Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and alpha-smooth muscle actin (alpha-SMA) were conducted with control group. The immunohistochemical stains for CD31 and alpha-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.
Actins/metabolism ; Antigens, CD31/metabolism ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Camptothecin/*analogs & derivatives/therapeutic use ; Chemotherapy, Adjuvant ; Colonic Neoplasms/*drug therapy ; Fluorouracil/therapeutic use ; Humans ; Hypertension, Portal/etiology ; Immunohistochemistry ; Leucovorin/therapeutic use ; Liver Cirrhosis/*diagnosis/etiology/pathology ; Liver Neoplasms/secondary/surgery ; Male ; Middle Aged ; Organoplatinum Compounds/*administration & dosage/adverse effects/therapeutic use ; Splenomegaly/*diagnosis/etiology ; Thrombocytopenia/etiology ; Tomography, X-Ray Computed

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.
Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.
Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

OBJECTIVETo analyze the clinicopathologic factors related to recurrence and metastasis of stage II or III colon cancer after radical resection.

METHODSThe clinical and pathological data of 628 patients with stage II or III colon cancer after radical resection from Jan. 2005 to Dec. 2008 in our hospital were retrospectively reviewed and analyzed.

RESULTSThe overall recurrence and metastasis rate was 28.5% (179/628). The 5-year disease-free survival (DFS) rate was 70.3% and 5-year overall survival (OS) rate was 78.5%. Univariate analysis showed that age, smoking intensity, depth of tumor invasion, lymph node metastasis, TNM stage, gross classification, histological differentiation, blood vessel tumor embolus, tumor gross pathology, multiple primary tumors, preoperative and postoperative serum concentration of CEA and CA19-9, and the regimen of adjuvant chemotherapy were correlated to recurrence and metastasis of colon cancer after radical resection. Multivariate analysis showed that regional lymph node metastasis, TNM stage, the regimen of postoperative adjuvant chemotherapy, and preoperative serum concentration of CEA and CA19-9 were independent factors affecting the prognosis of colon cancer patients.

CONCLUSIONRegional lymph node metastasis, TNM stage, elevated preoperative serum concentration of CEA and CA19-9, the regimen of postoperative adjuvant chemotherapy with single fluorouracil type drug are independent risk factors of recurrence and metastasis in patients with stage II-III colon cancer after radical resection.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens, Tumor-Associated, Carbohydrate ; metabolism ; Carcinoembryonic Antigen ; metabolism ; Chemotherapy, Adjuvant ; Colectomy ; Colonic Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Proportional Hazards Models ; Retrospective Studies ; Survival Rate ; Young Adult

The human colorectal carcinoma-associated GA733 antigen epithelial cell adhesion molecule (EpCAM) was initially described as a cell surface protein selectively expressed in some myeloid cancers. Gangliosides are sialic acid-containing glycosphingolipids involved in inflammation and oncogenesis. We have demonstrated that treatment with anti-EpCAM mAb and RAW264.7 cells significant inhibited the cell growth in SW620 cancer cells, but neither anti-EpCAM mAb nor RAW264.7 cells alone induced cytotoxicity. The relationship between ganglioside expression and the anti-cancer effects of anti-EpCAM mAb and RAW264.7 was investigated by high-performance thin-layer chromatography. The results demonstrated that expression of GM1 and GD1a significantly increased in the ability of anti-EpCAM to inhibit cell growth in SW620 cells. Anti-EpCAM mAb treatment increased the expression of anti-apoptotic proteins such as Bcl-2, but the expression of pro-apoptotic proteins Bax, TNF-alpha, caspase-3, cleaved caspase-3, and cleaved caspase-8 were unaltered. We observed that anti-EpCAM mAb significantly inhibited the growth of colon tumors, as determined by a decrease in tumor volume and weight. The expression of anti-apoptotic protein was inhibited by treatment with anti-EpCAM mAb, whereas the expression of pro-apoptotic proteins was increased. These results suggest that GD1a and GM1 were closely related to anticancer effects of anti-EpCAM mAb. In light of these results, further clinical investigation should be conducted on anti-EpCAM mAb to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer.
Animals ; Antibodies, Monoclonal/*immunology/*therapeutic use ; Antigens, Neoplasm/*immunology ; Apoptosis/drug effects ; Cell Adhesion Molecules/*immunology ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colon/drug effects/immunology/metabolism/pathology ; Colonic Neoplasms/*drug therapy/genetics/*immunology/pathology ; Gangliosides/genetics/*immunology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice ; Mice, Inbred BALB C

Dendritic cells (DCs) play a role in natural killer (NK) cell activation, while NK cells are also able to activate and mature DCs. Toll-like receptors (TLRs) on the surface of DCs and NK cells induce the maturation and activation of these cells when engaged with their cognate ligand. We investigated to generate potent DCs by maturation with NK cells in the presence of TLR agonist in vitro and tested the efficacy of these DC vaccinations in mouse colon cancer model. The optimal ratios of DCs versus NK cells were 1:1 to 1:2. Immature DCs were mature with NK cells in the presence of lipopolysaccharide, which is TLR4 agonist, and further addition of IL-2 induced phenotypically and functionally mature bone marrow-derived DCs. These potent DCs exhibited not only high expression of several costimulatory molecules and high production of IL-12p40 and IL-12p70, but also high allogeneic T cells stimulatory capacity, and the induction of the high activities to generate tumor-specific CTLs. Consistently, vaccination with these DCs efficiently inhibited CT-26 tumor growth in mouse colon cancer model when compared to other vaccination strategies. Interestingly, combination therapy of these DC-based vaccines and with low-dose cyclophosphamide showed dramatic inhibition effects of tumor growth. These results suggest that the DCs maturated with NK cells in the presence of TLR agonist are potent inducer of antitumor immune responses in mouse model and may provide a new source of DC-based vaccines for the development of immunotherapy against colon cancer.
Animals ; Cancer Vaccines/immunology/metabolism ; Carcinoma/immunology/pathology/*therapy ; Cell Line, Tumor ; Cells, Cultured ; Colonic Neoplasms/immunology/pathology/*therapy ; Dendritic Cells/*drug effects/*immunology/transplantation ; Female ; Immunotherapy, Adoptive/*methods ; Killer Cells, Natural/*immunology/physiology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred BALB C ; Toll-Like Receptor 4/agonists ; Toll-Like Receptors/*agonists

BACKGROUND AND OBJECTIVEColon cancer is one of the most common malignant tumors, and its pathogenesis is not fully understood. Transcriptional silencing by DNA methylation is believed to be an important mechanism of carcinogenesis. E-cadherin can suppress tumor cell invasion and metastasis, and is considered as an invasion/metastasis suppressor gene. Inactivation of E-cadherin gene often occurs in colon carcinoma. This study was to investigate the correlation between E-cadherin gene expression and the methylation status of E-cadherin 5' CpG islands in human colon carcinoma cell line HT-29, and to explore the mechanism of carcinogenesis of colon cancer.

METHODSImmunocytochemical dicho-step method and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of E-cadherin protein and mRNA in HT-29 cells after 5-Aza-CdR treatment; methylation specific PCR was used to analyze the methylation status at promoter of E-cadherin gene.

RESULTSThe expression of E-cadherin gene could be restored by 5-Aza-CdR treatment, immunocytochemical staining showed the positive expression ratio of E-cadherin increased from (21+/-7)% (1 micromol/L) to (39+/-13)% (5 micromol/L); E-cadherin genes were methylated and not expressed in HT-29 cells in the colon carcinoma.

CONCLUSIONSE-cadherin methylation plays an important role in the carcinogenesis of colon carcinoma cells and can re-express after the treatment with 5-Aza-CdR.

Antimetabolites, Antineoplastic ; pharmacology ; Azacitidine ; analogs & derivatives ; pharmacology ; Cadherins ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Colonic Neoplasms ; drug therapy ; DNA Methylation ; Gene Expression Regulation, Neoplastic ; HT29 Cells ; metabolism ; pathology ; Humans ; RNA, Messenger ; metabolism

OBJECTIVETo study the efficacy and safety of cetuximab combined with chemotherapy for patients with advanced colorectal cancer (ACRC) and unclear K-ras status.

METHODSClinical data of 102 ACRC patients, treated by cetuximab combined with chemotherapy in Sun Yat-sen Cancer Center from March 2005 to December 2008, were collected. The cumulative survival rate, objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) of the cases were calculated. The difference in ORR, DCR, PFS and oval survival (OS) between the regimens used as first-line and non-first-line treatment, and between the regimens including oxaliplatin and irinotecan were compared.

RESULTSThe overall ORR of cetuximab plus chemotherapy was 43.1%, DCR 73.5%, median PFS 4.0 months, OS 28.5 months, and the 1-year, 3-year, and 5-year survival rate was 89.2%, 50.9% and 27.5%, respectively. The differences in ORR (50.0% vs. 40.0%, P = 0.344), DCR (78.1% vs. 72.9%, P = 0.571) and OS (51.0 months vs. 35.0 months, P = 0.396) between the regimens as first line and as non-first line treatment were not statistically significant. However, the PFS of the regimen as first-line was longer than that as non-first-line treatment (PFS 5.5 months vs. 3.0 months, P = 0.001). The differences in ORR (54.2% vs. 40.0%, P = 0.223), DCR (79.2% vs. 74.7%, P = 0.654), PFS (5.0 months vs. 3.0 months, P = 0.726) and OS (36.0 months vs. 40.0 months, P = 0.759) between cetuximab plus oxliplatin and irinotecan were not statistically significant. The most common side effects of cetuximab plus chemotherapy were acneiform eruption (80.4%, grade 3-4 in 9.8%), neutropenia (66.7%, grade 3-4 in 18.6%), and diarrhea (19.6%, grade 3-4 in 5.9%). No treatment-related death was recorded.

CONCLUSIONPatients with advanced colorectal cancer and unclear K-ras treated by cetuximab combined with chemotherapy have good ORR and OS, and the regimen is safe with less adverse events for them. There is no significant difference between the efficacies of regimens as first line and as non-first line treatment, and between cetuximab plus oxliplatin and cetuximab plus irinotecan regimens.

Acneiform Eruptions ; chemically induced ; Adenocarcinoma ; drug therapy ; metabolism ; pathology ; secondary ; surgery ; Adult ; Antibodies, Monoclonal ; adverse effects ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Camptothecin ; administration & dosage ; analogs & derivatives ; Cetuximab ; Colonic Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Diarrhea ; chemically induced ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; drug therapy ; secondary ; Lung Neoplasms ; drug therapy ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Neutropenia ; chemically induced ; Organoplatinum Compounds ; administration & dosage ; Rectal Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Remission Induction ; Survival Rate ; ras Proteins ; metabolism

Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as well a possible anti-tumor agent. It inhibits proliferation of coloretal cancer cells in vitro and in vivo. In this study, its ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK1, IL6R and phosphorylated STAT3 were all reduced by triptolide treatment. Triptolide prohibited Rac1 activity and blocked cyclin D1 and CDK4 expression, leading to G1 arrest. Triptolide interrupted the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation. This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development.
Animals ; Cell Transformation, Neoplastic/*drug effects ; Colitis/complications ; Colonic Neoplasms/chemically induced/*drug therapy/metabolism/pathology ; Dextran Sulfate/toxicity ; Dimethylhydrazines/toxicity ; Diterpenes/*administration & dosage ; Epoxy Compounds/administration & dosage ; Humans ; Interleukin-6/biosynthesis ; Janus Kinases/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred ICR ; Mice, Nude ; Neoplasm Transplantation ; Phenanthrenes/*administration & dosage ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; Tumor Burden/drug effects ; rac1 GTP-Binding Protein/*biosynthesis

Use of adenoviruses as vehicle for gene therapy requires that target cells express appropriate receptors such as coxsakievirus and adenovirus receptor (CAR). We show here that CAR-deficiency in cancer cells, that limits adenoviral gene delivery, can be overcome by using adenovirus complexed with the liposome, Ad-PEGPE [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-ethylene glycol)-2000]. We first confirmed that CT-26 mouse colon cancer cells are deficient in CAR by RT-PCR, and then showed that CT-26 cells infected with Ad-GFP/PEGPE exhibited highly enhanced expression of green fluorescent protein (GFP), compared with those infected with Ad-GFP. GFP expression depends on the dose of liposome and adenovirus. Luciferase expression in livers treated with Ad-luc/PEGPE was about 1,000-fold less than those infected with Ad-luc. In a liver metastasis mouse tumor model developed by intrasplenic injection of CT-26 cells, luciferase expression following i.v. injection of Ad-luc/PEGPE was significantly higher in tumors than in adjacent non-neoplastic liver. Following systemic administration of Ad-GFP/PEGPE, GFP expression increased in tumors more than in adjacent liver while the reverse was true following administration of Ad-GFP. In the latter case, GFP expression was higher in liver than in tumors. This study demonstrates that systemic delivery of PEGPE-adenovirus complex is an effective tool of adenoviral delivery as it overcomes limitation due to CAR deficiency of target cells while reducing hepatic uptake and enhancing adenoviral gene expression in tumors.
*Adenoviridae/genetics/metabolism ; Animals ; Colonic Neoplasms/*genetics/metabolism/pathology/*therapy ; Dose-Response Relationship, Drug ; Gene Therapy ; *Gene Transfer Techniques ; Genetic Vectors ; Green Fluorescent Proteins/genetics ; Liposomes/administration & dosage/chemistry/pharmacokinetics/*therapeutic use ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; NIH 3T3 Cells ; Phosphatidylethanolamines/administration & dosage ; Polyethylene Glycols/administration & dosage ; Receptors, Cytoplasmic and Nuclear/deficiency/genetics ; Receptors, Virus/deficiency/*genetics ; Transcription Factors/deficiency/genetics ; Tumor Cells, Cultured