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Thomas Spector – One of the best experts on this subject based on the ideXlab platform.

  • BASIC SCIENCE INVESTIGATIONS Blocking Catabolism with Eniluracil Enhances PET Studies of 5-[18F]Fluorouracil
    , 2015
    Co-Authors: James R. Bading, Thomas Spector, Mian M. Alauddin, John D. Fissekis, Antranik H. Shahinian, Jinhun Joung, Peter S. Conti
    Abstract:

    Noninvasive methods for measuring the pharmacokinetics of chemo-therapeutic drugs such as 5-fluorouracil (FU) are needed for individu-alized optimization of treatment regimens. PET imaging of [18F]FU (PET/[18F]FU) is potentially useful in this context, but PET/[18F]FU is severely hampered by low tumor uptake of radiolabel and rapid catabolism of FU in vivo. Pretreatment with eniluracil (5Ethynyluracil) prevents catabolism of FU. Hypothesizing that suppression of catabo-lism would enhance PET/[18F]FU, we examined the effects of enilura-cil on the short-term pharmacokinetics of the radiotracer. Methods: Anesthetized rats bearing a subcutaneous rat colorectal tumor were given eniluracil or placebo and injected intravenously 1 h later with [18F]FU or [3H]FU. In the 18F studies, dynamic PET image sequences were obtained 0–2 h after injection. Tumors were excised and frozen at 2 h and then analyzed for labeled metabolites by high-performance liquid chrochromatography. Biodistribution of radiolabel was determine

  • Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil
    Investigational New Drugs, 2000
    Co-Authors: Melanie T. Paff, Stephen T. Davis, David P. Baccanari, Shousong Cao, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    Eniluracil (5Ethynyluracil, GW 776, 776C85) isbeing developed as a novel modulator of 5-fluorouracil (5-FU) forthe treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), thefirst enzyme in the catabolic pathway of 5-FU. By temporarilyeliminating this prevalent enzyme, eniluracil providespredictable dosing of 5-FU and enables oral administration of5-FU to replace intravenous bolus and continuously infuseddosing. New DPD is synthesized with a half-life of 2.6 days. Italso eliminates the formation of problematic 5-FU catabolites.Most importantly, in laboratory animals, eniluracil increases thetherapeutic index and absolute efficacy of 5-FU. Accompanyingreports in this journal indicate that eniluracil has promisingclinical potential.

  • α-Fluoro-β-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracil
    Biochemical pharmacology, 2000
    Co-Authors: Shousong Cao, David J. T. Porter, Stephen T. Davis, David P. Baccanari, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanalanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5Ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.

David J. T. Porter – One of the best experts on this subject based on the ideXlab platform.

  • α-Fluoro-β-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracil
    Biochemical pharmacology, 2000
    Co-Authors: Shousong Cao, David J. T. Porter, Stephen T. Davis, David P. Baccanari, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5Ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.

  • Reaction of 5Ethynyluracil with Rat Liver Xanthine Oxidase*
    Journal of Biological Chemistry, 1994
    Co-Authors: David J. T. Porter
    Abstract:

    Abstract 5Ethynyluracil is a time-dependent and tight binding inhibitor of xanthine oxidase. The maximal value of the first-order rate constant for onset of inhibition is 0.01 s-1, and the concentration of 5Ethynyluracil which gives one-half of this value is 190 microM. Because the t1/2 for formation of active enzyme from inhibited enzyme is greater than 30 h in the absence of NADH, inhibition of xanthine oxidase by 5Ethynyluracil is functionally irreversible. One equivalent of 5-[2-14C]Ethynyluracil/equivalent of active enzyme is required for complete inhibition. Allopurinol (100 microM), a potent inhibitor of xanthine oxidase, and cyanide (5 mM), an inactivator of the enzyme, do not abolish the binding of 5-[2-14C]Ethynyluracil to the enzyme. Because radiolabel is released from 5-[2-14C]Ethynyluracil-treated enzyme by treatment with 6 M guanidine HCl, a stable covalent bond is not formed between the inhibitor and the enzyme. However, the radiolabel released from inhibited enzyme is not 5Ethynyluracil. Moreover, NADH restores catalytic activity to the inhibited enzyme and displaces the radiolabel as 5-acetyluracil. Thermal denaturation of 5Ethynyluracil-inhibited xanthine oxidase results in the release of approximately equal amounts of 5-acetyluracil and a more hydrophilic product. Consequently, the 5Ethynyluracilxanthine oxidase complex yields different degradation products of 5Ethynyluracil under different denaturation conditions. Seven uracil analogues with 5-substituents were tested as time-dependent inhibitors of xanthine oxidase. 5Ethynyluracil is the only uracil analogue that potently inhibited xanthine oxidase. The reactivity of these uracil derivatives with sulfite was also determined. 5Ethynyluracil is many fold more susceptible to nonenzymatic nucleophilic addition of sulfite than are the other analogues. Thus, the potency of these uracil analogues as inhibitors of xanthine oxidase is related to the nonenzymatic reactivity of the analogues with sulfite.

  • 5-Ethynyl-2(1H)-pyrimidinone: Aldehyde oxidase-activation to 5Ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase
    Biochemical pharmacology, 1994
    Co-Authors: David J. T. Porter, Joan A. Harrington, Merrick R. Almond, Gregory T. Lowen, Thomas P. Zimmerman, Thomas Spector
    Abstract:

    Abstract 5Ethynyluracil is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) in vitro (Porter et al., J Biol Chem 267 : 5236–5242, 1992) and in vivo (Spector et al., Biochem Pharmacol , 46 : 2243–2248, 1993. 5-Ethynyl-2(1 H )-pyrimidinone was rapidly oxidized to 5Ethynyluracil by aldehyde oxidase. The substrate efficiency ( k cat / K m ) was 60-fold greater than that for N -methylnicotinamide. In contrast, xanthine oxidase oxidized 5-ethynyl-2(1 H )-pyrimidinone to 5Ethynyluracil with a substrate efficiency that was only 0.02% that of xanthine. Because 5-ethynyl-2(1 H )-pyrimidinone did not itself inactivate purified DPD in vitro and aldehyde oxidase is predominately found in liver, we hypothesized that 5-ethynyl-2(1 H )-pyrimidinone could be a liver-specific inactivator of DPD. We found that 5-ethynyl-2(1 H )-pyrimidinone administered orally to rats at 2 μg/kg inactivated DPD in all tissues studied. Although 5-ethynyl-2(1 H )-pyrimidinone produced slightly less inactivation than 5Ethynyluracil, the two compounds showed fairly similar patterns of inactivation of DPD in these tissues. At doses of 20 μg/kg, however, 5-ethynyl-2-pyrimidinone and 5Ethynyluracil produced equivalent inactivation of DPD. Thus, 5-ethynyl-2(1 H )-pyrimidinone appeared to be an efficient, but not highly liver-selective prodrug of 5Ethynyluracil.

Jaroslava Miksovska – One of the best experts on this subject based on the ideXlab platform.

David P. Baccanari – One of the best experts on this subject based on the ideXlab platform.

  • Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil
    Investigational New Drugs, 2000
    Co-Authors: Melanie T. Paff, Stephen T. Davis, David P. Baccanari, Shousong Cao, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    Eniluracil (5Ethynyluracil, GW 776, 776C85) isbeing developed as a novel modulator of 5-fluorouracil (5-FU) forthe treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), thefirst enzyme in the catabolic pathway of 5-FU. By temporarilyeliminating this prevalent enzyme, eniluracil providespredictable dosing of 5-FU and enables oral administration of5-FU to replace intravenous bolus and continuously infuseddosing. New DPD is synthesized with a half-life of 2.6 days. Italso eliminates the formation of problematic 5-FU catabolites.Most importantly, in laboratory animals, eniluracil increases thetherapeutic index and absolute efficacy of 5-FU. Accompanyingreports in this journal indicate that eniluracil has promisingclinical potential.

  • α-Fluoro-β-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracil
    Biochemical pharmacology, 2000
    Co-Authors: Shousong Cao, David J. T. Porter, Stephen T. Davis, David P. Baccanari, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5Ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.

  • dihydropyrimidine dehydrogenase inactivation and 5 fluorouracil pharmacokinetics allometric scaling of animal data pharmacokinetics and toxicodynamics of 5 fluorouracil in humans
    Cancer Chemotherapy and Pharmacology, 1996
    Co-Authors: S P Khor, Stephen T. Davis, David P. Baccanari, H Amyx, Donald J Nelson, Thomas Spector
    Abstract:

    The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase (DPD) inactivator, 5Ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (Vc) increased proportionately with body weight (Vc=0.58 B0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m2 of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85.

Stephen T. Davis – One of the best experts on this subject based on the ideXlab platform.

  • Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil
    Investigational New Drugs, 2000
    Co-Authors: Melanie T. Paff, Stephen T. Davis, David P. Baccanari, Shousong Cao, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    Eniluracil (5Ethynyluracil, GW 776, 776C85) isbeing developed as a novel modulator of 5-fluorouracil (5-FU) forthe treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), thefirst enzyme in the catabolic pathway of 5-FU. By temporarilyeliminating this prevalent enzyme, eniluracil providespredictable dosing of 5-FU and enables oral administration of5-FU to replace intravenous bolus and continuously infuseddosing. New DPD is synthesized with a half-life of 2.6 days. Italso eliminates the formation of problematic 5-FU catabolites.Most importantly, in laboratory animals, eniluracil increases thetherapeutic index and absolute efficacy of 5-FU. Accompanyingreports in this journal indicate that eniluracil has promisingclinical potential.

  • α-Fluoro-β-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracil
    Biochemical pharmacology, 2000
    Co-Authors: Shousong Cao, David J. T. Porter, Stephen T. Davis, David P. Baccanari, Youcef M. Rustum, Robert L. Tansik, Thomas Spector
    Abstract:

    We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5Ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.

  • dihydropyrimidine dehydrogenase inactivation and 5 fluorouracil pharmacokinetics allometric scaling of animal data pharmacokinetics and toxicodynamics of 5 fluorouracil in humans
    Cancer Chemotherapy and Pharmacology, 1996
    Co-Authors: S P Khor, Stephen T. Davis, David P. Baccanari, H Amyx, Donald J Nelson, Thomas Spector
    Abstract:

    The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase (DPD) inactivator, 5Ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (Vc) increased proportionately with body weight (Vc=0.58 B0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m2 of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85.