Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although a majority of cancer patients show no response or minimal response to any given chemotherapy, all patients are nevertheless placed on standard therapy regimens because there has been no way to identify beforehand those patients who are destined not to respond. Determining the biochemical factors relevant to drug response in each patient's tumor cells prior to treatment should allow optimal therapy to be selected for each patient on a rational basis. In this paper, we summarize studies aimed at determining whether analysis of the quantitative expression levels of genes or proteins involved in cancer drug activity in clinical specimens of tumor tissue could predict the effect of the drug on a tumor. This hypothesis has been tested mostly in 5-fluorouracil (5-FU)-based regimens in colorectal cancer. In the case of 5-FU, the quantitative expression levels of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase were found to be associated with tumor response. Using all three of these markers together resulted in very effective identification of responding patients. The salient results of these studies were that, using the PCR enhanced by newly developed methodology, gene expressions can be identified and measured in pretreatment biopsies that are quantitatively associated with either response or non-response to drugs that are used in treating colorectal cancer.
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PMID:[Molecular markers as basis for chemotherapy?]. 1119 61

Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy patients receiving capecitabine needed more frequent unscheduled home, day care, office and telephone consultations with physicians. In the light of clinical results from the phase III trial demonstrating increased efficacy in terms of response rate, equivalent time to progression (TTP) and survival (OS), and a superior safety profile, the results from this medical resource assessment indicate that capecitabine treatment of colorectal cancer patients results in a substantial resource use saving relative to the Mayo Clinic regimen of 5-FU/LV. This benefit is derived principally from the avoidance of hospital visits for i.v. drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions in comparison to patients treated with 5-FU/LV.
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PMID:Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. 1129 Apr 35

Doxifluridine (5'-DFUR), an active intermediate metabolite of capecitabine, is converted to 5-fluorouracil by thymidine phosphorylase (TP). We used immunohistochemical staining to investigate the relation between TP expression and 5'-DFUR effects in 40 patients with advanced/recurrent lung metastases from colorectal cancer. Cox regression analysis suggested that TP-positive cancer cells (risk ratio 3.72), were independent factors in survival whereas factors in progression-free survival were TP-positive cancer cells (2.93), and TP-positive stromal cells (0.24). It is suggested that TP expression in cancer cells and in stromal cells are opposite prognostic factors in patients treated with 5'-DFUR.
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PMID:Thymidine phosphorylase expression and effect of doxifluridine: a phase II study. 1141 Jul 77

Fluoropyrimidine therapy for elderly colorectal cancer patients remains controversial. Tumoral levels of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and the ratio of TP to DPD determined by an enzyme-linked immunosorbent assay were compared between colorectal cancer patients aged 75 or over (elderly group, n = 25) and those 74 years or less (control group, n = 87), in order to examine the characteristics of colorectal cancers in the elderly from the viewpoint of metabolic and anabolic pathways of fluoropyrimidines. The level of TP was 78.4 +/- 47.0 unit/mg protein in the elderly group and 82.4 +/- 70.9 unit/mg protein in the control group (p = 0.86). The level of DPD was 53.7 +/- 43.1 unit/mg protein in the elderly group and 52.6 +/- 37.7 unit/mg protein in the control group (p = 0.73). The ratio of TP to DPD was 2.0 +/- 1.2 in the elderly group and 1.8 +/- 0.9 in the control group (p = 0.44). These three parameters did not differ between the groups when divided according to Dukes' stage (Dukes' A.B versus Dukes' C.D). These results suggest that there are no age-specific characteristics in relation to conversion of fluoropyrimidines such as capecitabine and doxifluridine to 5-fluorouracil (FU) and degradation of 5-FU in colorectal cancers.
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PMID:[Tumoral levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in elderly colorectal cancer patients]. 1143 49

Xeloda (capecitabine) is a rationally designed, oral pro-drug of 5-fluorouracil (5-FU). It is rapidly and almost completely absorbed in the upper gastrointestinal tract. It is then catabolised in a three-enzyme system, the last step being catalysed by thymidine phosphorylase, which is upregulated in many human cancers. Clinical pharmacology studies have confirmed that this preferential activation actually occurs in human colorectal cancer. Phase I and II trials were performed in colorectal cancer to define the optimal dose and schedule of capecitabine. In two large scale phase III studies this agent has been shown to be at least as effective as a standard regimen of bolus 5-FU and leucovorin (Mayo regimen). Response was superior in the capecitabine arms of these studies with equivalence of progression-free and overall survival. In addition the oral regimen was associated with significantly less toxicity. It seems likely that this agent will replace intravenous 5-FU in the therapy of colorectal cancer and possibly in other cancers.
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PMID:Xeloda in colorectal cancer. 1145 82

Chemotherapy for advanced colorectal cancer is based on i.v. 5-fluorouracil (5-FU). Numerous attempts have been made to increase the therapeutic benefit of 5-FU through schedule modification and biomodulation, but only modest improvements have been achieved. Capecitabine is an oral fluoropyrimidine that was developed in response to the clinical need for new therapeutic options offering improved efficacy, tolerability, and convenience for patients. Capecitabine was rationally designed to mimic continuous infusion 5-FU. It is rapidly and almost completely absorbed through the gastrointestinal wall and is converted to 5-FU via a three-step enzymatic cascade. 5-FU is generated preferentially in tumor by exploiting the higher activity of thymidine phosphorylase in tumor tissue compared with normal tissue. Results of a randomized, phase II trial led to the selection of a regimen of capecitabine for further clinical development (1,250 mg/m(2) twice daily for 14 days followed by a 7-day rest period). Subsequently, two large, randomized, phase III trials were conducted to compare capecitabine with i.v. bolus 5-FU/leucovorin ([LV]; Mayo Clinic regimen) in patients with metastatic colorectal cancer. A prospective, integrated analysis of data from the studies showed that capecitabine offers superior activity and an improved safety profile compared with 5-FU/LV. This article summarizes these developments in the treatment of colorectal cancer and assesses the feasibility of replacing i.v. 5-FU-based therapy with oral capecitabine. In addition, retrospective analyses assessing the impact of the dose modification scheme on the efficacy and tolerability of capecitabine are presented, and dose recommendations in special populations are reviewed.
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PMID:The evolution of fluoropyrimidine therapy: from intravenous to oral. 1158 68

Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven anti-tumor activity in colorectal cancer that has demonstrated synergy with 5-fluorouracil (5-FU) in human tumor xenograft models. A series of phase II trials demonstrated that, as second-line therapy, oxaliplatin in combination with 5-FU/leucovorin (LV) is active and can overcome clinical resistance to 5-FU. Subsequently, two large, randomized, phase III trials demonstrated that the addition of oxaliplatin to 5-FU/LV significantly improved response rates and time to disease progression in the first-line setting, but had no statistically significant impact on survival. Oxaliplatin in combination with 5-FU/LV represents an important treatment option for patients in whom 5-FU-based therapy has failed and as first-line therapy. Oxaliplatin has also been investigated in combination with the oral fluoropyrimidine, capecitabine. As an oral agent that exploits the high intratumoral activity of thymidine phosphorylase to generate 5-FU preferentially within tumor tissue, capecitabine may improve the efficacy and tolerability of fluoropyrimidine/oxaliplatin combination therapy. A phase I dose-escalation study has been performed in patients with advanced/metastatic solid tumors to establish the most appropriate regimen. The study indicated that the combination is feasible and has substantial antitumor activity in patients with colorectal cancer. This article provides an overview of the clinical trial data for oxaliplatin and discusses how oxaliplatin may best be used in the future.
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PMID:Integrating oxaliplatin into the management of colorectal cancer. 1158 71

Capecitabine is a thymidine phosphorylase (TP)-activated oral fluoropyrimidine, rationally designed to generate 5-fluorouracil (5-FU) preferentially within tumors. This tumor selectivity is achieved through exploitation of the significantly higher activity of TP in tumor compared with healthy tissue. The high single-agent activity of capecitabine in breast and colorectal cancer suggests that capecitabine may have a role in the treatment of other tumor types that are sensitive to 5-FU, such as pancreatic cancer. Tumor types known to have a high level of TP activity, such as renal cancer, are especially attractive targets for capecitabine therapy. Capecitabine has potential as monotherapy in these tumor types, or as a combination partner for other cytotoxic agents with different mechanisms of action and little overlap of key toxicities. In particular, some cytotoxic drugs, such as the taxanes and cyclophosphamide, are known to upregulate TP activity in tumor tissue, offering the potential for synergistic action. The combination of capecitabine and docetaxel has demonstrated significant activity in women with anthracycline-pretreated breast cancer, and is the only cytotoxic combination to significantly increase survival compared with standard therapy in this setting. In addition, capecitabine as monotherapy or in combination with other cytotoxic agents has shown encouraging activity in pancreatic, ovarian, and renal cell cancers. This article discusses recent data from clinical trials investigating capecitabine in a range of tumor types, highlighting the potential future role of capecitabine as an alternative to traditional i.v. chemotherapy.
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PMID:Vision of the future: capecitabine. 1158 73

Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5-FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first-line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5-FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited.
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PMID:Capecitabine: a novel agent for the treatment of solid tumors. 1160 50

We investigated whether the efficacy of peroral doxifluridine and hepatic arterial 5-FU infusion on synchronous liver metastasis of colorectal cancer could be predicted based on the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in the primary colorectal lesions. Ten patients with synchronous liver metastasis of colorectal cancer were given doxifluridine (600-800 mg/body/day) orally and 5-FU (500 mg/body, once or twice a week) through the hepatic artery following resection of the primary lesions between June 1996 and July 2001. The levels of TP and DPD in the primary lesions were determined by an enzyme-linked immunosorbent assay. The level of TP, DPD, and the ratio of TP/DPD in patients with partial response (n = 4) were 89.8 +/- 30.0 U/mg protein, 23.5 +/- 25.7 U/mg protein, and 3.8 +/- 1.4, respectively, while those in patients with no response or progressive disease (n = 6) were 41.8 +/- 9.7 U/mg protein, 25.8 +/- 15.8 U/mg protein, and 2.2 +/- 1.6, showing significant difference (p < 0.01) in the level of TP between the groups. These results indicate that determining the level of TS in primary colorectal lesions may be useful for predicting the efficacy of this regimen for patients with synchronous liver metastasis of colorectal cancer.
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PMID:[Effect of peroral doxifluridine plus hepatic arterial infusion for synchronous liver metastasis of colorectal cancer--correlation with the expression of thymidine phosphorylase and dihydropyrimidine dehydrogenase in primary colorectal cancer lesions]. 1170 95


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