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1.
Gan To Kagaku Ryoho ; 42(3): 305-11, 2015 Mar.
Article in Japanese | MEDLINE | ID: mdl-25812498

ABSTRACT

BACKGROUND: Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. MATERIAL: Questionnaire analysis; From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti-emetic guideline published by (JSCO). RESULTS: Questionnaire; 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti-emetic therapy. CONCLUSIONS: Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan.


Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Nausea/prevention & control , Practice Guidelines as Topic , Vomiting/prevention & control , Antineoplastic Agents/therapeutic use , Humans , Nausea/chemically induced , Surveys and Questionnaires , Vomiting/chemically induced
2.
Oncology ; 87(1): 7-20, 2014.
Article in English | MEDLINE | ID: mdl-24968756

ABSTRACT

BACKGROUND: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. METHODS: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. RESULTS: KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. CONCLUSION: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Disease-Free Survival , Female , GTP Phosphohydrolases/genetics , Humans , Irinotecan , Kaplan-Meier Estimate , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Male , Membrane Proteins/genetics , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Treatment Outcome , ras Proteins/genetics
3.
PLoS One ; 9(3): e91335, 2014.
Article in English | MEDLINE | ID: mdl-24614412

ABSTRACT

BACKGROUND: The requirement of central venous (CV) port implantation is increasing with the increase in the number of cancer patients and advancement in chemotherapy. In our division, medical oncologists have implanted all CV ports to save time and consultation costs to other departments. Recently, upper arm implantation has become the first choice as a safe and comfortable method in our unit. Here we report our experience and discuss the procedure and its potential advantages. METHODS: All CV port implantations (n = 599) performed in our unit from January 2006 to December 2011 were analyzed. Procedural success and complication rates between subclavian and upper arm groups were compared. RESULTS: Both groups had similar patient characteristics. Upper arm CV port and subclavian implantations were equivalently successful and safe. Although we only retrospectively analyzed data from a single center, the upper arm group had a significantly lower overall postprocedural complication rate than the subclavian group. No pneumothorax risk, less risk of arterial puncture by ultrasound, feasibility of stopping potential arterial bleeding, and prevention of accidental arterial cannulation by targeting the characteristic solitary basilic vein were the identified advantages of upper arm CV port implantation. In addition to the aforementioned advantages, there is no risk of "pinch-off syndrome," possibly less patient fear of manipulation, no scars on the neck and chest, easier accessibility, and compatibility with the "peripherally inserted central catheter" technique. CONCLUSIONS: Upper arm implantation may benefit clinicians and patients with respect to safety and comfort. We also introduce our methods for upper arm CV port implantation with the videos.


Subject(s)
Arm/blood supply , Catheterization, Central Venous , Catheters, Indwelling , Catheterization, Central Venous/adverse effects , Catheters, Indwelling/adverse effects , Female , Humans , Male , Middle Aged , Phlebotomy , Preoperative Care , Retrospective Studies , Tomography, X-Ray Computed , Ultrasonics
4.
Oncol Rep ; 31(3): 1043-50, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24378760

ABSTRACT

The TP53 mutation (R175H) is one of the most common mutations in human cancer. It is a highly attractive strategy for cancer therapy to find the genes that lead the R175H-expressing cancer cells. The aim of this study was to identify the synthetic sick/lethal gene interacting with R175H. Using lentiviral bar-coded comprehensive shRNA library and a tetracycline-inducible R175H expressed in the SF126 human glioblastoma cell line (SF126-tet-R175H), we conducted high-throughput screening to identify the candidate genes that induce synthetic sickness/lethality in R175H-expressing cells. We identified 906 candidate gene suppressions that may lead to accelerated cell growth inhibition in the presence of R175H. Inhibitor of differentiation 1 (ID1) was one of the candidate genes, and its suppression by siRNA resulted in the acceleration of growth inhibition in cell lines both transiently and endogenously expressing R175H but not in TP53-null cell lines or other common p53 mutants (such as R273H). Flow cytometry analysis showed that ID1 suppression resulted in G1 arrest, and the arrest was accelerated by the expression of R175H. ID1 is a synthetic sick/lethal gene that interacts with R175H and is considered to be a novel molecular target for cancer therapy in R175H-expressing cells.


Subject(s)
Inhibitor of Differentiation Protein 1/genetics , Tumor Suppressor Protein p53/genetics , Cell Proliferation , Epistasis, Genetic , G1 Phase Cell Cycle Checkpoints , Gene Knockdown Techniques , Genes, Lethal , HCT116 Cells , Humans , Mutation, Missense , RNA Interference , RNA, Small Interfering/genetics , Tumor Suppressor Protein p53/metabolism
5.
Cancer Med ; 2(1): 1-10, 2013 Feb.
Article in English | MEDLINE | ID: mdl-24133622

ABSTRACT

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive mechanisms in human tumorigenesis. Till date, "super p53" mutants exhibiting more potent ability to induce apoptosis than wild-type p53 have been reported. These super p53s may provide a clue for development of novel therapeutic targets. However, the major mechanism underlying the super p53-dependent apoptosis remains unclear. To identify critical gene(s) in this mechanism, we performed a comprehensive and comparative expression analysis in p53-null Saos-2 cells with conditional expression of wild-type p53 and S121F, which was previously reported as a super p53 mutant. We identified damage-regulated autophagy modulator (DRAM) as one of the genes that were more upregulated by S121F than wild-type p53. Although knockdown of DRAM was not sufficient for reducing the ability of S121F to induce apoptosis, DRAM overexpression enhanced the ability in a wild-type p53-dependent manner. Here, we show that DRAM is an important gene for the enhancement of p53-dependent apoptosis. Additional analysis of the mechanism of super p53-dependent apoptosis may lead to the identification of novel drug targets for cancer therapy.


Subject(s)
Apoptosis/genetics , Glioblastoma/metabolism , Membrane Proteins/biosynthesis , Osteosarcoma/metabolism , Tumor Suppressor Protein p53/physiology , Apoptosis/physiology , Autophagy/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/genetics , Gene Knockdown Techniques , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Membrane Proteins/genetics , Mutation , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis/methods , Osteosarcoma/genetics , Osteosarcoma/pathology , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Up-Regulation/genetics
6.
Support Care Cancer ; 21(12): 3271-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23877927

ABSTRACT

PURPOSE: Gemcitabine is widely used for chemotherapy in many types of cancers. However, vascular pain frequently occurs during its infusion, which can be serious enough to cause treatment discontinuation. This study was conducted to determine whether dissolution with 5 % glucose solution would relieve vascular pain compared with the approved use of saline as the diluent. METHODS: Patients with cancer who were treated with weekly gemcitabine were eligible. Vascular pain was assessed during two consecutive administrations in a double-blind, randomized crossover study. One group was scheduled to receive gemcitabine dissolved in saline followed by gemcitabine in 5 % glucose solution. In the other group, 5 % glucose solution was followed by saline. The primary endpoint was frequency of vascular pain for the total infusions of each solvent and the secondary endpoints were intensity, as assessed on a visual analogue scale and duration of vascular pain. RESULTS: Eighty-seven patients were randomly assigned to each treatment schedule. Frequency of vascular pain was significantly lower with 5 % glucose solution compared with saline (40 versus 63 %; p < 0.001). The intensity of vascular pain was also reduced with 5 % glucose solution compared with saline (mean, 1.3 versus 2.7 points; p < 0.001). There was no significant statistical difference in duration of vascular pain between the 5 % glucose solution and saline solution groups (mean, 21 versus 18 min; p = 0.420). CONCLUSIONS: The use of 5 % glucose solution to dissolve gemcitabine significantly reduced the frequency and the intensity of vascular pain compared with the use of saline.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Deoxycytidine/analogs & derivatives , Glucose/administration & dosage , Pain/drug therapy , Vascular Diseases/drug therapy , Adult , Antimetabolites, Antineoplastic/administration & dosage , Cross-Over Studies , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Double-Blind Method , Female , Humans , Infusions, Parenteral , Male , Middle Aged , Neoplasms/drug therapy , Pain/chemically induced , Pain Measurement/drug effects , Vascular Diseases/chemically induced , Gemcitabine
7.
Gan To Kagaku Ryoho ; 40(3): 343-8, 2013 Mar.
Article in Japanese | MEDLINE | ID: mdl-23507596

ABSTRACT

The Great East Japan Earthquake was the first disaster we experienced after the administration of oncology care had mostly shifted from hospitals to outpatient departments in Japan. Disaster medical assistance teams(DMATs)were deployed immediately after the disaster, and actively assisted during the acute phase of the catastrophe. After experiencing the earthquake, we realized the necessity of medical support teams, even for chronic disease. Here we report a multicenter trial of regional medical cooperation for cancer chemotherapy. First, soon after the earthquake, representatives from the regional hospitals discussed the proper roles for each institution. As agreed to in the discussion, cancer patients were redistributed from a disaster base hospital to a local general hospital, and oncologists supported the other regional hospitals on a regular basis. This broad regional network functioned well and patients resumed their treatment as soon as the situation allowed. Second, we performed a survey of the patients and found that the most important problem was patients' lack of understanding of their own illnesses. Third, we conducted an opinion survey of medical professionals on regional medical cooperation. Based on the trial, we found it important in disasters to establish regional cooperation and solid communication systems, and to promote patient education.


Subject(s)
Community Networks , Earthquakes , Neoplasms/drug therapy , Patient Care Team , Adult , Aged , Aged, 80 and over , Female , Humans , Japan , Male , Middle Aged , Patient Education as Topic , Surveys and Questionnaires
8.
Oncol Lett ; 3(5): 978-982, 2012 May.
Article in English | MEDLINE | ID: mdl-22783376

ABSTRACT

After DNA damage, p53 is accumulated in the nucleus and transactivates downstream genes and induces apoptosis. There are two pathways in p53-dependent apoptosis, the transactivation-dependent and -independent pathway. In this study, we constructed p53-inducible glioblastoma cell lines and analyzed them for the induction of apoptosis and transactivation of p53-downstream genes after the nuclear or cytoplasmic expression of p53. To sequester p53 in the cytoplasm, we used p53 mutant with arginine to glycine substitution at residue 306 (R306G). Wild-type p53 retained the ability to arrest the cell cycle, and a p53 mutant with serine to phenylalanine substitution at residue 121 (S121F), which has a strong ability to induce apoptosis, retained this ability even when both the wild-type and p53 and S121F mutant were exclusively sequestered from the nucleus into the cytoplasm. Notably, cytoplasmically sequestered wild-type p53 and S121F mutant transactivated the downstream genes with distinct expression profiles, and the strong apoptotic ability of S121F was not associated with its transactivation activity. These results underscore the existence of transactivation-independent apoptosis and cytoplasmic function of p53.

9.
Cancer Sci ; 100(5): 956-60, 2009 May.
Article in English | MEDLINE | ID: mdl-19445025

ABSTRACT

Curcumin (diferuloylmethane) has chemopreventive and chemotherapeutic potentials against various types of cancers. We have developed a series of curcumin analogs to improve its low bioavailability by enhancing its potentials. The newly synthesized analog GO-Y030 [(1E, 4E)-1,5-bis-(3,5(-bismethoxymethoxyphenyl) penta-1,4-dien-3-one] showed a 30-fold greater growth suppression in vitro via similar molecular mechanisms to curcumin. The availability of this analog was examined by using a mouse model harboring the germ-line mutation of Apc, Apc(580D/+), in vivo. Apc(580D/+) mice had a very limited survival time with an intestinal obstruction due to polyposis. The average tumor number in mice fed GO-Y030 was reduced to 61.2% of those that were fed the basal diet (P < 0.05). Compared with Apc(580D/+) mice fed the basal diet (median survival time = 166.5 days), a significantly prolonged lifespan (213 days) was observed in Apc(580D/+) mice fed GO-Y030. The chemopreventive effect with GO-Y030 was improved, compared with curcumin (191 days). The survival benefit corresponded to the diminished intestinal tumor incidence in Apc(580D/+) mice fed GO-Y030. No adverse reactions were observed, judging from body weight or biochemical data concerning liver and renal damage. Degradation of accumulated beta-catenin with curcumin is one of the major mechanisms of chemoprevention in colorectal carcinogenesis. It was demonstrated that the number of beta-catenin-positive adenoma cells in Apc(580D/+) mice fed GO-Y030 was reduced.


Subject(s)
Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Cell Transformation, Neoplastic/pathology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/prevention & control , Curcumin/chemical synthesis , Curcumin/pharmacology , Ketones/chemical synthesis , Ketones/pharmacology , Adenoma/metabolism , Adenoma/pathology , Animals , Benzene Derivatives/chemistry , Cell Transformation, Neoplastic/metabolism , Colorectal Neoplasms/metabolism , Curcumin/chemistry , Disease Models, Animal , Genetic Predisposition to Disease , Ketones/chemistry , Mice , Molecular Structure , Survival Rate , beta Catenin/metabolism
10.
Proc Natl Acad Sci U S A ; 104(46): 18199-204, 2007 Nov 13.
Article in English | MEDLINE | ID: mdl-17989230

ABSTRACT

A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line19-Apc(580D/+)) showed a remarkably reduced incidence of intestinal adenomas (<5% compared with other lines). Extensive genetic analysis identified a deletion in the alpha-catenin (Ctnna1) gene as the cause of this suppression. Notably, the suppression only occurred when the Ctnna1 deletion was in cis-configuration with the Apc580D mutation. In all adenomas generated in line19-Apc(580D/+), somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of alpha-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc(580D/+), suggesting that alpha-catenin plays an essential role in the initiation of intestinal adenomas. Although accumulating evidence obtained from human colon tumors with invasive or metastatic potential has established a tumor-suppressive role for alpha-catenin in late-stage tumorigenesis, the role of alpha-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of beta-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for alpha-catenin. Thus, alpha-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.


Subject(s)
Adenoma/pathology , Intestinal Neoplasms/pathology , alpha Catenin/physiology , Adenoma/genetics , Animals , Base Sequence , DNA Primers , Genes, APC , Intestinal Neoplasms/genetics , Mice , Phenotype , alpha Catenin/genetics
11.
Gan To Kagaku Ryoho ; 34(8): 1227-31, 2007 Aug.
Article in Japanese | MEDLINE | ID: mdl-17687203

ABSTRACT

Cancer of unknown primary site (CUP) is not a rare entity and accounts for 3-5% of all malignant neoplasias. CUPs are diagnosed with metastatic lesion so they are all in the advanced stage. Systemic chemotherapy is applied in many cases, but the ideal therapeutic strategy has not yet been determined. CUP shows much histological and therapeutic heterogeneity. Histologically, half of CUPs are adenocarcinoma and the rest are undifferentiated carcinomas. We analyzed the clinical and therapeutic characteristics 22 cases of CUP patients. Most CUP patients are found from lymph node swelling. There is no significant tendency as to the site of lymph node metastasis. Bone metastases are frequently encountered. It seems undifferentiated carcinomas are more responsive to chemotherapy. Chemo-sensitive patients are likely to have a longer life expectancy. In our experience all of the chemo-responsive cases are treated with platinum-based chemotherapy. Today several platinum-based combination chemotherapies are reported, but there is no large-scale randomized study. Because of its variety, individualized therapy may be ideal for CUP.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymph Nodes/pathology , Neoplasms, Unknown Primary/drug therapy , Neoplasms, Unknown Primary/mortality , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Bone Neoplasms/secondary , Carboplatin/administration & dosage , Combined Modality Therapy , Drug Administration Schedule , Etoposide/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasms, Unknown Primary/pathology , Paclitaxel/administration & dosage , Prognosis , Survival Rate
12.
Int J Cancer ; 121(3): 559-66, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17417775

ABSTRACT

Second-site suppressor (SSS) mutations in p53 found by random mutagenesis have shown to restore the inactivated function of some tumor-derived p53. To screen novel SSS mutations against common mutant p53s, intragenic second-site (SS) mutations were introduced into mutant p53 cDNA in a comprehensive manner by using a p53 missense mutation library. The resulting mutant p53s with background and SS mutations were assayed for their ability to restore the p53 transactivation function in both yeast and human cell systems. We identified 12 novel SSS mutations including H178Y against a common mutation G245S. Surprisingly, the G245S phenotype is rescued when coexpressed with p53 bearing the H178Y mutation. This result indicated that there is a possibility that intragenic suppressor mutations might restore the protein function in an intermolecular manner. The intermolecular mechanism may lead to novel strategies for restoring inactivated p53 function and tumor suppression in cancer treatment.


Subject(s)
Genes, p53 , Apoptosis , Cell Line, Tumor , Computer Simulation , DNA Mutational Analysis , Humans , Saccharomyces cerevisiae/genetics , Suppression, Genetic , Transcriptional Activation , Transfection
13.
Int J Clin Oncol ; 11(6): 454-60, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17180514

ABSTRACT

BACKGROUND: Definitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation. METHODS: Nedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. RESULTS: Twelve patients were enrolled. At a docetaxel dose of 30 mg/m(2) and a nedaplatin dose of 80 mg/m(2), one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80 mg/m(2), respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission. CONCLUSION: The recommended doses of docetaxel and nedaplatin were 30 and 80 mg/m(2), respectively. This combination could be a potential second-line treatment for this target population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Drug Resistance, Neoplasm , Esophageal Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/radiotherapy , Cisplatin/administration & dosage , Docetaxel , Dose-Response Relationship, Drug , Esophageal Neoplasms/pathology , Esophageal Neoplasms/radiotherapy , Female , Fluorouracil , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/radiotherapy , Organoplatinum Compounds/administration & dosage , Remission Induction , Salvage Therapy , Taxoids/administration & dosage
14.
Mol Cancer Ther ; 5(10): 2563-71, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17041101

ABSTRACT

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of beta-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers.


Subject(s)
Antineoplastic Agents/chemical synthesis , Curcumin/analogs & derivatives , Curcumin/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Benzene Derivatives , Caspase 3/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Curcumin/pharmacology , Drug Screening Assays, Antitumor , Gene Expression Profiling , Humans , Ketones , Structure-Activity Relationship
15.
Gan To Kagaku Ryoho ; 33(7): 969-72, 2006 Jul.
Article in Japanese | MEDLINE | ID: mdl-16835489

ABSTRACT

A 44-year-old man had a tumor in the lower thoracic esophagus at a health check, and was initially diagnosed as an undifferentiated carcinoma of the esophagus by the esophago-gastric endoscope. Although curative chemoradiotherapy was scheduled after the diagnosis, the interim evaluation revealed that the tumor was malignant melanoma of the esophagus with right renal metastasis. Since then, CVD (cisplatin, vindesine and dacarbazine) therapy, palliative radiotherapy and DAC-Tam (dacarbazine, nimustine, cisplatin and tamoxifen) therapy were carried out, but all of them proved ineffective, and multiple newly metastatic lesions appeared in liver and lymph nodes. Oral intake was impossible because of progressing stricture of the esophagus. As a fourth-line therapy, weekly paclitaxel therapy was started, and his oral intake was improved after the second course. He received the therapy as an outpatient for four months. After the third course, tumor lesions were evaluated as a partial response by CT. Consequently, five courses of the therapy were performed with modest adverse effects. Weekly paclitaxel therapy was reasonably safe as reported in other reports and considered to be a promising regimen for malignant melanoma of the esophagus.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Esophageal Neoplasms/drug therapy , Melanoma/drug therapy , Paclitaxel/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Drug Administration Schedule , Esophageal Neoplasms/pathology , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/radiotherapy , Kidney Neoplasms/secondary , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Liver Neoplasms/secondary , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Melanoma/secondary , Quality of Life
16.
Gan To Kagaku Ryoho ; 32(7): 991-5, 2005 Jul.
Article in Japanese | MEDLINE | ID: mdl-16044961

ABSTRACT

The aim of this study was to evaluate the efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (I-LV) in 50 patients with advanced or recurrent colorectal cancer in our institute. The dose of 5-FU was 600 mg/m2 and the dose of l-LV was 250 mg/m2. Objective response were 36.8% of patients who had administration of full-dose and 14.8% of patients who had the administration of reduced dose or prolonged interval. No significant difference was observed in clinical benefit rates between patients administrated in full-dose and patients in reduced dose or prolonged interval. Median survival time (MST) of patients in reduced dose or prolonged interval is longer than patients in full-dose. These data suggest that 5-FU/l-LV can be given in the outpatient and yields improved prognosis and minimal adverse reactions even in patients in reduced dose or prolonged interval.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Diarrhea/chemically induced , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Leukopenia/chemically induced , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Lymphatic Metastasis , Male , Middle Aged , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Retrospective Studies , Survival Rate
17.
Cancer Res ; 65(6): 2108-14, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15781620

ABSTRACT

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism.


Subject(s)
Apoptosis/genetics , Transcriptional Activation/genetics , Tumor Suppressor Protein p53/genetics , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Growth Processes/genetics , Humans , Mutation , Osteosarcoma/genetics , Osteosarcoma/pathology
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