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Glutathione S-transferase (GST) exhibits antidotal effects on numerous drugs, including platinum-based antineoplastic drugs. Furthermore, GST Pi 1 (GSTP1) polymorphism is associated with peripheral neuropathy. In the present study, it was determined whether GSTP1 can predict adverse events associated with platinum-based antitumor agent-induced peripheral neuropathy among Japanese patients. The subjects included 122 patients, among whom 105 patients had colorectal, 16 had gastric, and one patient had pancreatic cancer. It was indicated that wild type (AA) GSTP1 was expressed in 99 patients (81.1%), whereas heterozygous (AG) and homozygous (GG) GSTP1 polymorphisms were present in 22 (18.0%) and 1 (0.8%) patients, respectively. Among patients with colorectal cancer, the expression of homozygous GSTP1 was observed in 88 patients (83.8%), whereas that of heterozygous GSTP1 was observed in 17 patients (16.2%). Peripheral neuropathy of grade ≥3 occurred in 10 patients (9.5%) receiving mFOLFOX therapy (a biweekly cycle consisting of a 2-h infusion of 85 mg/m2 oxaliplatin and 200 mg/m2 leucovorin followed by a bolus administration of 400 mg/m2 5-fluorouracil and a continuous 48-h infusion of 2,400 mg/m2 5-fluorouracil) for colorectal cancer, which included 6 patients with the AA allele (6.8%) and 4 patients with the AG allele (23.5%). The number of peripheral neuropathy cases of grade ≥3 was increased among patients with the AG allele, compared with patients with the AA allele (P=0.032). In patients with gastric cancer, the AA and AG types of GSTP1 were expressed in 11 (68.8%) and 5 (31.2%) patients, respectively. Cisplatin, administered to patients with gastric cancer, did not induce peripheral neuropathy. The aforementioned indicated that GSTP1 genetic polymorphism is associated with peripheral neuropathy induced by oxaliplatin treatment for colorectal cancer, and therefore serves as a predictive marker. Furthermore, early dose reduction or drug withdrawal should be implemented depending on the severity of peripheral neuropathy as a potential method for reducing the number of patients discontinuing the drug, due to adverse events involving peripheral neuropathy.

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A 70-year-old female underwent follow-up colonoscopy after colonic polypectomy. The colonoscopy revealed the presence of a 7-mm submucosal tumor in the sigmoid colon. The tumor surface was smooth and covered with normal mucosa. It was diagnosed as a submucosal tumor, and polypectomy was performed. Histopathological examination of the resected specimen revealed moderately to poorly differentiated adenocarcinoma measuring 2 × 5 × 3 mm with marked peritumoral lymphocytic infiltration and lymphoid follicle formation. It was diagnosed as carcinoma with lymphoid stroma (lymphoepithelioma-like carcinoma), SM (1,800 µm), ly2, v0, budding; grade 1. We confirmed the indication for noncurative additional surgical resection and performed laparoscopic sigmoid colectomy. No metastases were observed in the dissected lymph nodes.

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PURPOSE: For hepatic tumors that cannot be identified on routine ultrasonography (US), we marked the target area using real-time virtual sonography (RVS) with indocyanine green (ICG)-ethanol (1:100) during surgery, and performed hepatic resection while observing the fluorescence. EXPERIMENT: An ICG-ethanol mixture locally injected into mouse liver was retained in the same area for more than 4 h. The same mixture locally injected into pig liver at a depth of 3 cm could be observed using an infrared camera. CASE: An ICG-ethanol mixture (500 µl) was locally injected under RVS guidance into a metastatic hepatic tumor that was visible only on magnetic resonance imaging (MRI), and hepatic resection was performed while Photodynamic Eye (PDE) images were being observed. The metastatic lesion (3 mm in diameter in a pathological specimen) could be successfully resected. CONCLUSION: This method was useful for resecting US-invisible hepatic tumors.

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Our case was a 65-year-old male, with the chief complaints of diarrhea and abdominal distention. Three years earlier, the patient had undergone transcatheter arterial embolization and radiofrequency treatment based on a diagnosis of hepatocellular carcinoma due to hepatitis B by another doctor. In October 2007, the patient developed diarrhea and increased abdominal distention. In December, CT examination conducted by the previous doctor revealed a 20-cm tumor within the pelvis. The patient was diagnosed with sigmoid colon cancer based on barium enema examination using gastrografin, and was introduced to our hospital for treatment. He was diagnosed with low-differentiated carcinoma by biopsy of the colon during endoscopy and underwent sigmoidectomy based on a diagnosis of sigmoid colon cancer. The tumor had infiltrated the bladder, and a tumorectomy was conducted through partially combined resection. The tumor was a huge lesion occupying the inside of the lumen, and histopathological findings revealed that the tumor, the main part of which lay beneath the mucous membrane, had a transitional image composed of both spindle-shaped atypical cells and sarcomatoid shape. The result of immunostaining was CK7(+), CK20(-), AFP(-), and the patient was diagnosed as having carcinosarcoma of the colon. Carcinosarcoma of the colon is a malignant tumor with poor prognosis, and the mean survival period in past reports was approximately 6 months. The patient was treated with FOLFIRI+Bevacizumab therapy according to chemotherapy for colon cancer, but he was refractory to the therapy.

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The appearance of neuropathy that is a harmful phenomenon of Oxaliplatin, the key drug of FOLFOX, is strongly concerned in individual pharmacological variability. Further more, the frequency of neuropathy appearance was reported to be 74.3%. In this study, we examined a correlation between GSTP1(342G>A)and ABCC2(1249G>A)of genetic polymorphism. The mean FOLFOX drug dosage was 8.6 times. The first, second and third line treatment was 36, 32 and 9 cases, respectively. Then, the 50% survival duration of each treatment was 801, 360 and 328 days, respectively. These results showed that the first line treatment was highly lengthened the survival duration compared with the second and third line treatment. The response rate was 24.2%, and the lesion control rate was 74.2%. However, some of the toxicities we have seen included the followings: acute nervousness; 74.3%, chronic nervousness; 67.1%, allergic reaction; 26.3%, blood toxicity development; 68.4% and digestive organ symptom; 30.3%. The reasons for change in treatment were due to PD 41.6% and toxicity 51.4%, and that 45.9% of the latter was caused by neuropathy. As for a successful rate of the treatment, the wild type and hetero type of GSTP1, a metabolism enzyme of Oxaliplatin, were 53.3% and 41.7%, respectively. As for a correlation between the dose frequency and GSTP1 SNP was p=0.57, and that a correlation between the dose frequency and ABCC2 was p=0.11. We confirmed that a curative effect of the first line treatment of FOLFOX was high, and that the cases in which the treatment was terminated due to neuropathy prolonged the survival duration. It is important to control the appearance of toxicity in order to continue the treatment. The SNP analysis of the ABCC2 protein may become an index of the treatment for continuation.

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OBJECTIVE: Oxaliplatin, a key part of the standard regimen for colorectal cancer in Western countries, has become available in Japan. In a hemodialysis patient with cecal cancer, we investigated the efficacy, safety, pharmacokinetics, and dialysability of oxaliplatin. METHODS: A 65-year-old man who had cecal cancer was treated with oxaliplatin (40 mg/m(2)) and l-leucovorin(l-LV) (200 mg/m(2)), which were administered simultaneously over 120 min via the side and main arms of a Y-tube, respectively. Then 5-FU (400 mg/m(2)) was administered rapidly via the side tube, followed by 5-FU (2,000 mg/m(2)) over 46 hours via the main tube. The patient had chronic renal failure due to diabetic nephropathy and hemodialysis was performed 3 times a week. Blood samples were collected from the dialyzer before and after each hemodialysis session to examine platinum clearance. RESULTS: The patient received 3 courses of oxaliplatin before he died of cancer. During hemodialysis, the platinum level fell from 0.32 µg/mL to 0.15 µg/mL. CONCLUSION: Since patients with renal failure have various associated disorders and oxaliplatin has a long half-life, it is necessary to obtain more pharmacokinetic data to investigate its accumulation and dialysability during long-term treatment. Such data will assist in treating the rapidly increasing number of hemodialysis patients with colorectal cancer.

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The patient was a 70-year-old man who in November 2000 had undergone pancreatoduodenectomy for a diagnosis of lower bile duct cancer by his previous physician. Left cervical and intra-abdominal lymph node enlargement were detected at 3 years 4 months postoperatively, and a biopsy resulted in a histopathological diagnosis of metastasis by bile duct cancer. Intravenous S-1,120 mg/body, on days 1-14, and CDDP, 20 mg/body, on day 14 was started in April 2004. It was conducted safely on an outpatient basis with no adverse events, and it was possible to achieve survival for 29 months. S-1/CDDP therapy seemed to be capable of serving as a useful treatment for gallbladder and bile duct cancer in the future.

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The patient was a 44-year-old male in whom low anterior resection of the rectum, partial pneumonectomy, and liver biopsy were performed because of suspicion of synchronous liver and pulmonary metastases of rectal cancer which caused familial adenomatous polyposis. Because anticancer drug sensitivity testing by the HDRA method performed on tissue collected from the cancer immediately postoperatively revealed sensitivity to 5-FU and CPT-11, and measurement of nucleic acid metabolizing enzymes showed a high level of DPD, a 5-FU metabolizing enzyme, combination therapy with TS-1 and CPT-11 was started. TS-1, 120 mg/body, was administered on 14 consecutive days followed by a 7-day rest period, and CPT-11, 120 mg/body, was administered on day 1 and day 8. One cycle was defined as 3 weeks,and cycles were repeated. Grade 2 diarrhea occurred, but the CPT-11 dose was reduced to 100 mg/body, and treatment was continued. CR was achieved when the 4th course had been completed. Thoracic and abdominal CT was performed after 4 courses, but no recurrent foci were detected in the residual lung tissue, and all of the metastatic liver foci had resolved. To date 6 courses have been completed, and no relapses have been detected by thoracic CT. We report a case in which it was possible to predict efficacy as a result of treatment based on anticancer drug sensitivity testing and measurements of nucleic acid metabolizing enzymes.

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BACKGROUND: As a mode of colorectal cancer recurrence, liver metastasis plays an important role. One of the factors reported to predict liver metastasis is the detection of trace amounts of tumor cells in the blood. For this purpose, cancer cell-induced cytokeratins (CKs) are generally identified, using the reverse transcriptase-polymerase chain reaction (RT-PCR). In the present study, we aimed to detect trace amounts of tumor cells, based on CK20, in the circulating venous blood, and we examined pathological factors, liver metastasis, and prognosis. METHODS: The subjects were 57 colorectal cancer patients who had undergone operation. We examined the cancer-induced marker (CK20) in circulating venous blood by RT-PCR and investigated the relationships between this marker, pathological factors, and prognosis. RESULTS: Detection ratio of CK20 mRNA was 42.1%, and CK20 was significantly correlated with the pathological factor of lymph node metastasis (P = 0.037). The 5-year survival rate for CK20-positive patients was 62.5% and that for the CK20-negative patients was 87.5%; there was a significant difference (P = 0.048) between the two groups. Recurrence was recognized in six patients; two were positive for CK20 and four were negative for CK20. CONCLUSIONS: These findings indicate that CK20 is strongly related to lymph node metastasis and prognosis, suggesting its usefulness for the diagnosis of colorectal cancer recurrence. However, CK20 did not predict liver metastasis.

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Synchronous or metachronous liver metastasis occurs in approximately 15% of colorectal cancer patients and is an important negative prognostic factor. We therefore need an effective therapy to prevent metastasis. It has become apparent that cyclooxygenase (COX)-2 plays an important role in cancer growth, invasion and metastasis and that there is potential for chemoprevention via inhibition of these processes. We injected colon 26, a colorectal cancer cell line, in CDF1 mouse spleen and, from the following day, two kinds of COX-2 inhibitor (etodolac and nimesulide) were administered orally. Two weeks later, the animals were sacrificed, the liver was excised, and we counted the number of metastatic nodules on the liver surface. In addition, COX-2 mRNA, matrix metalloproteinase (MMP)-9 mRNA, and tissue inhibitor of MMP (TIMP)-1 mRNA of cancer tissue were measured by means of real-time RT-PCR. The number of metastatic nodules on the liver surface was significantly lower in the etodolac-treated group than in controls (p=0.001), but no significant difference was noted in the nimesulide-treated group. The expression of COX-2 mRNA was also significantly lower in the etodolac-treated group than in controls (p=0.04), but not in the nimesulide-treated group. In addition, the expression of MMP-9 mRNA was significantly lower in the etodolac group than in controls (p=0.02), but not in the nimesulide group. Among the groups, there were no significant differences in TIMP-1 mRNA. Expression of COX-2 mRNA and MMP-9 mRNA correlated significantly (r=0.78, p=0.001), but there was no correlation between either COX-2 mRNA and TIMP-1 mRNA expression or between MMP-9 mRNA and TIMP-1 mRNA expression. These findings indicate that the selective COX-2 inhibitor, etodolac, suppresses liver metastasis by reducing MMP-9 activity.

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We constructed a novel database of the proteome of DLD-1 colon cancer cells by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) of fluorescence-labeled proteins followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) analysis. The database consists of 258 functionally categorized proteins corresponding to 314 protein spots. The majority of the proteins are oxidoreductases, cytoskeletal proteins and nucleic acid binding proteins. Phosphatase treatment showed that 28% of the protein spots on the gel are phosphorylated, and mass spectrometric analysis identified 21 of them. Proteins of DLD-1 cells and of laser-microdissected colon cancer tissues showed similar distribution on 2D gels, suggesting the utility of our database for clinical proteomics.

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The combination of laser microdissection and two-dimensional gel electrophoresis (2-D PAGE) has been developed to perform proteomic analysis on specific populations of cells in cancer tissues. However, as conventional low sensitivity silver staining was used for spot detection, the microdissection required to obtain an adequate amount of protein for 2-D PAGE is laborious and only a restricted number of protein spots could be visualized. As a consequence, this technology was impractical for direct clinical applications and had a limited impact on cancer studies. To solve these problems, we developed an application in which fluorescent dyes label the proteins extracted from microdissected tissues prior to 2-D PAGE separation. In this application, a small amount of protein, less than 6.6 microg, was enough to generate a 2-D profile with approximately 1500 protein spots. This technique was applied to compare the proteome of normal intestinal epithelium with that of adenoma in Min mice. Thirty-seven protein spots reproducibly showed significant differences in intensities. Mass spectrometric analysis and Western blotting identified eight of them, including prohibitin, 14-3-3zeta, tropomyosin 3 and Hsp84. These results indicate that fluorescence labeling of proteins from microdissected tissues prior to 2-D PAGE is a powerful cancer proteomic study tool.

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Aberrant accumulation of beta-catenin protein because of mutation of either the beta-catenin or adenomatous polyposis coli gene plays an essential role in the development of colorectal carcinoma. We established previously a stable clone of the rat small intestinal epithelial cell line IEC6, which is capable of inducing stabilized beta-catenin protein lacking NH(2)-terminal glycogen synthase kinase-3beta phosphorylation site under a strict control of the tetracycline-regulatory system. This clone, IEC6-TetOFF-beta-catenin DeltaN89, shows in vitro polypoid growth on the removal of doxycycline and seems to be an appropriate model for analyzing the molecular mechanisms of early intestinal carcinogenesis. Of >2000 protein spots displayed by newly developed two-dimensional difference gel electrophoresis, 22 were found to be up- or down-regulated on the induction of stabilized beta-catenin. The majority of these proteins fell into two categories: (a) redox-status regulatory proteins and (b) cytoskeleton-associated proteins. Representatively, a key redox-status regulatory protein, manganese superoxide dismutase, up-regulated in IEC6 cells expressing stabilized beta-catenin protein, was overexpressed in adenoma and adenocarcinoma cells of familial adenomatous polyposis patients in parallel with the accumulation of beta-catenin. These results suggest that aberrant accumulation of beta-catenin might contribute to colorectal carcinogenesis by affecting redox status in the mitochondria of intestinal epithelial cells.

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Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor/lymphoid enhancer factor complex has been considered crucial for the initiation of intestinal tumorigenesis. The human multidrug resistance (MDR)1 (ABCB1) gene contains multiple beta-catenin-T-cell factor4-binding elements in its promoter and is one of the immediate targets of the complex. In the current study, we have further substantiated the biological involvement of MDR1 in intestinal tumorigenesis based on the following evidence: (a) aberrant induction of the Mdr1a (Abcb1a) gene product, P-glycoprotein, associated with nuclear accumulation of the beta-catenin protein, was observed even in nascent microscopic adenomas of Min mice; (b) Mdr1-deficient Min (Apc(Min/+)Mdr1a/b(-/-)) mice developed significantly fewer intestinal polyps than did Apc(Min/+)Mdr1a/b(+/+) mice; and (c) Inhibitors of P-glycoprotein, verapamil, and cyclosporin A had a suppressive effect on the in vitro polypoid growth of IEC6 expressing stabilized (DeltaN89) beta-catenin protein. Inhibitors of P-glycoprotein may be included in a novel class of chemopreventive agents against colorectal carcinogenesis.

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