Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was < or = 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.
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PMID:5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. 813 56

A combination chemotherapy was used to treat patients with advanced cancer of the extrahepatic biliary system not amenable to surgical resection. Between February 1985 and April 1992, 22 consecutive patients entered into the study; 17 (11 with extrahepatic bile duct cancer and 6 with gallbladder cancer) were evaluable for response and toxicity. The treatment schedule was as follows: epirubicin 20 mg/m2 given as a bolus, followed by methotrexate 150 mg/m2 as a 30-minute infusion, 1 hour later 5-fluorouracil 600 mg/m2 as a 30-minute infusion. Leucovorin rescue (15 mg orally every 6 hours for eight doses) was started 24 hours after methotrexate. This course was administered once a week in 3 successive weeks followed by a 2 to 3 weeks rest period. A total of 174 courses was given. No objective tumor regression was observed. This regimen was well tolerated, the main toxicity being gastrointestinal. The median survival time for the 17 evaluable patients was 9 months.
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PMID:Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system. A phase II study. 819 6

Folinic acid (dlFA) is increasingly used in clinical oncology. The active isomer lFA is intensively metabolized into l5-methyltetrahydrofolate (l5MTHF), the relative proportions of lFA, dFA and l5MTHF in blood varying considerably between oral and i.v. FA administration. The purpose of the study was to compare the in vitro activities of pure lFA and pure l5MTHF at equivalent drug exposure [area under curve (AUC)], taking into account their respective chemical stability in the culture medium. The in vitro growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test] was evaluated on five human tumor cell lines after methotrexate (MTX)-folate or 5-fluorouracil (5FU)-folate exposures. Not only were the activities of lFA and l5MTHF compared, but also clinically relevant mixtures of lFA + dFA + l5MTHF corresponding to the proportions found at steady state during oral (PO mixture, 4, 39 and 57%, respectively) and i.v. administrations (i.v. mixture, 7, 81 and 12%, respectively). Measurement of folates demonstrated the marked lability of l5MTHF (65.8% loss over 5 days in the culture medium) as compared to lFA (2.6% loss). Whatever the pharmacological model tested (MTX-folate or 5FU-folate), comparison of the folate effects at equivalent drug exposure taking into account their relative stability showed that l5MTHF was never more potent than lFA. Moreover, a higher efficiency of lFA was demonstrated for the cell line most sensitive to 5FU; in this case, as expected, the i.v. mixture was more potent than the PO mixture. This study shows that depending on the tumor, lFA can be more potent than its main circulating metabolite l5MTHF. Along with the limited capacity of oral absorption, the choice between oral and i.v. route for FA administration in patients should take into consideration the different pharmacological activities between lFA and l5MTHF which suggest that the oral route is potentially detrimental to the optimal activity of the 5FU-FA combination as compared to i.v. administration.
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PMID:Combination of reduced folates with methotrexate or 5-fluorouracil. Comparison between 5-formyltetrahydrofolate (folinic acid) and 5-methyltetrahydrofolate in vitro activities. 825 Sep 62

Nonhypoxic cell radiosensitizers, principally the halogenated pyrimidines and hydroxyurea, have been studied in the laboratory and clinical setting for more than 30 years. Early clinical experience in the 1960s and 1970s with the thymidine analogs 5-bromodeoxyuridine (BUdR) and 5-iododeoxyuridine (IUdR) was disappointing because normal tissue toxicity eliminated any potential for therapeutic gain. Inadequate delivery systems for intravenous and intraarterial infusions also contributed to the decline of this strategy. More recently, laboratory investigations have revealed further information regarding the mechanism of IUdR/BUdR radiosensitization. This knowledge provided a rationale for the sequence and timing of drug and radiation exposure, which could be both effective and tolerable. Advancing technology also provided safer infusion devices, and a resurgence in clinical trials combining IUdR or BUdR and radiation resulted. Current laboratory studies are now providing data on tumor cell kinetics, which is being applied to ongoing clinical trials. Fluoropyrimidines, principally 5-fluorouracil (5-FU), were also used in early clinical trials and unlike IUdR/BUdR were found to have significant activity as single agents against a variety of tumor types. The clinical integration of 5-FU and radiation occurred more slowly, but recent trials have demonstrated a therapeutic gain. Improved rates of local control and survival with combined 5-FU and radiation versus radiation alone have now been demonstrated in patients with rectal, esophageal, and anal carcinomas. However, the mechanism of interaction between the fluoropyrimidines and radiation remains uncertain and continues to be investigated with the hope of improved clinical outcome. As the cellular pathways influenced by the halogenated pyrimidines have been defined, the potential for biochemical modulation of these agents has been recognized. Leucovorin, the most commonly applied modulator, has been shown to enhance the activity of 5-FU in patients with metastatic colorectal carcinoma. These studies serve as an example for current trials that use biochemical modulators of IUdR, BUdR, and 5-FU as radiosensitizers. Hydroxyurea, currently used in the treatment of chronic leukemia, has also been considered a radiosensitizer. As with IUdR/BUdR, the clinical trials have often been inconclusive and interest in this radiosensitizer has waned. A poor understanding of the mechanism of action and tumor cell/normal tissue kinetics may be responsible for the lack of overall success with this strategy. Current investigations of cell kinetics in humans and potential mechanisms of hydroxyurea action could provide information critical to future trials of hydroxyurea radiosensitization.
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PMID:The clinical rationale for S-phase radiosensitization in human tumors. 828 9

Leucovorin, given usually by i.v. injection or orally changes to 5, 10-methylene tetrahydrofolate in tumor as well as normal cells. And in normal FdUMP, an active metabolite of 5-FU, binds tightly to thymidylate synthase in the presence of cofactor, 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Phase I study using l-leucovorin (l-LV), an active form of leucovorin, combined with 5-FU, was conducted. In the weekly schedule, 5-FU was fixed to 600mg/m2, and l-LV dose was escalated from 125 mg/m2 to 250mg/m2, if toxicity was acceptable. On the other hand, in the five consecutive-day schedule, 5-FU was fixed to 370mg/m2 and l-LV was escalated from 25mg/m2 to 50mg/m2, 100mg/m2 and 200 mg/m2. l-LV 10mg/m2 was tested as reference. On weekly schedule of l-LV 250mg/m2, grade III diarrhea was seen in 2 cases and grade IV leucopenia was seen in one. In five consecutive-day schedule, at each dose of l-LV, stomatitis, nausea plus vomiting, anorexia, anemia and leucopenia were seen. However, the increase of toxicities were not seen by dose escalation of l-LV. Then, we have been conducted a randomized early phase II study using 250 mg/m2 of l-LV weekly (arm A) and 100mg/m2 (arm B) or 10mg/m2 (arm C) of l-LV for 5 consecutive days in gastric and colorectal cancer by multicenter cooperative study. Plasma concentrations of l-LV were maintained > 10(-5) mol/L for over 5 hrs. after 2 hrs. infusion of 250 mg/m2 of l-LV and for over one hr. after a rapid injection of 100mg/m2 of l-LV.
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PMID:[Phase I study of 5-fluorouracil and l-leucovorin]. 845 86

We experienced a case of small cell carcinoma of the esophagus treated by operation. A 57-year-old female was examined for a complaint of dysphagia. The radiologic and endoscopic examination revealed Borrmann III like tumor (8 cm long) at lower esophagus (EiEa). Endoscopic biopsy led to a diagnosis of poorly differentiated squamous cell carcinoma. Chest X-ray and chest CT showed no lung tumor, no swelling of lymph node and no invasion of esophageal tumor. Lower esophagectomy, proximal gastrectomy and esophago-gastrostomy through intrathoracic route was performed. Histopathologically, resected tumor was diagnosed as small cell carcinoma (Oat-cell type) with rosette formation. Grimerius stain revealed negative reaction and immunohistochemical stain by NSE monoclonal antibody revealed positive reaction in tumor cells. Histological staging was a0, n1(+), M0, P1(zero), stage II. Recurrence at paraaortic lymph node occurred in 2 months after the surgery. Chemotherapy (CDDP, 5-FU and Leucovorin) was performed, but not effective. She died from multiple metastases in 5 months after the surgery (6 months after the diagnosis).
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PMID:[A case of small cell carcinoma (oat-cell type) of the esophagus]. 874 55

This study examined a combined treatment for colorectal carcinoma, the dual biochemical modulation therapy, consisting of 5-FU, Leucovorin (LV) and Cisplatin (CDDP). We compared its anti-tumor effects with other treatments: 5-FU alone, CDDP alone and 5-FU with LV. Primary diffuse infiltrated colorectal carcinoma is well known for its biological malignancy and its lack of response to chemotherapy. We used SRM cells from a cell line of carcinoma of the rectum, and subcutaneously injected them into nude mice. The anti-tumor effects were estimated from the growth rate, inhibition rate and thymidylate synthetase inhibition rates in the tumor tissue. Results indicated that even if the concentration of 5-FU and LV were reduced by half, these combined with CDDP were more effective than other therapies. Dual biochemical modulation therapy is particularly promising because the reduction of the dosages would reduce the side effects while still serving as an excellent anti-tumor therapy.
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PMID:[Dual biochemical modulation therapy using 5-FU, leucovorin and cisplatin on human rectal carcinoma xenografts in nude mouse]. 875 2

Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in group B that were not evaluable because they abandoned therapy after the first cycle. Toxicity was increased in group B; anemia, nausea and vomiting, and alopecia (p < 0.055) were more severe in group B, but not statistically different when compared to group A. Neutropenia, thrombocytopenia, mucositis, and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate was increased in the schedule with the addition of LV, at the cost of increased toxicity and with no difference in survival. A randomized trial comparing FEM-LV with new generation regimens would determine whether the addition of LV qualifies FAM equally active with these.
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PMID:5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial. 882 83

Folinic acid (leucovorin) is frequently used to augment and modulate the clinical activity of 5-fluorouracil (5-FU) in patients with advanced gastrointestinal (Gl) cancer. However, there are conflicting opinions concerning the optimal doses for these patients, and whether folinic acid modulates the clinical activity of 5-FU in patients with non-Gl cancer. To elucidate these questions, model experiments have been performed on human tumor cell lines in vitro to determine the modulatory activity of various concentrations of folinic acid on 5-FU mediated cytotoxicity using a clonogenic assay. Three cell lines of colon cancer and 3 of glioblastoma origin were exposed to 5-FU alone or with folinic acid for 24 hours. It was observed that relatively low concentrations of folinic acid enhanced the cytotoxicity of 5-FU against the colon cancer lines whereas higher concentrations were less effective. Folinic acid did not enhance the 5-FU mediated killing of the glioma cell lines at any concentration (0.01-100 micrograms/ml). On the contrary, folinic acid seemed to counteract the cytotoxic effect of 5-FU in a reasonably dose-dependent fashion. These results may suggest that the value of folinic acid in the treatment of non-Gl cancer with 5-FU should be evaluated within the framework of controlled clinical trials, and that high doses of folinic acid may not necessarily be more effective than low.
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PMID:Dual effects of folinic acid in 5-fluorouracil induced killing of human tumor cell lines in vitro. 891 76

Either folic or folinic acid enhanced the antimetastatic activity of recombinant murine interferon beta (rMulFN beta) toward highly metastatic colon carcinoma 26 (Co 26Lu). Folinic acid administered with rMuIFN beta markedly increased asialoGM1+CD4+ and asialoGM1+CD8+ T cell production in the peritoneal cavity but not in the thymus and spleen. Peritoneal cells expressed killing activity toward Co 26Lu cells in vitro. In athymic nude mice, the above combination produced many asialoGM1+CD4+ and few asialoGM1+CD8+ T cells in the peritoneal cavity, but did not decrease lung metastatic colonies. AsialoGM1+CD4+ T cells would thus appear to have no or only very weak killing activity toward these tumor cells. The antimetastatic activity of folinic acid with rMuIFN beta was significantly decreased with anti-asialoGM1 and anti-CD8 antibodies. Inactivated CD8+ and asialoGM1+ cells cease to have killing activity toward Co 26Lu cells as shown by Winn's assay. AsialoGM1+CD8+ cell production was markedly induced in the peritoneal cavity by treatment with rMuIFN beta and folinic acid. AsialoGM1+CD8+ T cells may be inhibiting lung metastasis of Co 26Lu. Folinic acid and interferon are used in combination therapy with 5-fluorouracil for biochemical modulation. Folinic acid with interferon, as adjuvant therapy, may promote the induction of CD8+ T cell production with consequent prevention of metastasis.
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PMID:Markedly induced asialoGM1+CD8+ T cell production and enhancement of antimetastatic activity by interferon beta with folic or folinic acid. 917 66


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