Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors of thymidylate synthetase, 5-fluoro-2'-deoxyuridine (FUDR) and 5-fluorouracil (FU), enhanced in vitro thymidine labeling of human breast carcinoma cells. Their use resulted in an increase in the measured thymidine labeling index (TLI) of breast carcinomas by increasing detectability of labeled nuclei in autoradiographs. The TLI was measured with FU or FUDR enhancement in primary breast carcinomas from nine women younger than age 50, and from 30 women 50 years or older. The mean and geometric mean TLI were 8.0 and 6.3 respectively for the younger group, and 4.0 and 2.8 respectively for the older group. Similar significant age-associated differences were noted in a series of 133 TLI measurements without FU or FUDR. The TLI was not significantly correlated with primary breast carcinoma size or number of axillary nodal metastases. The capacity to form axillary metastases must be related to factors other than the rate of cell replication in breast carcinomas.
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PMID:Thymidine labeling index of human breast carcinoma. Enhancement of in vitro labeling by 5-fluorouracil and 5-fluoro-2'-deoxyuridine. 14 21

The inhibition of thymidylate synthase (TS) by the fluorouracil (5-FU) metabolite 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) is considered to be one of the main mechanisms of action of 5-FU. The inhibition of TS is mediated by the formation of a ternary complex between TS, FdUMP, and the folate cofactor 5,10-methylene tetrahydrofolate. The activity of TS, its inhibition by FdUMP, and the binding of FdUMP to TS have been determined in biopsy specimens of colorectal tumors, liver metastases, normal colon mucosa, and liver obtained from patients who never had received chemotherapy, and patients treated with 5-FU or 5-FU with leucovorin (LV). In nontreated patients we observed a large variation in the activity of TS both at 1 microM and 10 microM dUMP (40- to 80-fold difference). In contrast, in normal colonic mucosa this variation was less than 10-fold. FdUMP binding in tumors also varied considerably but was not detectable in normal mucosa. The deviations from normal (ie, as found in mucosa) kinetic patterns of TS may represent a mutant TS form. Thirty-five patients with advanced colorectal cancer received 5-FU (500 mg/m2) at 1 to 48 hours prior to surgery. In biopsy specimens of tumor and normal tissues the residual catalytic activity of TS and the percentage of free-binding sites for FdUMP (TS-free) were determined. After dissociation of FdUMP, total catalytic activity of TS- and total FdUMP-binding sites (TS-tot) were determined. Total and residual catalytic TS activity in primary tumors and metastases showed a large variation. TS-tot and TS-free in tumors also varied considerably. At least eight patients with an undetectable TS-free showed response to subsequent intraarterial treatment with 5-FU. To several patients leucovorin (2-hour infusion of 500 mg/m2) was administered with a 5-FU bolus (500 mg/m2) in the middle of the infusion. Biopsy specimens were obtained about 48 hours after treatment. In these patients inhibition of TS was markedly enhanced compared with patients who did not receive LV. The large variation in TS may be related to the observed variation in clinical response to 5-FU treatment.
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PMID:Time course of inhibition of thymidylate synthase in patients treated with fluorouracil and leucovorin. 155 55

The effects of preoperative treatment by continuous intravenous infusion of Tegafur, the antagonist of DNA synthesis, were histopathologically studied in 34 patients with gastric cancer. Histologically the treatment was found to be effective in 41.2% of patients with cancer invasion in the mucosa, 58.8% in the submucosa, 61.3% in the muscularis propria, 59.3% in the subserosa and 86.9% of those with metastatic lymph nodes. The treatment was effective, when assessed in terms of the histological type of cancer, in 90.9% of cancers of the differentiated type (papillary adenocarcinoma, well differentiated tubular adenocarcinoma and moderately differentiated tubular adenocarcinoma) and 47.8% of those of the poorly differentiated type (poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet-ring cell carcinoma), showing a higher rate of efficacy in the differentiated type cancers. Meanwhile, even among patients with cancer of poorly differentiated type, a high efficacy rate (90.0%) was found in those with metastatic cancer of the lymph nodes. No relationship was found between the total doses of Tegafur and histological effects. There was a tendency, however, for a higher frequency of a good response in patients administered more than 4,000 mg of Tegafur. In the patients with a histologically positive effect, 5-FU concentration in the tumor tissue was higher than 0.071 microgram/g. However, some patients showed no response despite a high concentration. This finding suggested that sensitivity to 5-FU and 5-FU metabolism vary depending on the tumor. The inhibitory effect of Tegafur on DNA synthesis is produced through inhibition of thymidylate synthase (TS) by the Tegafur metabolite FdUMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Histopathological studies on antitumor effect of tegafur administered by continuous intravenous infusion]. 211 40

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.
Cancer Metastasis Rev 1987
PMID:Biological and biochemical properties of new anticancer folate antagonists. 354 36

The expression of several resistance markers (P-glycoprotein, glutathione S-transferase-pi, thymidylate synthase, dihydrofolate reductase) was analyzed in matched primary tumors and lymph node metastases from 21 patients with lung cancer using immunohistochemistry. The analysis showed that expression of these resistance proteins is generally congruent in primary lung cancer and simultaneously resected lymph node metastases. This suggests that in general the resistance of a primary tumor predicts for the resistance of the metastases and vice versa.
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PMID:Detection of resistance proteins in matched primary lung tumors and lymph node metastases. 791 93

We assayed thymidylate synthase (TS) activity and performed flow-cytometric DNA analyses in fresh tumor tissues from 38 patients with ovarian cancer. TS activity was closely correlated with prognosis but was not related to age, clinical stage, histologic type or lymph node metastases. Patients with TS activity higher than 2.0 pmol/g tissue had significantly worse prognoses than those with lower levels (p < 0.01). Also, patients with DNA aneuploidy or high S-phase fractions (> 20%) had worse prognoses than those with DNA diploidy or lower fractions. Results suggest that TS activity may be a good prognostic indicator in ovarian cancer.
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PMID:Thymidylate synthase activity as a prognostic factor in ovarian cancer. 820 16

'Tomudex' (ZD1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2 given once every 3 weeks or 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin (LV) 20 mg/m2 for 5 days (the Mayo regimen), given every 4-5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25-29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P = 0.059, odds ratio 1.7, 95% confidence limits 0.98-2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.
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PMID:'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group. 856 46

Surgery is currently the first-line treatment option for primary colorectal cancer (CRC) and resectable metastatic disease. Cytotoxic chemotherapy is used for adjuvant treatment as well as for the treatment of advanced disease; the combination of 5-fluorouracil (5-FU) plus leucovorin is currently the standard chemotherapeutic regimen used in most centers. In many countries patients with CRC do not receive chemotherapy because some clinicians perceive that the benefits of such treatment do not compensate for the potential negative effects on patient quality of life in terms of toxicity and inconvenient dosage schedules. However, recent evidence suggests that the use of cytotoxic chemotherapy can lead to an improvement in quality of life and effective palliation in CRC. A number of new treatment options are becoming available for the treatment of this malignancy. These include new anticancer agents such as thymidylate synthase inhibitors, monoclonal antibodies and topoisomerase I inhibitors, and new treatment methods including hepatic arterial or i.p. chemotherapy, cryosurgery and chemo-embolization. With the increased referral of patients to oncologists and the use of a multidisciplinary team approach, these new agents and new methods of treatment can be fully evaluated for the treatment of CRC, and should ultimately improve the treatment and outcome of this common disease.
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PMID:Colorectal cancer--an undertreated disease. 891 29

Over the past year, several new anticancer agents have entered the clinic and are undergoing further phase II clinical development at the time of this writing. There has been a sudden influx of rationally designed drugs with novel therapeutic effects ranging from direct cellular toxicity to inhibition of blood vessel formation and of metastases. This review focuses only on cytotoxic drugs that have been in clinical development for the past 5 years; however, only recently have these drugs found a "niche" in the clinic. These drugs include novel taxanes (eg, docetaxel), the camptothecin analogues (eg, irinotecan [CPT-11]), the newer generation of thymidylate synthase inhibitors (eg, raltitrexed [ZD 1694, Tomudex]), nucleoside analogues (eg, gemcitabine), and oral alternatives to intravenous 5-fluorouracil. Most of these agents have completed or have entered phase II or III testing, and the results of these trials will be available to us over the next few years.
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PMID:Promising new agents in oncologic treatment. 897 73

The increasing interest in 5-fluorouracil (5-FU) modulation and the development of new antifolates has focused attention in recent studies on the expression of the target enzyme thymidylate synthase (TS) as a determinant of drug sensitivity and resistance. Resistance to TS-directed drugs has been shown to occur in vitro and in vivo with increased expression of the enzyme (determined by enzymatic assays as well as protein and gene expression assays). Several studies have evaluated the role of TS as a prognostic indicator of clinical response to chemotherapy containing TS-directed drugs. We have used a polyclonal antibody to recombinant human TS to establish a silver-enhanced immunogold staining method to localize TS in human tumours. Human tumour cell lines with acquired resistance to TS inhibitors owing to increased levels of TS were used to confirm the specificity of immunostaining. Stained sections were evaluated by image analysis. Immunostaining in tumour sections was greatly reduced (>80%) by preabsorption of the antiserum with recombinant TS. The method was used to determine the extent of TS immunostaining in 134 primary human colorectal tumours. The results were then compared with the clinical outcome and response to chemotherapy for the treatment of subsequent metastatic disease. A wide range (approximately 100-fold) of TS immunostaining was observed in these primary tumour sections. Normal mucosal tissue levels were 5-10 times lower than those observed in the adjacent tumour tissue. The values for TS immunostaining did not correlate with clinical endpoints, such as time from diagnosis to relapse, response to chemotherapy for disseminated disease, nor with Dukes' staging. This lack of correlation may be because this group of patients was selected on the basis of their need for palliative chemotherapy and did not include patients who were cured of their disease. Also, primary tumour TS expression may not give a good indication of the TS expression in metastatic lesions. The prognostic significance of TS protein expression in primary and metastatic lesions requires further evaluation.
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PMID:Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy. 906 14


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