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)

This in vivo study examines the ability of 5'-amino-5'-deoxythymidine (5'-AdThd) to modulate 5-iododeoxyuridine (IdUrd) cellular metabolism in two human colon cancer xenografts (HT 29 and HCT-116), two actively proliferating normal mouse tissues (bone marrow and intestine), and a quiescent normal mouse tissue (liver). 5'-AdThd is a thymidine analogue that at low concentrations (<30 micrometer) can increase thymidine kinase activity, which is the rate-limiting enzyme for activation of IdUrd. We reported recently that the in vitro incubation of HT 29 and HCT-116 cells in 5'-AdThd + IdUrd resulted in an enhancement of 5-iodo-2'-dUTP pools, IdUrd DNA incorporation, and subsequent radiosensitization compared with incubation with IdUrd alone (Clin. Cancer Res., 1: 407-416, 1995). These in vitro effects were more significant in the radioresistant cell line HT 29. Using a 6-day continuous infusion of IdUrd (50 or 100 mg/kg/day) and/or 5'-AdThd (200 mg/kg/day), no increase in systemic toxicity (percentage of body weight loss) was observed in athymic nude mice with 5'-AdThd alone or when combined with IdUrd. There was significant dose-dependent, systemic toxicity with IdUrd, which was reversible within 3 days of completing the lower-dose IdUrd infusion. However, a comparison of plasma levels during the 6-day continuous infusion of IdUrd +/- 5'-AdThd showed a significant interaction of IdUrd and 5'-AdThd, resulting in higher plasma levels by day 6 of both compounds and the principal metabolites, iodouracil and deoxyuridine, which is consistent with nonlinear saturating effects on dihydrouracil dehydrogenase. Coadministration of IdUrd and 5'-AdThd resulted in an increase in the percentage of IdUrd DNA incorporation in the two proliferating normal tissues, which was significant only with the lower IdUrd dose. No effect on IdUrd DNA incorporation was found in normal liver at either IdUrd dose +/- 5'-AdThd. Similar to our in vitro data, the continuous infusion of IdUrd and 5'-AdThd showed a significant effect by increasing the percentage of IdUrd DNA incorporation in HT-29 xenografts at both IdUrd doses, whereas coadministration of 5'-AdThd had no such effect in HCT-116 xenografts.
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PMID:In vivo modulation of iododeoxyuridine metabolism and incorporation into cellular DNA by 5'-amino-5'-deoxythymidine in normal mouse tissues and two human colon cancer xenografts. 981 59

We evaluated the combination SN38 (7-ethyl-10-hydroxycamptothecin) -5fluorouracil (5FU) +/- folinic acid (FA) on six human colon cancer cell lines expressing spontaneous sensitivity to both drugs. Tumoral parameters potentially related to drug sensitivity were investigated: topoisomerase I (topo I) cleavable complexes formed with SN38, thymidylate synthase (TS) activity, folylpolyglutamate synthetase activity and dihydropyrimidine dehydrogenase activity. Drugs (SN38 and/or 5FU +/- FA) were applied for 72 hr, either sequentially or together. The concentration ratio between SN38 and 5FU was 100. Cytotoxicity (MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] test), DNA flow cytometry and isobologram analysis (Chou and Talatay) were performed. Based on 5FU IC50 values and isobologram analyses, the most cytotoxic schedule was SN38 followed by 5FU - FA, with high synergistic effects. Flow cytometry indicated that SN38 induced a more or less marked S-G2 block in all cell lines. Sensitivity to SN38, 5FU +/- FA, or combinations were not linked to the potential above-cited tumoral parameters. Interestingly, an inverse correlation was demonstrated between TS activity and topo I cleavable complexes (r2 = 0.78, P = 0.019). These data emphasize the critical importance of the irinotecan-5FU schedule and strongly support this association for the treatment of potentially 5FU-sensitive tumors.
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PMID:Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity. 982 30

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibitor of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an inhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models. We have therefore compared the antitumor effect of oral S-1 with that of continuous infusion of 5-FU in rats bearing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcoma-bearing rats by consecutive administration of 30 mg/kg/day of oral S-1 and 40 mg/kg/day infusion of 5-FU. However, a significant difference between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was attained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concentrations in gastrointestinal tissue to that in the tumor was lower in the S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpoint of antitumor potency and toxicity.
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PMID:Anticancer activity and toxicity of S-1, an oral combination of tegafur and two biochemical modulators, compared with continuous i.v. infusion of 5-fluorouracil. 984 Jul 29

Orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), uridine phosphorylase (UP), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthetase (TS) are enzymes which analyze the salvage synthesis within the biosynthesis of the nucleic acid route of colon cancer. These enzymes were measured in carcinoma and normal tissue. OPRT was 0.065 +/- 0.041 nmol/min/mg protein, TP 4.04 +/- 2.81 nmol/min/mg protein, UP 1.79 +/- 1.19 nmol/min/mg protein, DPD 23.8 +/- 12.0 pmol/min/mg protein, and TS 6.1 +/- 4.4 pmol/g tissue in the normal tissue, and OPRT was 0.199 +/- 0.146 nmol/min/mg protein, TP 13.63 +/- 6.04 nmol/min/mg protein, UP 5.84 +/- 2.37 nmol/min/mg protein, DPD 22.0 +/- 13.4 pmol/min/mg protein, TS 16.9 +/- 7.8 pmol/g tissue in the carcinoma. OPRT, TP, and UP in the carcinoma mainly existed about 3.06-3.37 times that in normal tissue and TS at about 2.77 times. No significant difference was seen in DPD. A correlation was found between OPRT in normal tissue and carcinoma. Biosynthesis of nucleic acid via salvage synthesis is actively stimulated. Enzymatic activity related to uracil was high, and was thought to be closely connected to the growth of the cancer.
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PMID:[Analysis of the salvage synthesis within biosynthesis of nucleic acid route in colon cancer]. 1096 98

Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11.
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PMID:Determinants of prognosis and response to therapy in colorectal cancer. 1117 41

We have investigated the correlation between the in vitro chemosensitivity to 5-FU, measured using the collagen gel droplet embedded culture drug sensitivity test (CD-DST), and the anti-tumor effect of UFT, a prodrug of 5-FU, in metastatic tumors from orthotopic implanted colon cancer in nude rats. Human colon cancer cells (KM12SM) were injected into the cecal wall of the nude rats. Five weeks later, the implanted cecal tumors were removed. Oral UFT (a daily dose of 30 mg/kg) was administered postoperatively for four weeks. After the UFT administration period, the lung and lymph nodes were analyzed macroscopically and microscopically. In vitro chemosensitivity to 5-FU in the lung and lymph node metastases was tested using CD-DST, and the enzymatic activities of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in the lung and lymph node metastases were measured. A daily administration of UFT produced an inhibitory effect on lung metastasis compared with the control group. However, there was no difference in the frequency of lymph node metastasis. The inhibition rate produced by 5-FU in CD-DST was significantly higher for lung metastases than for lymph node metastases. There was no difference in the TS and DPD activities between the metastatic tumoral tissues. These results suggest that the organ specificity of the anti-tumor effects of UFT on colon metastases may be determined by CD-DST of 5-FU for individual tumors. The TS and DPD activity in the tumoral tissues may not affect the organ specificity of the anti-tumor effect of UFT on colon metastases.
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PMID:[Relationship between the anti-metastatic effect of UFT and in vitro chemosensitivity to 5-FU in metastatic tumors from orthotopic implanted colon cancer in nude rats]. 1138 14

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.
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PMID:[New oral anticancer drug, TS-1 (S-1)--from bench to clinic]. 1143 58

We have assessed pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) activity to compare the chemosensitivity of 5-fluorouracil (5-FU) and doxifluridine (5'-DFUR). Tumor samples were prepared from fresh surgical specimens of 28 patients with advanced colon carcinoma. The activity levels of the two enzymes were assessed as indicators of chemosensitivity to 5'-DFUR and 5-FU. PyNPase activity was analyzed using the HPLC method, and DPD activity was assessed according to the methods of Naguib et al. (1985). A histoculture drug response assay (HDRA) was conducted according to the methods described by Furukawa et al. (1992). The mean and standard deviation of PyNPase activity in the tumor tissue was 110 +/- 48.6 &mgr;g 5-FU/mg protein/h, which was statistically higher than the corresponding value obtained in normal tissue (60 +/- 43.1 &mgr;g 5-FU/mg protein/h) (P < 0.005). When chemosensitivity to the two drug forms was compared in 16 samples obtained from 16 cases with colon cancer, 1 specimen was sensitive to both drug forms, 3 specimens were exclusively sensitive to 5'-DFUR, 5 specimens were exclusively sensitive to 5-FU, and the other 7 specimens were insensitive to both drugs, without significance. High PyNPase activity was associated with a high chemosensitivity to 5'-DFUR, and high DPD activity correlated with a low chemosensitivity to 5-FU. However, the converse relationship was not found. We suggest that the activity of PyNPase and DPD represents a reliable indicator for the chemosensitivity of colon cancer to 5'-DFUR and 5-FU, respectively.
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PMID:Pyrimidine nucleoside phosphorylase and dihydropyrimidine dehydrogenase indicate chemosensitivity of human colon cancer specimens to doxifluridine and 5-fluorouracil, respectively. 1181 May 6

Patients with International Union Against Cancer (UICC) stage IIb and III colon cancer and stage II and III rectal cancer may receive adjuvant chemotherapy with 5-fluorouracil (5-FU). High levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) have been associated with resistance to 5-FU in advanced colorectal cancer. The aim of this study was to investigate the association of TS and DPD mRNA levels with recurrence-free survival in patients with colorectal cancer who are receiving adjuvant 5-FU-based chemotherapy. TS and DPD mRNA quantitation was retrospectively performed in primary colorectal cancer specimens from patients receiving adjuvant 5-FU using a reverse transcription- polymerase chain reaction technique. The median TS mRNA level in patients with a recurrence (n = 142) was 0.68, and in patients without a recurrence (n = 206) the median level was 0.80 (P < 0.01). Patients with a recurrence who had a low TS level (TS < or = 0.9; n = 102) had a median recurrence-free survival of 18 months (range 3.0 to 54 months), and those with a high TS level (TS > 0.9; n = 40) had a median recurrence-free survival of 11 months (range 1.7 to 53 months; P = 0.0024). There was no difference in the median recurrence-free survival of patients with low and high DPD mRNA levels. The TS mRNA level may be a useful marker to predict the time to recurrence in patients with colorectal cancer who are receiving adjuvant 5-FU treatment.
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PMID:Association of time to recurrence with thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression in stage II and III colorectal cancer. 1202 83

A 68-year-old male with a history of gastric resection for gastric cancer underwent resection of the sigmoid colon for a sigmoid colon cancer in February, 2000. The cancer was classified as stage III b. After operation, l-LV + 5-FU therapy was administered, but metastases to the abdominal wall, right inguinal lymph node and spleen developed in succession, and resection was repeated. In October 2001, 1 year and 8 months after sigmoidectomy, however, multiple metastasis to the intraperitoneal lymph node had developed. As surgery was not indicated, TS-1/CDDP combined chemotherapy was started. TS-1 80 mg/day was administered for 4 weeks, the drug was withdrawn for 2 weeks and CDDP 80 mg was injected by intravenous drip at the 8th day of TS-1 administration, which was used as one course. From the second course after inception of the administration, CA19-9 decreased, and after the third course the upper intraperitoneal metastatic lesion disappeared on CT. CR has been continued for 4 months up to the present. Our results suggest a possibility that this therapy is effective not only for gastric cancer but also for colon cancer. This therapy can be administered at home. It is considered to be a useful therapy from the viewpoint of QOL as well. The high DPD activity of the tumor may have been one reason this treatment was effective. This case also seems significant from the viewpoint of attaining individualization of the drug selection in chemotherapy.
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PMID:[A case report--TS-1/CDDP combined chemotherapy found effective for metastatic recurrence after operation for colon cancer]. 1261 Aug 80


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