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PubMed1975

Use of arterial infusion of 5-fluorouracil either alone or in combination with supervoltage radiation as a treatment for carcinoma of the prostate and bladder.

Arterial infusion of 5-fluorouracil either alone or in combination with supervoltage radiation achieves a definite objective improvement in patients with estrogen-resistant adenocarcinoma of the prostate. This improvement has been documented by a decrease in tumor size, improvement in intravenous pyelograms, and a change in cancer grade from undifferentiated to well differentiated. The quality of life in each case has been good, with 45 per cent of the patients treated in this category currently alive and well. The use of protracted arterial infusion of 5-fluorouracil in patients with stage C and D adenocarcinoma and transitional cell carcinoma of the bladder has had an even more satisfying outcome. Of those patients treated, 90 per cent are still alive and free of disease from six to sixty-six months. Eight of the patients have survived over two years with an excellent quality of life. A long-term outpatient infusion program is necessary to achieve these good results. It is also difficult and time-consuming. In addition to having well trained paramedical personnel constantly available, the patients must live within a reasonable radius of the treatment center so they can be treated almost immediately if problems develop. A fairly large number of patients must be treated in order to develop familiarity with the technics and to maintain a level of proficiency.

Adenocarcinoma↗
PubMed1977

Effects of pH on the properties of normal and 5-fluorouracil-containing tRNAs.

Transfer RNAs isolated from Escherichia coli B grown in the presence of 5-fluorouracil (FIUra) show variations in their aminoacylation levels when compared with normal samples. Some of these variations result from the more stringent aminoacylation reaction conditions required for FIUra-tRNAs. Increasing the reaction pH from 7 to 9 for example, generally causes a lowering of amino acid acceptance by the analog-containing tRNAs, while leaving control samples largely unchanged. This decreased activity appears to result primarily from fluorouracil ionization, which in turn disrupts intramolecular hydrogen bonding and promotes an overall increase in the molecular dimensions of FIUra-tRNAs at elevated pH values. Sensitivity to pH differes with the amino acid examined, with lysine showing dramatic changes and glutamine and proline being largely unaffected.

Amino Acyl-tRNA Synthetases↗
PubMed1988

Mechanisms of cross-resistance to methotrexate and 5-fluorouracil in an A2780 human ovarian carcinoma cell subline resistant to cisplatin.

Some properties of the human ovarian carcinoma line A2780 and a subline three times more resistant than the parent line to cisplatin are compared in this report. The rates of uptake and release of cisplatin were similar in the two cell lines. Resistance to cisplatin was associated with: (a) cross-resistance to 5-fluorouracil and methotrexate; (b) a 2.5-fold increase in thymidylate synthase, as measured by both enzyme activity and the capacity to complex 5-fluorodeoxyuridylate; and (c) an increase in the intracellular pools of 5,10-methylenetetrahydrofolate and tetrahydrofolate. These data suggest that cross-resistance to 5-fluorouracil and methotrexate in A2780 cells may be a consequence of increases in their respective target enzymes.

Biological Transport↗
PubMed1989

Inhibition by methotrexate of the stable incorporation of 5-fluorouracil into murine bone marrow DNA.

As a consequence of the inhibition of de novo purine synthesis by methotrexate (MTX) there is an increase in 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration. In cells where 5-fluorouracil (FUra) is activated via orotate phosphoribosyltransferase (OPRtase), increased PRPP results in greater conversion of FUra to nucleotides. In the murine CD8F1 breast tumor system, MTX markedly enhances the antitumor activity of FUra, increasing both the activation of FUra to FUMP and the incorporation of FUTP into RNA. However, in contrast to reported tumor tissue culture studies, MTX pretreatment in vivo prevents the stable incorporation of FUra into CD8F1 bone marrow DNA. Pretreatment with MTX (300 mg/kg) 2.5 hr prior to [3H]FUra (100 mg/kg), with a 2-hr labeling, reduced the level of FUra in DNA from 921 pmol to 66 pmol/mg of DNA. Without MTX pretreatment, 59% of the total incorporation of FUra into nucleic acids was into DNA when FUra was administered. After MTX the percentage of incorporation into DNA was reduced to 9%. Additionally, the ratio of [3H]FUra to 32P in DNA when both were given simultaneously was reduced by greater than 90%, suggesting that MTX must be specifically blocking the incorporation of FUra rather than nonspecifically preventing its incorporation by inhibiting DNA synthesis. In contrast, MTX failed to reduce the formation of DNA containing fluorouracil residues from FdUrd. To test whether MTX prevents the initial incorporation of FUra into DNA, or acts to enhance removal by the DNA glycosylase repair system, DNA was prelabeled in vivo with [3H]FUra, and MTX or MTX plus dThd was then administered. The level of FUra in bone marrow DNA was not reduced by subsequent treatment with MTX, or MTX plus dThd, indicating that MTX does not enhance the removal of FUra from DNA. The level of total free fluorodeoxynucleotides formed from FUra was reduced by two-thirds following MTX pretreatment, suggesting that the action of MTX in preventing the stable incorporation of FUra into DNA was to reduce the availability of FdUTP.

Animals↗
PubMed1990

In vivo 19F NMR spectroscopy of the antimetabolite 5-fluorouracil and its analogues. An assessment of drug metabolism.

The metabolism of 5-fluorouracil (5FU) and its analogues 2'-deoxy-5-fluorouridine (2'FdURD), 5'-deoxy-5-fluorouridine (5'FdURD) and R,S-1-(tetrahydro-2-furyl)-5-fluorouracil (Ftorafur) has been studied by 19F NMR in rat liver and the rat S. G. Prolactinoma. In experiments using i.v. bolus injections of 0.46 mmol/kg 5FU was cleared more rapidly from the liver than 5'FdURD (t1/2 of 4.7 +/- 0.6 vs 15.8 +/- 0.8 min, P less than 0.001). Alphafluoro-beta-alanine (FBALA) production was almost identical after 5FU or 2'FdURD but slower and more sustained after 5'FdURD and still slower after Ftorafur. Both 5FU and 2'FdURD caused formation of toxic fluoronucleotides in S.G. Prolactinomas when administered i.v. (0.92 mmol/kg bolus). After i.v. infusion (0.23 mmol/kg/hr for 4 hr) 5FU produced fluoronucleotides whereas 2'FdURD did not; however, both 5FU and 2'FdURD (0.19 mmol/kg daily i.p. for 7 days) suppressed tumour growth. FBALA was observed in tumors following 5FU and 2'FdURD. Infusion of FBALA itself (0.17 mmol/kg/hr for 4 hr i.v.) led to signal in the tumour, so this compound could have been formed in the liver. These data demonstrate that 19F NMR can monitor drug metabolism in vivo.

Animals↗
PubMed1994

Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer.

BACKGROUND/AIMS: Colon cancer is one of the major health problems in industrialized countries, and its incidence appears to be increasing. Surgical resectability is the most important prognostic determinant, although despite apparently curative surgery, recurrent tumors are common. Metastatic disease cannot be cured, and thus, there is a need for better adjuvant therapies. METHODS: Two hundred and thirty-nine patients with surgically resected colon cancer in Dukes' stage B2 or C were randomly assigned to chemotherapy or observation alone to determine whether adjuvant chemotherapy could effectively reduce the rate of cancer recurrence. One hundred and twenty-one patients in stage B2 and 118 patients in stage C were enrolled in the study. Adjuvant treatment consisted of folinic acid 200 mg/m2, intravenously, plus 5-fluorouracil 400 mg/m2, intravenously, on days 1-5 every 4 weeks for 12 cycles. RESULTS: In stage B2, no significant difference between the adjuvant arm and the observation arm was noted. In stage C, adjuvant chemotherapy produced an advantage over observation in terms of a reduction in cancer recurrence rate with prolongation of a disease-free interval (P = 0.0016) and an improvement in overall survival (P = 0.0025). CONCLUSIONS: This study shows that folinic acid plus 5-fluorouracil adjuvant chemotherapy is effective in patients with surgically resected Dukes' stage C colon carcinoma.

Chemotherapy, Adjuvant↗
PubMed1981

Evaluation of 5-fluorouracil in the treatment of actinic keratosis of the lip.

Topically applied 5-fluorouracil has recently gained acceptance in the treatment of actinic keratosis of the lip; however, histologic evidence confirming the effectiveness of the therapy has not yet been established. Pretreatment biopsies were performed on six patients to confirm actinic damage and grade the degree of dysplasia. After 5-fluorouracil therapy, biopsies of tissue adjacent to the previous biopsy sites were performed to determine the success of treatment. Histologic evaluation showed residual dysplasia in all posttreatment biopsy material, even though the clinical stigmata of the actinic lesions had been improved or eliminated.

Administration, Topical↗
PubMed1976

Bowen's disease of shaft of penis. Successful treatment with 5-fluorouracil.

Bowen's disease is a precancerous lesion of the superficial layers of the skin. The topical application of 5-fluorouracil has been successfully used in the treatment of such lesions. An ususual case of Bowen's disease of the skin of the penile shaft treated successfully with topical 5-fluorouracil is presented along with a review of different modes of treatment.

Administration, Topical↗
PubMed1985

Chemotherapy for adenocarcinomas of bladder and urachal origin: 5-fluorouracil, doxorubicin, and mitomycin-C.

Eight patients with unresectable adenocarcinoma of the bladder or urachus were treated with chemotherapy. Four had received cisplatin-based chemotherapy (CISCA), all 4 failed to respond. All 8 received intravenous and/or intra-arterial 5-fluorouracil, doxorubicin hydrochloride (Adriamycin), and mitomycin-C. Three of the 5 responding patients had short responses while 2 had achieved long-term control of disease. One is in complete remission for eleven plus months, and 1 patient had a partial remission of nineteen plus months. Five patients had serum CEA levels measured at presentation. In the 3 patients with an elevated CEA at presentation who responded to chemotherapy a corresponding drop in the initial level was seen. 5-Fluorouracil-based chemotherapy is effective in the management of adenocarcinoma of the bladder.

Adenocarcinoma↗
PubMed1987

Effects of cyclophosphamide alone and scheduled methotrexate-5-fluorouracil combination chemotherapy on transplantable R-3327 prostatic adenocarcinoma in F1 hybrid male rat.

Male F1 hybrid rats bearing the R-3327 transplantable adenocarcinoma demonstrating similar growth patterns within the original sample of animals were carefully separated into control and treatment groups for each growth pattern. This assured treatment of tumors with similar cell kinetics within each group. In one group, cyclophosphamide (100 mg/kg) was injected intraperitoneally once every four weeks for eight weeks (total of two doses). In the second group, methotrexate (7.5 mg/kg) followed in ninety minutes by 5-fluorouracil (50 mg/kg) were injected intraperitoneally once each week for eight weeks (total of eight doses). These drug dosages did not depress the white cell count of the animals, and they tolerated the medicines well. Excellent suppression of tumor growth was obtained in each group with the cyclophosphamide treatment group being significant at the 0.01 level and the methotrexate-5-fluorouracil treatment group being significant at the 0.05 level.

Adenocarcinoma↗
PubMed1985

The cyclophosphamide, hexamethylmelamine, 5 fluorouracil (CHF) regimen in the treatment of advanced and recurrent ovarian cancer.

Fifty-one patients with advanced ovarian carcinoma were treated with a combination of cyclophosphamide, hexamethylmelamine, and 5-fluorouracil, CHF. Compared to the hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) regimen, the omission of methotrexate in CHF did not detract from its antitumor activity and it was well tolerated with only mild to moderate toxicity. The CHF combination was as effective as Hexa-CAF and was particularly active in patients who had nonmeasurable/residual disease, classified as less than 2 cm in its greatest diameter at the initiation of chemotherapy. In future studies, CHF should be prospectively compared to other combination using Adriamycin and cis-platinum that with extended use can cause renal and cardiac damage in long-term survivors.

Adult↗
PubMed1987

Adjuvant effects of calmodulin antagonists to 5-fluorouracil on tumor cell proliferation and the mechanisms.

The adjuvant effect of calmodulin antagonists (W-5 and W-7) to 5-fluorouracil (5-FU) was studied by using two human cultured cell lines derived from ovarian adenocarcinoma. Enhancement of the uptake of 5-[6-3H]fluorouracil ([3H]FU) by cancer cells was observed only when calmodulin antagonists were added in the presence of [3H]FU. Similarly, the adjuvant effect by W-5 or W-7 on cancer cell proliferation was also observed only when calmodulin antagonists were added in the presence of 5-FU.

Adenocarcinoma↗
PubMed1989

Adjuvant effects of calmodulin antagonists on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur) and a mixture of ftorafur and uracil (UFT) in nude mice bearing human ovarian carcinomas.

Effects of N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur, FT) and a mixture of FT and uracil (UFT) were determined in nude mice bearing human ovarian carcinoma (KF cells). All nude mice developed palpable tumor 17 days after KF cell inoculation unless treated. A combination of UFT and calmodulin antagonists (W-5 and W-7) resulted in a delay in tumor formation in nude mice. One of 10 nude mice treated with a combination of UFT and W-5 and 3 of 10 nude mice treated with UFT and W-7 did not develop tumors during the experimental period. Tumor volumes in groups treated with the combinations of UFT and calmodulin antagonists were significantly smaller than those in the untreated group after 31 days of tumor inoculation. In addition, tumor volumes in a group treated with UFT plus W-7 were significantly smaller than not only those in the untreated group but also those in groups treated with UFT alone, FT alone, W-5 alone, or W-7 alone. The longest median survival time was also observed in the group treated with UFT plus W-7. 5-Fluorouracil (5-FU) content of the tumors of groups treated with FT plus W-5 or W-7 was similar to that of the group treated with FT alone. On the other hand, 5-FU content of a group treated with UFT plus W-7 was about twofold higher than that of a group treated with UFT alone. These results suggest that a synergistic effect of W-7 and UFT on inhibition of tumor growth and prolongation of survival time may result from accumulation of 5-FU in the tumor.

Animals↗
PubMed1989

Chemotherapy in a pregnant rat model. 2.5-fluorouracil: nonlinear kinetics and placental transfer.

As more women postpone childbearing into their later reproductive years (M. A. Adams, G. P. Oakley, and J. S. Marks, J. Amer. Med. Assoc. 247, 493, 1982), the incidence of cancer in pregnancy is likely to increase. Information regarding the placental transfer and pharmacokinetics of antineoplastic agents is limited. The purpose of this study was to determine the kinetics of 5-fluorouracil, a fluorinated pyrimidine with known nonlinear kinetics (J. M. Collins, R. L. Dedrick, F. G. King, et al., Clin. Pharmacol. Ther. 28, 235, 1980) in a pregnant rat model and compare maternal and fetal disposition. A significant amount of 5-fluorouracil crosses the placenta and the relative fetal exposure increases in a dose-dependent fashion. In the pregnant rat model, 5-FU exhibited nonlinear pharmacokinetics as reflected by an increasing half-life, and a greater than proportional increase in the area under the concentration-time curve (AUC) with increasing dose. Fetal saturation of elimination occurred at a lower dose than in the maternal compartment. The significance of these findings to observed embryotoxicity is discussed in a pharmacodynamic model relating the pharmacokinetic behavior of a drug to its embryotoxic effects.

Animals↗
PubMed1990

5-Fluorouracil neurotoxicity.

Two cases of 5-fluorouracil-induced neurotoxicity from the University of North Carolina are presented. 5-Fluorouracil metabolism is briefly discussed with reference to possible mechanisms for the neurotoxicity. A possible role for thiamine supplementation in the prevention of this unusual complication is supported by our experience.

Adult↗
PubMed1985

The molecular basis for the differential sensitivity of B and T lymphocytes to growth inhibition by thymidine and 5-fluorouracil.

Cultured leukemic lymphocytes originating from patients with T, B and non-T, non-B (null) leukemia were tested for their sensitivity to thymidine and 5-fluorouracil. T cells were found to be 5-7 fold more sensitive to thymidine growth inhibition than B-cells. At 10(-3) M concentration of thymidine, T cells showed a progressive (up to 75%) decline in the populating trypan blue-excluding cells, after 72 h. At this concentration of thymidine B cells showed slight inhibition at 24 and 48 h, then at 72 h the surviving cell level returned almost to the level of unperturbed cells. Thymidine at 10(-5) M concentration, caused 40% cell growth inhibition of T cells, however, at this concentration it had little or no effect on B cells. 5-fluorouracil effects on B and T lymphocytes are opposite to that of thymidine. B cells were on an average 5-7 times more sensitive to 5-FU than T cells. 5-FU at 10(-6) M caused up to 45% inhibition of B-cell growth but at this concentration it had no effect on the growth of T cells. B-, T- and null-lymphocytes sensitivity to thymidine and 5-FU was correlated with the level of the catabolic enzyme thymidine phosphorylase. B cells had, on average, 5-fold more thymidine phosphorylase than T or null cells. Furthermore, the enzyme from the B-cell line (HR1K) chromatographed differently on DEAE-Sephadex than the normal peripheral blood lymphocytes enzyme. The normal enzyme from peripheral blood lymphocytes when adsorbed to DEAE-Sephadex was eluted at a salt concentration of 0.3 M KCI, Enzyme activities of HR1K did not adsorb to the DEAE-Sephadex column but were adsorbed to a phosphocellulose column. Enzyme from normal and leukemic lymphocytes showed similar molecular weights of 130,000 dalton as determined by gel filtration.

B-Lymphocytes↗
PubMed1984

In vivo 19F-NMR of 5-fluorouracil incorporation into RNA and metabolites in Escherichia coli cells.

19F resonances from RNA with 5-fluorouracil incorporated could be observed in intact Escherichia coli cells, as well as in tRNA isolated from the cells. 19F-NMR signals from the metabolic breakdown products of the fluorinated RNA were also detected in vivo. By observing the 19F-NMR spectrum, variations in the metabolic disposition of administered 5-fluorouracil could be monitored as a function of time and be compared when the cells were deprived of oxygen and other nutrients, subjected to ethidium bromide treatment, or grown in the presence of mitomycin C.

Escherichia coli↗