A. Leyva

Universidade Federal do Ceará

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Herbert M. Pinedo

Amsterdam University Medical Centers

Godefridus J. Peters

Amsterdam University Medical Centers

E. Laurensse

Vrije Universiteit Amsterdam

J. Lankelma

University of Amsterdam

Jan H. Schornagel

The Netherlands Cancer Institute

H. M. Pinedo

Amsterdam UMC Location VUmc

Cláudia Pessoa

Universidade Federal do Ceará

I Kraal

Vrije Universiteit Amsterdam

Manoel Odorico de Moraes

Universidade Federal do Ceará

Boudewijn J.M. Braakhuis

Amsterdam UMC Location VUmc

Cooperative Institutions

University of Amsterdam

Vrije Universiteit Amsterdam

Amsterdam UMC Location VUmc

The Netherlands Cancer Institute

Universidade Federal do Ceará

Utrecht University

Oncode Institute

Amsterdam University Medical Centers

Universidade de Fortaleza

Leiden University

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Sensitivity of human, murine, and rat cells to 5-fluorouracil and 5'-deoxy-5-fluorouridine in relation to drug-metabolizing enzymes.

PubMed (1986)

Godefridus J. Peters Emile J. Laurensse A. Leyva Jan Lankelma Herbert M. Pinedo

Six cell lines differing in histological origin were studied regarding the growth inhibitory effect of fluoropyrimidines in relation to their metabolism. The human colon carcinoma cell line WiDr was most sensitive to 5-fluorouracil (FUra) (50% growth inhibitory concentration, 0.7 microM) and to its analogue 5'deoxy-5-fluorouridine (5'dFUR) (50% growth inhibitory concentration, 18 microM). The murine B16 melanoma cell line was moderately sensitive to FUra but least sensitive to 5'dFUR. The 50% growth inhibitory concentration values in the human melanoma cell lines IGR3 and M5, the transformed human intestine cell line intestine 407 and the rat hepatoma cell line H35 varied for FUra between 1.7 and 5.0 microM, and for 5'dFUR between 54 and 160 microM. Several enzymes from pyrimidine metabolism responsible for FUra metabolism were measured with FUra as a substrate. The activity of uridine phosphorylase, which catalyzes the conversion of 5'dFUR to FUra, was lowest in B16 cells correlating with the low sensitivity to 5'dFUR. When adenosine 5'-triphosphate was included in the reaction mixture for uridine phosphorylase, FUra was rapidly channeled into FUra nucleotides via its nucleoside. The rate of channeling appeared to correlate with the nucleoside phosphorylase activity in the various cell lines. In several cell lines activities of nucleotide-degrading enzymes were rather high and interfered with the measurement of orotate phosphoribosyl transferase (OPRT) with FUra as substrate. Addition of the phosphatase inhibitor glycerol-2-phosphate partly prevented breakdown of the newly formed 5-fluorouridine 5'-monophosphate and enabled measurement of OPRT. The WiDr cell line had a relatively high OPRT activity which could explain its sensitivity to FUra. The activity of thymidylate synthase was measured at a suboptimal concentration of 1 microM and at the optimal concentration of 10 microM deoxyuridine 5'-phosphate. With all cell lines the ratio between the activities at 10 and 1 microM was between 2.3 and 3.6. The activity of thymidylate synthase was lowest in WiDr and IGR3 cells and 3-4 times higher in M5 and Intestine 407 cells. The inhibition of 0.01 microM 5-fluorodeoxyuridine 5'-monophosphate was 80-90% at 1 microM deoxyuridine 5'-phosphate and 50-70% at 10 microM deoxyuridine 5'-phosphate with all cell lines. At 0.1 microM 5-fluorodeoxyuridine 5'-monophosphate enzyme activity was inhibited by 95-100%. The incorporation of FUra into RNA was relatively low in IGR3 cells and 3-5 times higher in all other cell lines.(ABSTRACT TRUNCATED AT 400 WORDS)

Uracil

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Citations (189)

Purine nucleosides as cell-specific modulators of 5-fluorouracil metabolism and cytotoxicity

European Journal of Cancer and Clinical Oncology (1987)

Godefridus J. Peters Emile Laurensse A. Leyva Herbert M. Pinedo

Inosine

Nucleic acid analogue

Thymidine

Purine metabolism

10.1016/0277-5379(87)90053-8

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Citations (55)

Characterization of methotrexate recovered from the urine of high dose patients for the purpose of clinical re-use

European Journal of Cancer (1965) (1978)

A. Leyva P.D. Baygell A. C. Van Loenen P. van Asten C. Pintus

10.1016/0014-2964(78)90056-7

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Citations (3)

Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity.

PubMed (1984)

A. Leyva C.J. van Groeningen I Kraal H.E. Gall Godefridus J. Peters

The clinical effects and pharmacokinetics of high-dose uridine were determined in seven patients with advanced-stage cancer and in one healthy volunteer. Uridine was also examined for its effect on 5-fluorouracil toxicity in two patients. Uridine was administered as a 1-hr i.v. infusion at doses of 1 to 12 g/sq m. Plasma and urine samples were analyzed for uridine and uracil using high-pressure liquid chromatography. In 23 courses of uridine alone, the only toxicity observed was transient shivering after one of two courses at 12 g/sq m. This side effect was also seen after administration of uridine (10 g/sq m) during combination with 5-fluorouracil. The pretreatment plasma uridine concentration was elevated from low micromolar to millimolar levels with uridine administration at doses up to 12 g/sq m. Maximal areas under the concentration-time curve were about 5 mmol/liter/hr. Both peak plasma level and area under the curve for uridine increased linearly with dose. Uridine plasma decay curves were biphasic with a terminal half-life of 118 min. Half-life, volume of distribution (634 ml/kg), and total clearance (4.98 ml/kg/min) appeared to be independent of dose. Plasma uracil concentration increased gradually after administration of uridine to plateau levels. Maximal plasma uracil concentrations were about one-tenth that of peak uridine concentrations. The plasma uracil level declined with a half-life of about 40 min after uridine levels decreased to 300 microM. Total urinary excretion of uridine was 24% of the dose, while the amount of uracil recovered in urine was 3.4%. In two patients, uridine rescue was attempted during 5-fluorouracil dose escalation. Uridine at 5 to 6 g/sq m given on 1 or on 2 days after 5-fluorouracil did not prevent myelosuppression and gastrointestinal toxicity associated with increasing plasma concentrations of 5-fluorouracil. These data show that uridine administered as a 1-hr infusion at doses which provide peak plasma uridine concentrations in the millimolar range is well tolerated. Rapid elimination of uridine primarily due to catabolism results in modest exposure to substantially elevated plasma uridine concentrations. Preliminary findings suggest that prolonged treatment with uridine may be required to test its potential to rescue patients from 5-fluorouracil toxicity.

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Citations (82)

Pharmacokinetics and biological responses after treatment of the rat R‐1 rhabdomyosarcoma with methotrexate

International Journal of Cancer (1993)

J. B. A. Kipp A. Leyva A. H. van Gennip Henk B. Kal

Time relationships of drug concentrations in tissue of a transplantable rat rhabdomyosarcoma and of tumour responses up to 120 hr after treatment with methotrexate (MTX) were analysed and compared. MTX was shown to be retained within the tumour in a substantial concentration for several days, although no evidence of MTX polyglutamation was obtained. The response data confirm that MTX is active in the tumour for up to at least 3 days after injection. Within the first day after MTX treatment the nucleotide pools are only partly depleted. This indicates that the inhibition of DNA synthesis is still incomplete at the time when salvage precursors in increasing amounts are becoming available from decaying cells. From flow cytometric analysis of cell-cycle progression it is concluded that subsequent cohorts arriving in early S-phase were retarded, but not inhibited, in their progression through the S phase. At 3 days after MTX treatment the mean rate of cell-cycle progression as well as the relative clonogenic capacity were maximally reduced to 30% and 1% of control values, respectively. From 3 to 5 days the rate of cell-cycle progression was gradually restored, whereas from day 5 onwards the clonogenic capacity increased at a high rate corresponding to the proliferation rate of exponentially growing rhabdomyosarcoma cells in culture. However, a continuous reduction of cell recovery lasting for at least 12 days after treatment contributed to an 8-day delay in tumour volume growth.

Clonogenic assay

10.1002/ijc.2910540614

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Citations (0)

Effect of pyrimidine nucleosides on body temperatures of man and rabbit in relation to pharmacokinetic data.

Pharmaceutical Research (1987)

Godefridus J. Peters Cees J. van Groeningen Emile J. Laurensse I Kraal A. Leyva

Cytidine

Uracil

Bolus (digestion)

10.1023/a:1016410817898

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Citations (36)

Synergism between purines and thymidine in reversal of methotrexate toxicity in mice using continuous infusions

M.P. Uitendaal Jan H. Schornagel A. Leyva Herbert M. Pinedo

Purine metabolism

Thymidine

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Citations (0)

Activity of Differentiation-inducing Agents and Conventional Drugs in Head and Neck Cancer Xenografts

Acta Oto-Laryngologica (1988)

Guus A.M.S. van Dongen Boudewijn J.M. Braakhuis Marian Bagnay A. Leyva G. B. Snow

Three putative differentiation inducing agents and five conventional drugs which have been shown to be active in patients with squamous cell carcinoma of the head and neck (HNSCC), were tested for activity against HNSCC transplanted in nude mice. Drugs were administered at a maximum tolerated dose level. By testing the effect of conventional drugs the value of the nude mouse xenograft model for testing new drugs was assessed. Bleomycin as well as cisplatin showed antitumour effects in nude mice, although toxicity and thereby the effectiveness of cisplatin varied during the 5-year period in which the experiments were performed. Bleomycin caused responses in 4 out of 13 tumour lines and cisplatin, when administered at a high dose, was active in 2 out of 5 tumours. 5-Fluoroura-cil and cyclophosphamide were only moderately active, while methotrexate was inactive. These data indicate that the model might be of value in the detection of new anticancer drugs although it may have a tendency to underestimate the activity of some drugs. We used the nude mouse xenograft model to test the antitumour activity of three differentiation inducing agents, the polar-planar solvents hexamethylene bisacetamide (HMBA) and N, N-dimethylformamide (DMF) and the antimetabolite 5-aza-2′-deoxycytidine (5-aza-dCyd). HMBA appeared to be inactive. In contrast, DMF was active in 1 out of 4 tumour lines while 5-aza-dCyd was active in 2 out of 5 lines tested. Furthermore, the whole panel of differentiation inducers and conventional drugs was tested for antitumour activity against three HNSCC tumour lines. The data indicate that in some human HNSSC tumours the differentiation inducing agents 5-aza-dCyd and DMF have a better antitumour activity than the conventional drugs. In contrast no antitumour activity of HMBA was found.

Nude mouse

10.3109/00016488809119507

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Citations (3)

Effects of human ascites fluid on cloning efficiency (CE) of human tumor cell lines in agar

HJ Broxterman C. Sprenkels-Schotte A. Leyva Herbert M. Pinedo

Cloning (programming)

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Antiproliferative effects of compounds derived from plants of Northeast Brazil

Phytotherapy Research (2000)

C. Pessoa E. R. Silveira Telma L. G. Lemos Lori A Wetmore Manoel Odorico de Moraes

Ten compounds derived from plants indigenous to Northeast Brazil were examined for antiproliferative effects on human cells in vitro. The effects of these phytochemicals on cell growth were determined by the MTT microtitre assay with 3-day continuous drug exposure. Three human cell lines were used: CEM leukaemia, SW1573 lung tumour and CCD922 normal skin fibroblasts. Four active compounds were found with IC(50) values less than 10 microg/mL in the two cancer cell lines. Oncocalyxones A and C, both 1,4-anthracenediones from Auxemma oncocalyx (Boraginaceae), showed cytotoxicity with mean IC(50) values of 0.8-2, 7-8 and 12-13 microg/mL against CEM, SW1573 and CCD922, respectively. One diterpene and one flavonoid, both from Egletes viscosa (Compositae), were also active. 12-Acetoxy-hawtriwaic acid lactone was cytotoxic with mean IC(50) values of 6, 10 and 10 microg/mL, respectively. 4,5-Dihydroxy-3,3,7, 8-tetramethoxy flavone (ternatin) was only growth-inhibitory with mean IC(50) values of 2, 1 and 10 microg/mL, respectively. These four most active compounds were examined further for their effects on DNA integrity and on DNA synthesis. All but ternatin caused substantial DNA damage and marked inhibition of 5-bromo-2'-deoxyuridine incorporation within 24 h. This study demonstrated the antiproliferative activity of four novel phytochemicals, three of which are DNA-reactive and inhibit DNA synthesis. Further studies are warranted to evaluate these compounds for antitumour potential.

10.1002/(sici)1099-1573(200005)14:3<187::aid-ptr572>3.0.co;2-i

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Citations (51)