mass spectrometry. Most secretome constituents were nominally cellular proteins. By mass spectrometry screening, 14-3-3 protein sigma (14-3-3 σ), protein S100-A8, protein S100-A9, galectin-7, lactotransferrin (lactoferrin, LF) precursor, serotransferrin (transferrin) precursor, and vitamin D binding protein precursor were identified. Western blotting confirmed the presence of 14-3-3 σ and LF. We found that upregulation of 14-3-3 σ was associated with apoptosis, and downregulation of LF was found to suppress tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: A 76-year-old man with renal dysfunction received FOLFIRI due to a relapse in his pelvis after surgery for sigmoid colon cancer. FOLFIRI was continued for approximately 21 months with stabilization of disease observed on CT scans, but his tumor marker levels increased and tumors showed progression. He then began treatment with cetuximab/CPT-11, but disease progression was observed. XELOX in a low-dose was then administered, but this therapy was discontinued because of progression. He could not receive the other antitumor agents, due to mutations of the KRAS gene and renal dysfunction. Therefore, FOLFIRI was restarted, because it can be continued for long periods of time. Consequently, his tumor marker levels decreased with stabilization of disease on CT scans, and he continued the therapy for 7 months while maintaining quality of life. Ultimately, this case suggested that if there was effectiveness from a previous treatment, retreatment would be successful as chemotherapy for colon cancer in the difficult situation of selecting the other effective antitumor agents.
Gan to kagaku ryoho. Cancer & chemotherapy 08/2012; 39(8):1267-70.
[Show abstract][Hide abstract] ABSTRACT: We retrospectively reviewed the medical records of 32 chemonaïve patients with either breast, lung or prostate cancer, who were treated with docetaxel (DOC) monotherapy, and evaluated whether the proportion of peripheral blood monocytes was capable of predicting the occurrence of neutropenia following chemotherapy. In the granulocyte-colony stimulating factor (G-CSF) non‑administration group, the monocyte percentage was inversely correlated with the decrease in neutrophils (P=0.01; corrected correlation coefficient, -0.71). The neutrophil count decreased by ≥30% in 7 of 8 patients with <5% monocytes, whereas it decreased by >30% in 1 of 6 patients with ≥5% monocytes (P=0.01). Three of 8 patients with <5% monocytes experienced grade 4 neutropenia, while in the group with ≥5% monocytes, 1 of 6 patients experienced grade 4 neutropenia. The frequency of grade 3 or 4 neutropenia was lower in patients with ≥5% monocytes than in patients with <5% monocytes, but the difference was not significant (P=0.41). Following G-CSF administration, grade 3 or 4 neutropenia had the tendency of lasting longer in patients with <5% monocytes than in those with ≥5% monocytes; however, the monocyte percentage was not correlated with the grade of neutropenia (P=0.34). The monocyte percentage following chemotherapy was inversely correlated with the decrease in neutrophils. The percentage of monocytes that are available in clinical practice may be predictive of neutropenia following chemotherapy. Our findings suggest that patients with <5% monocytes following DOC monotherapy are at risk of severe neutropenia and should be carefully monitored.
[Show abstract][Hide abstract] ABSTRACT: Hospitals supply goods to patients practicing intermittent self‐catheterization (ISC), yet procedures for distribution have yet to be standardized, making it difficult to track the types of goods that are shipped and their amounts. The aim of this study was to standardize the types and amounts of goods provided by medical facilities on the basis of the survey results. We conducted a survey of medical facilities and patients regarding the status of goods supplied for ISC. Data were collected from January to May 2010 from 5 outpatient urology clinics and 26 patients practicing ISC. The first finding of this research is that the amount of supplied goods was insufficient and part of the supply method was incorrect. The second is that the status of goods supplied changed not only with ISC, but also with hospital characteristics. The third is that hospital costs averaged $63·10; the supplied catheter number affected hospital costs. Patient costs per month averaged $26·50, clearly showing that patients experience an economic burden. Patient costs were high in cases in which the percentage of types of goods supplied was low. A researcher analysed survey data to determine issues and procedures relevant to the supply of goods. The study showed a need to develop an optimal supply system for ISC patients and identified issues in the current system in Japan that require resolution.
International Journal of Urological Nursing 01/2012; 6(3). · 0.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Development and progression of pancreatic cancer involves general metabolic disorder, local chronic inflammation, and multistep activation of distinct oncogenic molecular pathways. These pathologic processes result in a highly invasive and metastatic tumor phenotype that is a major obstacle to curative surgical intervention, infusional gemcitabine-based chemotherapy, and radiation therapy. Many clinical trials with chemical compounds and therapeutic antibodies targeting growth factors, angiogenic factors, and matrix metalloproteinases have failed to demonstrate definitive therapeutic benefits to refractory pancreatic cancer patients. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target in common chronic and progressive diseases, including cancer. Here we review accumulating evidence for a pathologic role of GSK3β in promoting tumor cell survival, proliferation, invasion, and resistance to chemotherapy and radiation in pancreatic cancer. We also discuss the putative involvement of GSK3β in mediating metabolic disorder, local inflammation, and molecular alteration leading to pancreatic cancer development. Taken together, we highlight potential therapeutic as well as preventive effects of GSK3β inhibition in pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: Stress responses of pancreatic cancer cells are detected in case of chemotherapy. We have reported the expression of various
stress proteins in pancreatic cancer cells with special reference to tumor aggressiveness. Here, we elucidated a previously
unknown function of SMG-1, one of PI3 kinases, in the signal transduction of stress responses. Gemcitabine induces epithelial–mesenchymal
transition (EMT), producing EMT-inducing factors. Regulation of stress responses might lead to the control of metastasis and
the overcome of drug resistance in pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to clarify why a homecare patient had an anxiety and the type of difficulties while having an intermittent self-catheterization at home. We used a questionnaire survey to conduct an oral interview for 25 homecare patients, who regularly had an intermittent self-catheterization. The survey results were codified into single phrase units of meaning, and then separated into categories. The results revealed that 70 to 80% of patients who had an intermittent self catheterization in their own homes experienced an anxiety and encountered difficulties during the process. The findings emphasized the importance of providing a sort of support for homecare patients when they have an intermittent self-catheterization for the first time, as well as the importance of providing continued support until the patients are comfortable with the procedure. For a future support, these patients' anxiety need to be reduced and difficulties related to an intermittent self catheterization resolved during an outpatient visit.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2011; 38 Suppl 1:103-5.
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to clarify how catheter products are purchased by urinary homecare patients and to find problems associated with such purchases. We conducted a survey using a self-made questionnaire for 26 catheterized patients from Prefecture A, who were regular outpatients of the urology department. The results indicated that 17 patients(65. 4%)purchased catheter supplies on their own(13 males and 4 females, the mean age was 57. 9 years). The products purchased by the 26 patients were diverse including urine bags, syringes, catheters and tissues paper. Seven of the 17 patients(41%)responded that purchasing catheter supplies on their own was difficult, and 8(47%)responded that purchasing catheter supplies was an economic burden for them. The cost of purchasing catheter supplies varied greatly among the patients, and the price range was from 400 yen to 12, 000 yen. The cost was generally associated with the feelings of economic stress: it happens every month; it is a burden for some patients who need them for life time.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2011; 38 Suppl 1:106-8.
[Show abstract][Hide abstract] ABSTRACT: This study investigated the current status of goods supplied by medical facilities to outpatients practicing ISC.
The status of goods supplied was investigated by interviewing 4 medical facilities and 26 outpatients practicing ISC, using a questionnaire.
1. Of all goods supplied for use by outpatients practicing ISC, 53. 0%were supplied by medical facilities. The outpatients bought some goods required for ISC by himself. Moreover, some goods were supplied by prescription. 2. When a hospital was consulted, while there were those to whom goods are not supplied from a hospital, there were those to whom much kinds and quantity are supplied from the hospital. As for the patient to whom many kinds and the goods of quantity are supplied, goods expense formed about 70% of ISC administration fee.
In order to establish goods feed system, it was necessary to examine a common knowledge of the structure of goods supply to doctors or nurses and the validity of the ISC administration fee system from now on.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2011; 38 Suppl 1:109-11.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is obstinate and resistant to gemcitabine, a standard chemotherapeutic agent for the disease. We previously showed a therapeutic effect of glycogen synthase kinase-3β (GSK3β) inhibition against gastrointestinal cancer and glioblastoma. Here, we investigated the effect of GSK3β inhibition on pancreatic cancer cell sensitivity to gemcitabine and the underlying molecular mechanism.
Expression, phosphorylation, and activity of GSK3β in pancreatic cancer cells (PANC-1) were examined by Western immunoblotting and in vitro kinase assay. The combined effect of gemcitabine and a GSK3β inhibitor (AR-A014418) against PANC-1 cells was examined by isobologram and PANC-1 xenografts in mice. Changes in gene expression in PANC-1 cells following GSK3β inhibition were studied by cDNA microarray and reverse transcription (RT)-PCR.
PANC-1 cells showed increased GSK3β expression, phosphorylation at tyrosine 216 (active form), and activity compared with non-neoplastic HEK293 cells. Administration of AR-A014418 at pharmacological doses attenuated proliferation of PANC-1 cells and xenografts, and significantly sensitized them to gemcitabine. Isobologram analysis determined that the combined effect was synergistic. DNA microarray analysis detected GSK3β inhibition-associated changes in gene expression in gemcitabine-treated PANC-1 cells. Among these changes, RT-PCR and Western blotting showed that expression of tumor protein 53-induced nuclear protein 1, a gene regulating cell death and DNA repair, was increased by gemcitabine treatment and substantially decreased by GSK3β inhibition.
The results indicate that GSK3β inhibition sensitizes pancreatic cancer cells to gemcitabine with altered expression of genes involved in DNA repair. This study provides insight into the molecular mechanism of gemcitabine resistance and thus a new strategy for pancreatic cancer chemotherapy.
Journal of Gastroenterology 11/2011; 47(3):321-33. · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 72-year-old man came to our hospital due to edema, malaise, and poor appetite in May 200X. He was diagnosed as cardiac tamponade, and open surgery revealed tumors in the right atrium and the left ventricule. Tumor tissue was revealed to be angiosarcoma by the pathological findings. Metastases to the brain, lungs, liver, and adrenal glands were found. The patient was treated with interleukin-2(IL-2)for 7 weeks. However, there was no anti-tumor effect, and the patient died in September, 200X. We reported a very rare case of cardiac angiosarcoma associated with cardiac tamponade, who was treated with IL-2 monotherapy.
Gan to kagaku ryoho. Cancer & chemotherapy 08/2011; 38(8):1353-5.
[Show abstract][Hide abstract] ABSTRACT: Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis and is characterized by increase in cell motility, increase in expression of mesenchymal cell markers, loss of proteins from cell-to-cell junction complexes, and changes in cell morphology. Here, the morphological effects of a representative EMT inducer, transforming growth factor (TGF)-β1, were investigated in human lung adenocarcinoma (A549) cells and pancreatic carcinoma (Panc-1) cells. TGF-β1 caused morphological changes characteristic of EMT, and immunostaining showed loss of E-cadherin from cell-to-cell junction complexes in addition to the upregulation of the mesenchymal marker vimentin. During scanning electron microscopy (SEM) with an ionic liquid, we observed EMT-specific morphological changes, including the formation of various cell protrusions. Interestingly, filopodia in mitotic cells were clearly observed by SEM, and the number of these filopodia in TFG-β1-treated mitotic cells was reduced significantly. We conclude that this reduction in such mitotic protrusions is a novel effect of TGF-β1 and may contribute to EMT.
Microscopy Research and Technique 03/2011; 74(11):1024-31. · 1.59 Impact Factor