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)

Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21(WAF1/CIP1)-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21(WAF1/CIP1) prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes.
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PMID:Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line. 1500 86

A 58-year-old man who had colon cancer with liver and multiple lung metastases underwent ileocecal resection on May 10, 2002. MTT assay of 5-FU and CPT-11 was performed with resected material, with both medicines accepted for sensitivity. On June 4, he received combination chemotherapy with CPT-11 + 5-FU/l-LV. The liver metastasis disappeared and was judged CR from a CT of the abdomen. Almost all the multiple lung metastases had disappeared or were decreased in size. They were therefore judged NC from a CT of the chest. Moreover, CEA and CA19-9 decreased to within normal limits. While he was receiving bimonthly chemotherapy with only CPT-11 as a maintenance therapy, liver and lung metastases did not change. Combination chemotherapy with CPT-11 + 5-FU/l-LV is effective. The anticancer drug sensitivity examination is only one index, however. Considering adverse effects and medical costs, individualized therapy based on the sensitivity test for anticancer drugs should be performed.
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PMID:[A case report of colon cancer with liver and lung metastases responding to combination chemotherapy with l-LV, 5-fluorouracil and CPT-11]. 1504 55

A 54 year-old male was admitted for highly advanced ascending colon cancer with multiple bone and liver metastases and pleuritis carcinomatosa. He was treated with pharmacokinetic modulating chemotherapy (PMC) and low-dose CPT-11. UFT (400 mg) was orally administered daily and a 2-hour infusion of l-leucovorin (250 mg/m2/day) with a continuous infusion of 5-FU (600 mg/m2/24 h) was given once a week on an outpatient basis. CPT-11 (80 mg/body/2 h) was administered every 2 weeks. Partial response was obtained in the liver for 6 months and in the primary lesion for 9 months. Significant decrease of pain from the multiple bone metastases was observed for 4 months without severe side effects, which led to an improvement in performance status and quality of life for the patient. He survived more than 11 months after initial treatment. The duration of his stay at home was 288 days, accounting for 83% of the treatment period. This case suggests the efficacy of home anticancer therapy with PMC and low-dose CPT-11 for highly advanced colon cancer in terms of QOL.
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PMID:[A case of highly advanced ascending colon cancer with multiple bone and liver metastases and pleuritis carcinomatosa treated with pharmacokinetic modulating chemotherapy and low-dose CPT-11]. 1504 56

In preclinical tumor models, inhibition of nuclear factor-kappaB (NF-kappaB) has been associated with increased sensitivity to chemotherapeutic agents such as irinotecan (CPT-11). This is based on the fact that a variety of chemotherapy agents such as CPT-11 activate NF-kappaB to result in the expression of genes such as c-IAP1 and c-IAP2 that might be responsible for the inhibition of chemotherapy-induced apoptosis. In this study, RNA interference [small interfering RNA (siRNA)] was used to down-regulate the NF-kappaB p65 subunit in the HCT116 colon cancer cell line, and its role, in the presence and absence of CPT-11, was assessed on cell growth and apoptosis. Reduction of endogenous p65 by siRNA treatment significantly impaired CPT-11-mediated NF-kappaB activation, enhanced apoptosis, and reduced colony formation in soft agar. Furthermore, the in vivo administration of p65 siRNA reduced HCT116 tumor formation in xenograft models in the presence but not the absence of CPT-11 administration. These data indicate that the administration of siRNA directed against the p65 subunit of NF-kappaB can effectively enhance in vitro and in vivo sensitivity to chemotherapeutic agents.
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PMID:Enhanced chemosensitivity to irinotecan by RNA interference-mediated down-regulation of the nuclear factor-kappaB p65 subunit. 1516 78

A novel intraluminal colon tumor model was established in mice by intrarectal instillation of colon cancer cells followed by short-term induction of colitis by an irritant agent. Male BALB/c mice were fed a diet containing 3% (w/w) dextran sulfate sodium (DSS) for 7 days to induce colitis, and colon 26 cells (1-2 x 10(6) cells/mouse) were infused intrarectally after the mice had been deprived of food for the last 18 h of DSS treatment. The tumor incidence (%) and size (mean volume +/- SD, mm(3)) at the rectal mucosa were 35% (2 +/- 3), 95% (96 +/- 79), 95% (141 +/- 137) and 94% (325 +/- 270) at 1, 2, 3 and 4 weeks after instillation of tumor cells, respectively. Histopathological analyses revealed that a solid tumor was formed initially at the rectal mucosa at 1 week after instillation, then became invasive into the submucosal and muscular tissues at 3 weeks after implantation. Intrarectal instillation of human colon cancer cells, LS174T (1 x 10(7) cells/mouse), mixed with "Matrigel" (0.5 mg/mouse), an extracellular matrix solution, in SCID mice led to formation of rectal tumors at 4 weeks after instillation, and immunohistochemical analysis revealed that the tumor cells expressed human carcinoembryonic antigen, suggesting that the tumor nodule was derived from the instilled LS174T cells. Oral or intravenous administration of a camptothecin (CPT) derivative, CPT-11, resulted in a significant reduction in tumor incidence and tumor volume in the colon 26-intraluminal implantation system. In conclusion, it was suggested that the present intraluminal colon tumor model is useful for examination of chemotherapeutic agents and also intraluminal factors (dietary compounds, intestinal microflora, etc.) that might function to suppress or enhance the growth of colorectal cancer in situ.
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PMID:A novel mouse model of rectal cancer established by orthotopic implantation of colon cancer cells. 1518 33

The combination of the topoisomerase I (Topo I) inhibitor CPT-11 with the anti-epidermal growth factor receptor (EGFR) agent Gefitinib (Iressa, ZD1839) represents a promising medical approach for colorectal cancer patients. In this report, we provide pre-clinical evidences for their optimal combination schedule in HT-29 and LoVo human colon cancer cell lines. We analyzed the different effects that three different combination schedules of SN-38 (the active CPT-11 metabolite) and Gefitinib (Gefitinib before; Gefitinib simultaneously; Gefitinib after SN-38) have on cell growth, cell cycle, apoptosis, and expression/phosphorylation of EGFR, Topo I and some steps of the signal transduction pathway. We first determined the IC(50) of each drug choosing the 5 days exposure for Gefitinib (0.6 and 3.8 microM for LoVo and HT-29 cells, respectively) and 1 day exposure for SN-38 (0.31 and 0.5 microM for LoVo and HT-29 cells, respectively). The different drug combination schedules were tested in various concentrations by using equiactive concentrations of the two drugs. The cytotoxicity of Gefitinib and SN-38 combination was schedule- and concentration-dependent but not cell line-specific. The most synergistic schedule was Gefitinib given after SN-38, with combination indexes (CI) of 0.007 and 0.454 in HT-29 and LoVo, respectively. Analysis of bio-molecular targets showed that Gefitinib was able to modulate SN-38 ability to inhibit Topo I, to accumulate cells in S-phase, and to induce apoptosis. Interestingly, SN-38 was able to activate EGFR and its signal transduction pathway. Confirming preliminary clinical experience of Gefitinib with other cytotoxic drugs, it seems that Gefitinib after SN-38 represents the best cytotoxic combination schedule but the biomolecular basis for this synergism remain to be completely elucidated.
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PMID:The schedule-dependent enhanced cytotoxic activity of 7-ethyl-10-hydroxy-camptothecin (SN-38) in combination with Gefitinib (Iressa, ZD1839). 1518 25

The patient was a 67-year-old man in whom hepatic metastasis from transverse colon cancer was detected 15 months after transverse colectomy (D2). We treated the patient by systemically administering 2 courses of 5-FU 750 mg/day with l-LV 350 mg/day (once weekly for 6 weeks per course). Assessment of therapeutic effects by CT showed PD in the patient. As a second-line therapy, we treated the patient by systemically administering 3 courses of 5-FU 750 mg/day, l-LV 350 mg/day and CPT-11 40 mg/day x 3 days (once a week for 4 weeks per course). After 3 courses of this chemotherapy, CT examination revealed a reduction in the tumor size of the liver, and CEA levels decreased at the end of this chemotherapy. This chemotherapy also showed no high-grade toxicities. l-LV/5-FU/low-dose CPT-11 seems to be effective for metastatic colon cancer, and safe from the toxicity standpoint.
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PMID:[A case of hepatic metastasis from colon cancer successfully treated with 5-FU, levofolinate (l-LV) and low-dose CPT-11]. 1533 52

The patient was a-54-year-old man. Sigmoidectomy was performed for sigmoid colon cancer in 1991. Partial liver resection in 1992 and microwave coagulation therapy (MCT) in 1994 were carried out for liver metastasis. Complete remission of the metastasis was achieved. In June 2002, multiple liver and lung metastases were identified. 5-FU, CDDP therapy was applied as systemic chemotherapy. The liver metastasis was improved and the level of CEA was reduced. However, a new lesion appeared in the right lobe of the liver, followed by an increase of the CEA level. Although CPT-11, 5-FU, CDDP therapy was applied, it was not effective. The reason was considered to be from the decrease of drug delivery resulting from an unbalanced blood supply in the right lobe of the liver. Right lobectomy and radio-frequency ablation was performed on June 17, 2003. The level of CEA was dramatically decreased. Additionally, CPT-11, 5-FU, CDDP therapy was applied. The patient has survived for 11 years after liver metastasis was first detected.
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PMID:[A successfully resected case of colorectal cancer with multiple liver metastases treated with systemic chemotherapy]. 1533 53

We report a case of recurrent colon cancer resistant to 5-FU, whose QOL and PS has been well maintained with low-dose CPT-11/CDDP administered on an outpatient basis for more than 28 months. A 42-year-old male had lymph node recurrence 27 months after curative resection of colon cancer. He had been administered pharmacokinetic modulating chemotherapy (PMC, oral tegafur/uracil plus fluorouracil infusion) after surgery. Combined treatment with CPT-11 (50 mg/m2)/CDDP (6 mg/m2) was performed on an outpatient basis. Nine months of NC was obtained without any severe side effect. Modified administration of this treatment with 5'-DFUR and TS-1 lead to further maintenance of quality of life and performance status. This case suggests the efficacy of low-dose CPT-11/CDDP for cases of 5-FU-resistant colon cancer in terms of QOL and PS.
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PMID:[A case of 5-FU-resistant recurrent colon cancer treated with low-dose CPT-11/CDDP on an outpatient basis]. 1544 71

This article reviews the available data regarding the acticity of postoperative adjuvant systemic therapy for colorectal cancer as first and second-line treatment in metastatic disease. The efficacy of adjuvant treatment of patients with stage III colorectal cancer is well established. 5-fluorouracil (5-FU) and folic acid over 6 months (still) represent todays standard and should serve as comparison in randomized studies. The risk of relapse is low in stage II colon carcinoma and consequently the efficacy is relatively small compared to stage III. New investigation indicate, Capecitabene has the potential to replace 5-FU/FS as standard treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. In metastatic disease combination of 5-FU/folic acid plus CPT-11 or OXA are treatment of choice for the first-line therapy of metastatic colorectal carcinoma. FOLFOX is high-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer. It resulted in prolongation of the median progress free survival from 6,8 to 8,8 months and increased the survival for 4,5 months. New perspectives are novel chemotherapeutic and targeted agents in metastatic colorectal cancer: For the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.
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PMID:[Adjuvant and palliative anticancer treatment of colon carcinoma in 2004]. 1549 53


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