Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this adjuvant three-arm multicenter trial, we studied whether modulating the standard 5-fluorouracil (5-FU) treatment with either folinic acid (FA) or interferon-alpha-2a (IFN-alpha) was superior to the recommended standard of adjuvant treatment in R0 resected colon cancer, 5-FU plus levamisole (LEV) for 12 months, in terms of toxicity and outcome. From July 1992 to October 1999, a total of 813 patients with resected colon cancer in stage II (T4N0M0; n = 63) or stage III (TxN1-3M0; n = 750) were randomized into three treatment groups and stratified according to N stage and participating centers (64 hospitals). The patients received a postoperative loading dose of 5-FU (450 mg/m2 on days 1 to 5 [arms A and C]) or 5-FU (450 mg/m2) plus FA (Rescuvolin, Medac, Hamburg, Germany, 200 mg/m2 on days 1 to 5 [arm B]). After completion of the first chemotherapy cycle, LEV was administered orally at a dosage of 150 mg per day on days 1 to 3, once every 2 weeks. After a 4-week chemotherapy-free interval, the treatment was continued weekly for 52 weeks. Treatment in one arm A ("standard") (n = 279) consisted of 5-FU intravenously (450 mg/m2 on day 1, once a week) plus LEV. 5-FU plus LEV was modulated in arm B (n = 283) with FA (200 mg/m2 on day 1, once a week) and in arm C (n = 251) with IFN-alpha at 6 million units three times a week repeated weekly. Treatment dosages were adjusted if toxic events above WHO grade 2 occurred. Patients were closely followed to determine recurrence and survival; the latter was calculated according to Kaplan-Meier analysis. Toxic events above WHO grade 2, mainly leukopenia, diarrhea, and nausea, occurred in 113 (14%) of 649 patients who had completed treatment in arms A (8.4%), B (13.5%), and C (31.7%). Discontinuance rates were as follows: 28% for all patients, 29% in arm A, 21% in arm B, and 34% in arm C. Overall relapse rates were 27% for all patients, 30% in arm A, 24% in arm B, and 28% in arm C. Relapses were local (8%), distant (78%), or combined (12%). Four-year overall survival rates in arms A, B, and C were 66.1%, 77.5%, and 66.2%, respectively. The 4-year survival rate in arm B was significantly higher compared to arm A (P <0.02, log-rank test) with arm A being equal to arm C. Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV for 12 months). IFN-alpha modulation of 5-FU (plus LEV) adds to the toxicity with no therapeutic benefit.
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PMID:Toxicity and effects of adjuvant therapy in colon cancer: results of the German prospective, controlled randomized multicenter trial FOGT-1. 1141 51

The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-alpha) can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-alpha-sensitive) or KM12L4 IFN(R) (IFN-alpha-resistant) cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c.) injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, or 7 times/week). Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF) or matrix metalloproteinase-9 (MMP-9) mRNA and protein occurred in mice given daily injections of IFN-alpha. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-alpha induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-alpha-2a depends on frequent administration of the optimal biologic dose.
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PMID:Suppression of angiogenesis and therapy of human colon cancer liver metastasis by systemic administration of interferon-alpha. 1142 Jul 51

The regulation of urokinase plasminogen activator receptor (uPAR) gene expression by interferon-alpha (IFN-alpha, or Intron A) and interferon-gamma (IFN-gamma) was studied in a HCT116 colon cancer cell line. uPAR mRNA levels were increased in a dose- and time-dependent manner in cells stimulated with IFN-alpha or IFN-gamma. uPAR protein levels reflected IFN-alpha and IFN-gamma induction of uPAR mRNA production. Cycloheximide, a protein synthesis inhibitor, also induced uPAR mRNA accumulation either alone or in combination with IFN-alpha or IFN-gamma, suggesting that the effect on uPAR mRNA levels activated by IFN-alpha or IFN-gamma does not require de novo protein synthesis. Both sodium butyrate and amiloride inhibited the uPAR mRNA levels induced by IFN-alpha or IFN-gamma. These results may provide useful information for the treatment of patients receiving IFN-alpha or IFN-gamma.
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PMID:Interferon-alpha (Intron A) upregulates urokinase-type plasminogen activator receptor gene expression. 1207 Jul 11

Endogenous interferon gamma (IFNgamma) promotes the host response to primary tumors, and IFNgamma-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNgamma receptors did not differ among the isogenic cell lines. IFNgamma stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNgamma.
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PMID:Oncogenic Ki-ras inhibits the expression of interferon-responsive genes through inhibition of STAT1 and STAT2 expression. 1297 32

The immunosuppressive cytokine IL-10 is associated with poor prognosis in colon cancer. Although macrophages are involved in antitumor defenses, production of IL-10 by tumor cells may permit malignant cells escape to cell-mediated immune defenses. To investigate interactions between macrophages and tumor cells in humans, we cultured macrophages isolated from patients and tested the effect of these macrophages on the production of IL-10 by several tumor cell lines. Macrophages were isolated from pleural effusions of patients with malignancy and from noncancer control patients. We demonstrated that culture supernatants of macrophages from both sources strongly stimulated IL-10 production by the three different human colon adenocarcinoma cell lines, Colo 205, Colo 320, and HT29. Recombinant IL-6, but not IL-10, TNF-alpha, and IFN-alpha, stimulated the secretion of IL-10 by colon tumor cells. mAbs against IL-6 and IL-6R prevented the effect of macrophage culture supernatants and of rIL-6, respectively, on the production of IL-10 by the three cell lines. Cocultures of macrophages and colon cancer cells showed that these tumor cells first stimulated macrophages to produce IL-6, which was then followed by IL-6-induced IL-10 production by colon cancer cells. Finally, we showed that IL-10 gene regulation was mediated by STAT3, which was phosphorylated after the binding of IL-6 to IL-6R. This is the first demonstration that IL-6, secreted by macrophages, can induce a STAT3-mediated IL-10 production by colon tumor cells.
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PMID:Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. 1503 82

Adjuvant therapy has been tested widely in the treatment of cancers of the stomach, pancreas, and large bowel. In the USA, the use of postoperative chemoradiation in stomach cancer is considered a standard of care after the publication of the Intergroup Study 0116 in September 2001. This study demonstrated significant benefit in overall and disease-free survival for patients receiving postoperative treatment with fluorouracil (5-FU)/leucovorin chemotherapy and radiation after gastric resection. Adjuvant chemotherapy is not considered to be of significant benefit, and such therapy for patients with resected gastric cancer is investigational. There is interest in the use of neoadjuvant chemotherapy strategies as preoperative treatment followed by surgical resection. This approach has been tested in a randomized study of over 500 patients carried out by the Medical Research Council in the UK. This study demonstrated that patients receiving preoperative and postoperative epirubicin, cisplatin, 5-FU (ECF) chemotherapy, had a downstaging of tumor size, an increase in rates of curative resection, and an increase in disease-free but not overall survival. With pancreatic cancer, there is a controversy over postoperative chemoradiation after pancreatic resection. A recently completed Intergroup Study compared gemcitabine to 5-FU chemotherapy given before and after radiation in resected pancreatic cancer. Over 500 patients have been accrued to this study, which recently closed. In Western Europe, the results of a large clinical trial (ESPAC) have suggested that chemoradiation is not beneficial in patients with resected pancreatic cancer. In large bowel cancer, 5-FU-based adjuvant chemotherapy regimens are superior to surgery alone, particularly in node-positive patients. The use of newer combinations including 5-FU/leucovorin plus irinotecan and 5-FU/ leucovorin plus oxaliplatin are also of interest as chemotherapy in resected colon cancer patients. The recent publication of the MOSAIC trial demonstrated that 5-FU/leucovorin/oxaliplatin (FOLFOX 4) improves progression-free survival in node-positive patients over 5-FU/leucovorin alone. The results of studies of 5-FU/ leucovorin and irinotecan both in Europe (PETACC) and the USA (IFL vs 5-FU/leucovorin) are awaited with interest. Another area of interest in resected colon cancer is the use of molecular genetic monitoring to assess the likelihood of patient relapse. The data over the past several years have demonstrated that patients whose tumors do not have deletion of the deleted in colon cancer (DCC) gene on chromosome 18 have an improved outcome. Recent data are available with tumors that demonstrate microsatellite instability (MSI). Such tumors represent about 15% of all colon cancers and have an improved outcome when compared to those not expressing MSI, and may not benefit from adjuvant chemotherapy.
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PMID:Clinical overview: adjuvant therapy of gastrointestinal cancer. 1530 8

Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage-induced apoptosis. The combination IFN-beta and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damage-induced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage-induced IRF-5 activation. Thus, IRF-5-regulated pathways may serve as a target for cancer therapeutics.
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PMID:Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death. 1610 93

In July 2003, a 59-year-old man underwent a right hemicolectomy for sigmoid colon cancer. Hepatic intraarterial injection therapy with 5-FU/CDDP was not only ineffective against a liver metastasis but a lung metastasis was also found, and therefore systemic chemotherapy with CPT-11/5-FU/l-LV (IFL) was administered. After onetime IFL therapy, the CPT-11 was withheld due to ileus. Although 5-FU/l-LV therapy was administered, it was ineffective. IFL therapy was again performed, with the dose decreased by 20%, as part of ambulatory treatment. Not only the liver metastasis but also the lung metastasis decreased significantly in size after one course. In addition, no severe adverse reactions were observed during the treatment, which enabled the therapy to be continued as part of an ambulatory regimen. The results suggest that IFL therapy is effective against colon cancer with lung/liver metastasis and can be administered as part of ambulatory treatment.
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PMID:[A case of colon cancer with liver and lung metastases-efficacy of CPT-11/5-FU/l-LV (IFL) as part of ambulatory treatment]. 1618 37

We considered the appropriateness of RFA, which was performed in three cases of colorectal cancer with hepatic metastases accompanied by liver cirrhosis. Case 1 involved a patient with sigmoid colon cancer ss, n1 (+) with severe hepatic dysfunction and synchronous hepatic metastases (S5, S6, S8) in which RFA was performed. After 1 year and 6 months, recurrence (S3, S4) was detected in the residual liver, and the patient is currently undergoing the IFL (CPT-11/5-FU/Leucovorin) treatment. In case 2, following a partial hepatic resection, RFA was performed for cecal cancer ss, n2(+) with synchronous hepatic metastases (S5, S6, S8). After 11 months, recurrence (S5, S6, S7) occurred in residual liver and again RFA was performed following a partial hepatic resection. Lung metastases have occurred and currently IFL (CPT-11/5-FU/Leucovorin) and WHF treatments are underway. In case 3, 4 years and 8 months after cancer of the descending colon ss, n1 (+), RFA was performed on asynchronous hepatic metastases (S5, S7, S8). The patient died of peritonitis carcinomatosa one year after RFA. In all three cases, metastases were identified by dynamic CT as low density masses with no blood flow. Necrosis in all three metastases and local control had been achieved. There were no severe complications. Under the current conditions, local coagulation methods including RFA are appropriate in those cases in which resection are not possible such as multiple metastases with severe hepatic dysfunction, etc.
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PMID:[Radiofrequency ablation (RFA) in colorectal cancer with hepatic metastases]. 1631 5

The combination of irinotecan and a fluoro-pyrimidine is widely accepted as a treatment for advanced colorectal cancer. However, evaluable data on the feasibility of these combinations has not been presented, and an optimal sequence for administration has not been experimentally and clinically determined. The sequential effect of a combination of 5-FU and CPT-11 in the human colon cancer cell line LoVo was evaluated by WST-8 colorimetric assay. The cytotoxicity and cell cycle distributions of each drug were analyzed by apoptosis assay and flow cytometry. Further, the potential mechanisms of the sequence-dependent effects were investigated by a microarray technique, and confirmed by Western blot analysis. The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (p<0.05). In cell cycle distribution, 5-FU exposure for 24 h increased the S phase fraction in a dose-dependent manner; though there was no significant difference in cell cycle distribution in 24 h CPT-11 (0.01-1 microM) exposure. Microarray analysis revealed that expressions of some apoptosis related genes such as Bcl-2 changed, and were correlated with sequence-dependent cytotoxicity of the 5-FU --> CPT-11 sequence. Western blot analysis confirmed that the Bcl-2/Bax ratio was lower after 5-FU --> CPT-11 sequence than before. The sequence-dependent cytotoxic effect may depend on the sensitizing effect of 5-FU pretreatment on CPT-11 cytotoxicity. 5-FU followed by CPT-11 administration may be an optimal sequence for IFL treatment of advanced colon cancer.
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PMID:in vitro synergistic antitumor activity of a combination of 5-fluorouracil and irinotecan in human colon cancer. 1639 4


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