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

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FUra) by three enzymes located in the liver and tumors; the final step is the conversion of 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FUra by thymidine phosphorylase in tumors. The present study compared the efficacy of capecitabine and 5-FUra at their maximum tolerated doses in CXF280, HCT116, COLO205, and WiDr human colon cancer xenograft models, and measured subsequent 5-FUra and 5'-dFUrd levels in tumors and in the plasma and muscle. Capecitabine was effective in the first three models, whereas 5-FUra was effective only in CXF280, which is a cell line highly susceptible to fluoropyrimidines. In the three susceptible models, 5-FUra AUCs in tumors after capecitabine administration were 210 to 303 nmol x hr/g, whereas those after 5-FUra administration were 8.54 to 13.1 nmol x hr/g. In addition, capecitabine gave higher levels of 5-FUra AUC in tumors than in plasma (114- to 209-fold higher) and muscle (21.6-fold higher), whereas 5-FUra was not selectively distributed to tumors. In the refractory model, WiDr, 5-FUra AUC in tumors after capecitabine administration was only 62.8 nmol x hr/g, although the level of the intermediate metabolite 5'-dFUrd was high (AUC: 695 nmol x hr/g). The ratio of 5-FUra/5'-dFUrd levels in the WiDr tumors was 0.09, which was 23.8-fold lower than that in the HCT116 tumors. The mechanism of resistance would be the inefficient conversion of 5'-dFUrd to 5-FUra by thymidine phosphorylase in tumors. Thus, capecitabine might show its high efficacy as a result of delivering high levels of 5-FUra selectively to the tumors.
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PMID:Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. 960 32

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that was synthesized for the purpose of finding antitumor drugs with improved safety and efficacy profiles compared with those of 5-fluorouracil (5-FUra) and doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUrd). The present study compared the antitumor activities of the compound with those of other fluoropyrimidines in 12 human cancer xenograft models and their antimetastatic activities in murine tumor models. The antitumor efficacy of capecitabine was greater than those of 5'-dFUrd, UFT (a mixture of tegafur and uracil) and 5-FUra. Capecitabine was also much safer, particularly much less toxic to the intestinal tract, than the other compounds, indicating higher therapeutic indices. The therapeutic indices of capecitabine, 5'-dFUrd and 5-FUra were >40, >20 and 2.0 against the human CXF280 colon cancer xenograft, the most sensitive line to the fluoropyrimidines so far tested, and 5.1, 1.5, and <1.5 against the human HCT116 colon cancer xenograft with ordinary sensitivity, respectively. In addition, capecitabine, as well as 5'-dFUrd, selectively suppressed the spontaneous metastasis of mouse Lewis lung carcinoma in mice at extremely low doses, 32-64 fold lower than their minimum effective dose (MED) against the primary tumor growth. Capecitabine was even more antimetastatic than 5'-dFUrd. These results indicate that capecitabine has high therapeutic potential.
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PMID:Antitumor activities of a novel fluoropyrimidine, N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (capecitabine). 970 55

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) selectively in tumours through a cascade of three enzymes. The present study investigated tissue localisation of the three enzymes in humans, which was helpful for us to design the compound. Carboxylesterase was almost exclusively located in the liver and hepatoma, but not in other tumours and normal tissue adjacent to the tumours. Cytidine (Cyd) deaminase was located in high concentrations in the liver and various types of solid tumours. Finally, thymidine phosphorylase (dThdPase) was also more concentrated in various types of tumour tissues than in normal tissues. These unique tissue localisation patterns enabled us to design capecitabine. Oral capecitabine would pass intact through the intestinal tract, but would be converted first by carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-dFCyd) in the liver, then by Cyd deaminase to 5'-deoxy-5-fluorouridine (5'-dFUrd) in the liver and tumour tissues and finally by dThdPase to 5-FU in tumours. In cultures of human cancer cell lines, the highest level of cytotoxicity was shown by 5-FU itself, followed by 5'-dFUrd. Capecitabine and 5'-dFCyd had weak cytotoxic activity only at high concentrations. The cytotoxicity of the intermediate metabolites 5'-dFCyd and 5'-dFCyd was suppressed by inhibitors of Cyd deaminase and dThdPase, respectively, indicating that these metabolites become effective only after their conversion to 5-FU. Capecitabine, which is finally converted to 5-FU by dThdPase in tumours, should be much safer and more effective than 5-FU, and this was indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models.
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PMID:Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. 984 91

Capecitabine is an orally administered fluoropyrimidine carbamate that is preferentially converted to 5-fluorouracil in tumors relative to normal tissue. Three different dosing regimens were investigated in phase I studies: continuous monotherapy, intermittent monotherapy, and intermittent therapy supplemented with leucovorin. These studies defined the maximum tolerated dose for each regimen. Dose-limiting toxicities were diarrhea, hand-foot syndrome, and leukopenia. Each phase I study recommended a dose; these were directly compared in a phase II study. This phase II study showed that the intermittent regimen of capecitabine monotherapy was the most favorable on the basis of tumor response rates, time to progression, dose intensity, and toxicities. The intermittent regimen of capecitabine has been compared with the Mayo Clinic regimen of 5-fluorouracil/leucovorin in two large, phase III studies of patients with advanced colorectal cancer. The combined data from the two studies showed that capecitabine was superior to 5-fluorouracil/leucovorin in terms of tumor response rate (22% v 13%; P < .0001) and similar in terms of time to disease progression and overall survival. Capecitabine is now being compared with the Mayo Clinic regimen as an adjuvant treatment for patients with Dukes' C colon cancer.
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PMID:5-fluorouracil/leucovorin versus capecitabine in patients with stage III colon cancer. 1127 90

Docetaxel and capecitabine are being prescribed for the treatment of breast cancer. In this study, we tried to identify the optimal administration schedule in combination therapy with these anticancer drugs in human cancer xenograft models. Capecitabine was given p.o. daily for 2 weeks (days 1-14), whereas docetaxel was given i.v. on day 1, day 8, or day 15 in a 3-week regimen to the mice bearing MX-1 human breast cancer xenograft. The combination showed better antitumor efficacy than the monotherapy of either agent in either dosing regimen. However, the most potent and synergistic activity was observed when docetaxel was given on day 8. This potent effect appears to be characteristic of the combination of docetaxel with capecitabine or its intermediate metabolite 5'-deoxy-5-fluorouridine (doxifluridine; 5'-dFUrd). Docetaxel given on day 8 showed a potent effect in combination with 5'-dFUrd, but a much weaker effect was observed in combination with 5-fluorouracil or UFT, a fixed combination of tegafur and uracil. Better efficacy was also observed in the MAXF401 human breast cancer xenograft and in the mouse A755 mammary tumor when docetaxel was given at the middle of the capecitabine or 5'-dFUrd treatment rather than other dosing regimens. In contrast, the efficacy in WiDr human colon cancer xenograft was somewhat better when docetaxel was given on day 1. One possible explanation for the synergy is that docetaxel up-regulates tumor levels of thymidine phosphorylase, the enzyme essential for the activation of capecitabine and 5'-dFUrd to 5-fluorouracil. In fact, docetaxel up-regulated the thymidine phosphorylase levels 4.8- and 1.9-fold in the WiDr and MX-1 models, respectively. However, it did not significantly up-regulate in the MAXF401 and A755 models in which a potent combination effect was observed as well. Other mechanisms, particularly those for the synergy with docetaxel given at the middle during capecitabine/5'-dFUrd administration, would also exist. Based on these observations, clinical studies on the day 8 combination regimen with docetaxel and capecitabine/5'-dFUrd are warranted.
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PMID:Schedule dependency of antitumor activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and docetaxel in breast cancer models. 1130 60

The systemic anticancer drug therapy is indicated in the adjuvant as well as in the palliative setting. There is an indication for an adjuvant therapy in case of Dukes B (stadium II) as well as in Dukes C (stadium III) colon cancer. An indication in the palliative setting remains for the Dukes D (stadium IV) colon cancer patients. Locoregional chemotherapeutical approaches represent no standard procedure and cannot be recommended outside clinical trials because the real value of this therapy is unknown due to a lack of large randomized trials. The mainstay of treatment of colon cancer is 5-Fluoruracil (5-FU), which should be combined with folinic acid in case of bolus (2-4 min. injection) therapy. In the adjuvant situation the Mayo scheme administered over a period of half a year remains the standard of choice because this procedure is validated by large randomized trials and replaces the combination 5-FU + levamisol given over a period of one year in former times. In the palliative situation 5-FU based therapy remains the goldstandard although more options than 5-FU plus folinic acid are now available. Oxaliplatin and irinotecan are approved for the treatment of metastatic colon cancer in first line in combination with 5-FU. Capecitabine and Ralitrexed are drugs, which are approved outside of Germany and can be used as well if indicated. The median survival of patients with metastatic colon cancer is between 12 and 18 month. It will be discussed in which way this range depends on the chemotherapeutical strategy.
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PMID:[Chemotherapy of colonic carcinoma in the year 2001]. 1132 9

The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.
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PMID:Future treatment options with capecitabine in solid tumours. 1184 32

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) by 3 sequential steps of enzyme reactions. We investigated the possibility of using capecitabine to prevent metastasis with a metastasis model of gastrointestinal cancer developed by the intrarectal injection of green fluorescent protein (GFP)-expressing colon cancer HT-29 cells (HT-29-GFP) into nude mice. Lung and lymph node metastasis in the HT-29-GFP rectal xenograft was assessed through both observation of GFP fluorescence and quantification of metastasis by amplification of a cancer-related human DNA by TaqMan PCR. Furthermore, for each organ, we examined mRNA levels of cancer-specific thymidine phosphorylase (dThdPase), which is an essential enzyme for capecitabine activation, by the quantitative RT-PCR method. Capecitabine inhibited the HT-29-GFP xenograft growth by 60.8% and 43.8% in the subcutaneous and rectal xenograft models, respectively. Furthermore, it inhibited both lung and lymph node metastasis by 99.9%. dThdPase expression in the tumor cells of both the rectal xenograft and metastatic lung tumor cells was upregulated by 10.0- and 24.3-fold that in the HT-29-GFP cells in vitro, respectively. These results indicated that capecitabine might effectively inhibit or suppress metastasis via upregulation of dThdPase expression. Capecitabine administration might be highly expected to reduce metastasis and improve survival of patients with gastrointestinal cancers.
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PMID:Anti-metastatic effect of capecitabine on human colon cancer xenografts in nude mouse rectum. 1530 85

The oral fluoropyrimidine capecitabine (Xeloda) delivers 5-FU to the tumour site, thereby limiting the side effects and other complications associated with intravenous (i.v.) 5-FU. As an oral drug, capecitabine is preferred to 5-FU by many patients as it can be conveniently taken at home. In first-line metastatic colorectal cancer (MCRC), capecitabine results in superior response rates and equivalent progression-free and overall survival compared with i.v. 5-FU/LV. There is also increasing evidence for replacing i.v. 5-FU with capecitabine in combination with other anticancer agents (e.g. oxaliplatin and irinotecan) in MCRC and in the adjuvant treatment of early stage colon cancer. In anthracycline-pretreated metastatic breast cancer (MBC), adding capecitabine to docetaxel improves survival, time to progression (TTP) and response rates beyond docetaxel. Single-agent capecitabine is also effective in pretreated MBC and is a promising first-line therapy. Capecitabine has a favourable safety profile, the most frequent adverse events being hand-foot syndrome, stomatitis and diarrhoea. Because capecitabine is orally administered, it is possible to intervene promptly with dose interruption/reduction to resolve adverse events without impacting on efficacy. The increasing availability of capecitabine in the home-based setting requires careful consideration of the role of the oncology nurse, who is the key link between the patient and clinician for effective and efficient management.
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PMID:Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. 1534 78

Blood-borne metastases to the kidneys from solid tumors have received little attention in the medical literature because they usually occur in a setting of advanced systemic disease, and renal involvement is a relatively minor cause of symptoms. Although the frequency of metastases to the kidney in cancer patients is 7-13% in large autopsy series, incidental discovery of a renal metastasis as the first manifestation of a primary tumor is a very rare event. The most common primary malignancy to involve the kidney is bronchogenic carcinoma,followed by breast and gastrointestinal cancers. In this article, we report a patient with left colon cancer and isolated metastasis to the right kidney at the time of initial diagnosis. Left hemicolectomy and right nephrectomy were performed. Adjuvant systemic chemotherapy consisting of 5-fluorouracil (5-FU) and folinic acid (FA) was given. 5-FU and FA were stopped after four cycles because metastases to the lung and liver occurred about 3 mo after the surgery during adjuvant chemotherapy. Capecitabine was started. The patient died 9 mo after the discovery of the isolated renal metastasis. Nephrectomy is more for diagnostic clarification in the setting of synchronous primary because it has no effect on survival and its effect on quality of life is minimal; as seen in our case, the other organ metastases rapidly occur and the survival is limited. Nephrectomy may also compromise the choice of chemotherapy agents that require renal clearance, thus a careful evaluation of renal functions is necessary if a nephrectomy is performed. In the matter of a decreased renal clearance,the doses of these drugs should be decreased or the choice should be reevaluated.
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PMID:Colon cancer with isolated metastasis to the kidney at the time of initial diagnosis. 1536 38


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