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T R Jones

Publications and source records attributed to T R Jones.

At least 163 records · Page 9Linked to original sources
PubMed1986

Quinazoline antifolates inhibiting thymidylate synthase: variation of the amino acid.

Five new analogues (1c-g) of the antifolate N10-propargyl-5,8-dideazafolic acid (1a) are described in which the benzoyl-L-glutamate moiety was replaced by benzoic acid (desglutamyl-N10-propargyl-5,8-dideazafolic acid), benzoyl-L-aspartate, 4-phenylbutyrate, benzoylglycine, and benzoyl-L-alanine. The esters of the appropriate 4-aminophenyl (benzoyl) starting materials were sequentially alkylated upon nitrogen, first with a propargyl halide and then with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide. Saponification of the antifolate esters so produced gave the desired analogues. The new derivatives (1c-g) and also the known diethyl ester of 1a (1b) were tested for their inhibition of purified L1210 thymidylate synthase (TS) and for their inhibition of the growth of L1210 cells in culture. The TS inhibition of the analogues 1b-g was estimated by calculating the inverse relative potency, defined as the ratio IC50(compound)/IC50(1a). The results obtained were as follows: greater than 62, 84, 9, 333, 21, and 5, respectively. All were thus less inhibitory than 1a. None of the compounds improved upon 1a in inhibiting the growth of L1210 cells in culture.

Animals↗
PubMed1986

Carotid revascularization after cervical irradiation.

Carotid revascularization after cervical irradiation is often made more difficult by decreased vascularity, development of fibrosis, and loss of covering tissue by previous surgery. We present three cases to illustrate alternative approaches to carotid revascularization in these circumstances. One case describes the usual direct approach to carotid endarterectomy. The second describes a saphenous vein bypass from the subclavian artery to the internal carotid artery, while the third describes a saphenous vein carotid-carotid bypass following carotid blowout. We discuss advantages of each approach and describe characteristics of the changes that follow cervical irradiation.

Aged↗
PubMed1986

L-649,923, sodium (beta S*, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)- gamma-hydroxy-beta-methylbenzenebutanoate, a selective, orally active leukotriene receptor antagonist.

L-649,923, Sodium (beta S*, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)- gamma- hydroxy-beta-methylbenzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (Ki value of 400 nM) and to a lesser extent [3H]leukotriene C4 (Ki value of 8.6 microM) binding in guinea-pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotriene C4, D4, E4, and F4 but not those induced by acetylcholine, histamine, serotonin, prostaglandin F2 alpha, or U-44069 (stable endoperoxide analogue). Schild plot analysis indicated a competitive inhibition of contractions of guinea-pig ileum induced by leukotriene D4 (pA2 8.1) and contractions of guinea-pig trachea induced by leukotrienes E4 and F4 (pA2 7.1 and 6.9, respectively). In contrast, contractions of guinea-pig trachea induced by leukotrienes C4 (pA2 7.2; slope 0.6) and D4 (pA2 7.2; slope 0.7) were inhibited in a noncompetitive fashion. In vivo, intravenously administered L-649,923 selectively blocked bronchoconstriction induced in anesthetized guinea pigs by leukotriene C4 and D4 (ED50 values i.v. 0.38 and 0.26 mg/kg, respectively) but not that induced by histamine, arachidonic acid, serotonin, U-44069, or acetylcholine. Following intraduodenal administration, L-649,923, blocked leukotriene D4 induced bronchoconstriction (5 and 10 mg/kg). The present findings indicate that selective antagonists, such as L-649,923, may be useful for defining the role of leukotrienes in diseases such as bronchial asthma.

Airway Resistance↗
PubMed1986

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)- propylsulfonyl]-gamma-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist.

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfonyl]-gamma-oxo-benzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (KB value of 4.0 microM) and to a lesser extent [3H]leukotriene C4 (Ki value of 36.7 microM) binding in guinea pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotrienes C4, D4, E4, and F4 in concentrations that did not antagonize contractions induced by acetylcholine, histamine, serotonin, prostaglandin F2 alpha, or U-44069 (endoperoxide analogue). Schild plot analysis indicated that L-648,051 competitively antagonized contractions of guinea pig ileum induced by leukotriene D4 (pA2 7.7) and contractions of trachea induced by leukotrienes D4, E4, and F4 (pA2 7.3, 7.4, and 7.5, respectively). Contractions of guinea pig trachea induced by leukotriene C4 were inhibited in a noncompetitive fashion (Schild plot slope, 0.45). Developed contractions of trachea induced by the leukotrienes were rapidly reversed by L-648,051 greater than FPL-55712 greater than L-649,923. Intravenous L-648,051 selectively blocked bronchoconstriction induced in anaesthetized guinea pigs by intravenous leukotrienes C4, D4, and E4 but not that induced by arachidonic acid, serotonin, U-44069, or acetylcholine. The compound displayed poor activity following intraduodenal administration. The profile of activity for L-648,051 indicates that it may be a useful topical agent for studying the role of leukotrienes in diseases such as bronchial asthma.

Animals↗
PubMed1986

A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717.

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.

Acetylglucosaminidase↗
PubMed1986

Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse.

The tissue distribution, excretion, and metabolism of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) have been investigated in the mouse. Following 100 mg/kg of 2-14C-CB3717 ip, levels of radioactivity in the brain, testes, muscle, heart, and lung equilibrated slowly with those in the plasma and were no longer significantly lower 5 hours (lung) and 12 hours (brain, testes, muscle, and heart) after administration. In contrast, concentrations of 14C in the liver and kidney were markedly higher than those in the plasma at all time points studied (1.3 hours-23 days). High-performance liquid chromatographic (HPLC) analysis of livers removed 5 hours after drug administration and kidneys excised 24 hours after treatment indicated that, at these time points, greater than 50% of the radioactivity was in the form of unchanged CB3717. Furthermore, HPLC analysis of plasma removed over the period 0.5-6 hours demonstrated that all of the 14C could be accounted for as CB3717. Although the accumulation and retention of radioactivity in the liver and kidney were also apparent following 20 and 200 mg/kg of 14C-CB3717, the effect was less marked at the lower dose, thereby suggesting dose-dependent pharmacokinetics. In excretion studies (0-48 hours), the major route of elimination was found to be via the feces, with 46% of the 14C recovered; 26% of the dose was recovered as unchanged CB3717. Radioactivity excreted in the urine accounted for 20% of the administered 14C, while CB3717 eliminated via this route represented 15% of the dose. In addition to CB3717, a metabolite was detected in the feces which comprised 8% of the dose administered. The metabolite was shown to be 4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoic acid (CB3751) by HPLC and mass spectrometry. The formation of CB3751 could be catalyzed in vitro by the contents of the cecum and prevented in vivo by antibiotic pretreatment and is therefore considered to be the result of bacterial metabolism. CB3717 binds extensively to plasma proteins (92%; concentration range, 25-250 microM). These studies have shown that CB3717 does not apparently undergo extensive host metabolism in vivo, and therefore the biological properties of this novel antimetabolite are probably a function of the parent compound. In addition, the accumulation of CB3717 in the liver and kidney may be related to the hepatotoxic and nephrotoxic effects of this drug.

Animals↗
PubMed1985

Hybridization of herpes simplex virus DNA and human ribosomal DNA and RNA.

A small DNA segment from the inverted repeats at the termini of the unique long sequence region of herpes simplex virus DNA was found to hybridize with human 28 S ribosomal DNA and RNA but not 18 S ribosomal DNA and RNA. The hybridization occurred under stringent conditions and was not blocked by nucleic acids high in guanine plus cytosine content. These data strongly suggest that the hybridization represented authentic base sequence homology.

Chromosome Mapping↗
PubMed1985

Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pigs.

Pulmonary responses to intravenous leukotrienes C4, D4 and E4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD4, LTC4 and LTE4 (respective ED50 of 0.21 +/- .1, 0.64 +/- .2 and 2.0 +/- .1 microgram kg-1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-Rössler). Bronchoconstriction was antagonized by FPL-55712 (50-200 micrograms kg-1), and indomethacin (50-200 micrograms kg-1) but was not significantly altered by mepyramine (1.0 mg kg-1), methysergide (0.1 mg kg-1), intal (10 mg kg-1) mepacrine (5 mg kg-1) or dexamethasone (10 mg kg-1). The beta adrenoceptor blocker, timolol (5 micrograms kg-1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE4 but not LTD4 or LTC4 were partially antagonized by atropine (100 micrograms kg-1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD4 and LTE4 (2.8-3.2 micrograms kg-1 min-1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE4 and LTD4 was partly reversed by intravenous FPL-55712 (1.0 mg kg-1) and atropine (100 micrograms kg-1) but was almost completely reversed by FPL-55712 (3 - 10 mg kg-1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE4 as well as a small part of the initial response to continuous infusion of LTD4 and LTE4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.

Airway Resistance↗
PubMed1985

Quinazoline antifolates inhibiting thymidylate synthase: variation of the N10 substituent.

The synthesis of 12 new 5,8-dideazafolates with isopropyl, cyclopropylmethyl, 2-fluoroethyl, carbamoylmethyl, phenacyl, 3-fluorobenzyl, 5-uracilylmethyl, carboxymethyl, 2-carboxyethyl, 3-cyanopropyl, 3-hydroxypropyl, and cyanomethyl substituents at N10 is described. In general, the synthetic route involved monoalkylation of diethyl N-(4-amino-benzoyl)-L-glutamate, coupling of the resulting secondary amine with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide in N,N-dimethylacetamide with calcium carbonate as the base, and deprotection using mild alkali. The cyanomethyl derivatives was found to be unexpectedly base labile and was therefore prepared by mild acid deprotection of a di-tert-butyl ester. The compounds were tested as inhibitors of purified L1210 thymidylate synthase (TS). Four members of the series were more potent that the N10-hydrogen compound, but none was superior to the previously described N10-propargyl-5,8-dideazafolic acid. Selected compounds were examined as inhibitors of purified L1210 dihydrofolate reductase (DHFR). As desired, N10 substitution in general reduced DHFR inhibitory activity; these results are discussed. As a measure of cytotoxicity, the compounds were examined for their inhibition of the growth of L1210 cells in culture. None of the new substituents conferred enhanced potency relative to N10-propargyl-5,8-dideazafolic acid (ID50 = 5 microM), which, as the best TS inhibitor and a relatively poor DHFR inhibitor, continues to lead this series.

Alkylation↗
PubMed1985

Use of intravenous diazepam in patients on chronic hemodialysis undergoing surgery.

Diazepam is a drug commonly used for sedation in surgery done under local anesthesia. Since its primary metabolites are excreted in the urine, its safety for use in functionally anephric patients has not been determined. This report describes the results of diazepam use in chronic hemodialysis patients undergoing angioaccess procedures. Thirty consecutive angioaccess procedures with an average duration of 1 hour and 27 minutes were done in 22 different patients using an average of 25 mg diazepam per patient. No other sedation was used. All patients except one were considered to have satisfactory sedation. Only two patients developed superficial phlebitis which had no lasting adverse effect. It is concluded that intravenous diazepam may be used in anephric patients with a response and safety comparable to that reported in patients with normal renal function.

Adjuvants, Anesthesia↗
PubMed1984

Effect of dextran-charcoal treatment on the dissociation kinetics of glucocorticoid-receptor complexes: possible involvement of lipid.

Dissociation kinetics were determined at 0 degrees C for molybdate-stabilized glucocorticoid-receptor complexes in rat thymus cytosol. Exposure of complexes to dextran-coated charcoal had no effect on their chromatographic properties or transformation status, but dissociation rates measured after charcoal treatment were significantly lower than those determined by displacement with excess competing steroid. The dissociation rate of the [2,4,6,7-3H]prednisolone-receptor complex was similarly modified by chromatography on Lipidex 1000, but not by chromatography on Sephadex G-25 or G-75. It is concluded that treatment of glucocorticoid-receptor complexes with dextran-charcoal or Lipidex 1000 brings about a change in dissociation rate as a consequence of the removal of a lipid component from the complex.

Animals↗
PubMed1984

Sodium orthovanadate stimulation of DNA synthesis in Nakano mouse lens epithelial cells in serum-free medium.

Quiescent cultured Nakano mouse lens cells incubated for 40 hours with sodium orthovanadate incorporated 3H-thymidine at an accelerated rate; the greatest response occurred at 20 microM vanadate, whereas by 2 microM an incorporation rate equivalent to unstimulated cells was noted. Microscopic examination of the cells revealed that those exposed to concentrations of vanadate greater than 100 microM had lysed by the end of the 40-hour incubation. Reduction in vanadate exposure time to 1 hour caused the cells to incorporate the greatest amount of 3H-thymidine at a vanadate concentration of 200 microM to 500 microM. Half-maximum incorporation of 3H-thymidine (after a 40-hour incubation) was induced by a 2-hour incubation with 20 microM vanadate. Studies with insulin showed that while 20 ng/ml insulin alone did not increase 3H-thymidine incorporation, 20 ng/ml insulin in combination with 20 microM vanadate resulted in a significant increase in 3H-thymidine uptake over cells exposed to only vanadate. Insulin alone will increase cell number and insulin with vanadate are synergistic in the stimulation of DNA synthesis, but the two together show no further increase in cell number over that produced by insulin alone. Thus, vanadate can increase progression from G1/G0 to S-phase, but cannot stimulate cells to divide. Studies designed to detect DNA damage and repair rather than S-phase DNA synthesis demonstrated that vanadate was not causing increased 3H-thymidine uptake by damaging DNA. Cell counts revealed that vanadate, while able to induce DNA synthesis, does not induce mitosis. Autoradiography and equilibrium sedimentation experiments demonstrated that gene amplification was not occurring. A known vanadate exchange inhibitor blocked the ability of vanadate to increase 3H-thymidine incorporation which is consistent with the idea that cellular internalization of vanadate is required for this effect to be seen. 86Rb+ uptake experiments demonstrate that the vanadate concentration inducing 50% inhibition of (Na+, K+)ATPase is nearly two orders of magnitude more concentrated that vanadate concentrations shown capable of inducing 3H-thymidine uptake. This strongly suggests that (Na+, K+)ATPase inhibition is not the central mechanism by which DNA synthesis is stimulated by vanadate.

Animals↗
PubMed1984

Study of mechanisms mediating contraction to leukotriene C4, D4 and other bronchoconstrictors on guinea pig trachea.

Contractions of guinea pig trachea in the absence and presence of indomethacin to LTD4 greater than LTC4 greater than K+ greater than histamine greater than acetylcholine were reduced following a 45 minute exposure of the tissues to calcium-free Krebs' solution (Ca2+-free Krebs' solution), were further reduced by a transient exposure to EGTA (1.25 mM) in Ca2+-free Krebs' solution and were virtually abolished when tested in the presence of EGTA (0.125 mM) in Ca2+-free Krebs' solution. In normal Krebs' solution (2.5 mM Ca2+) the Ca2+ entry blockers nifedipine (N) much greater than D-600 greater than verapamil (V) greater than diltiazem (D) almost completely abolished the contractions to K+ but blocked only a component of the maximum response to the other agonists. After exposure to Ca2+-free Krebs' solution for 45 minutes, any residual contractions to LTC4 & LTD4, were reversed by low concentrations of N (0.3 microM) or D-600 (2.1 microM). Leukotrienes appear to mobilize a superficial and a bound store of Ca2+ which gains entry through at least two types of Ca2+ channels (or mechanisms), one of which is blocked by N and D600. K+-induced contractions appear to be dependent on superficial and tightly bound Ca2+ but entry is solely through channels which are blocked by the Ca2+ entry blockers studied. Contraction to histamine and acetylcholine persisted following exposure of the tissues to Ca2+ free Krebs' solution but contractile activity was virtually abolished in Ca2+ free Krebs' solution containing EGTA. Residual contractions to histamine and part of the residual contractions to acetylcholine in Ca2+-free Krebs' solution were blocked by low dose N (0.3 microM) or D600 (2.1 microM). These findings suggest a major role for extracellular Ca2+ during spasmogen-induced contraction in this tissue.

Acetylcholine↗
PubMed1984

Studies of the androgen receptor in dispersed fibroblasts: investigation of patients with androgen insensitivity.

The practical application of a simple, reproducible androgen receptor assay using dispersed fibroblasts is described for the investigation of patients with the androgen insensitivity syndrome (AIS). The concentration of androgen receptors (Bmax) in genital skin fibroblasts derived from normal subjects is 814 +/- 168 X -18 moles/microgram DNA (mean +/- SD) and the binding affinity (Kd) is 0.91 +/- 0.26 X 10(-10)M at 37 degrees C, using [3H]-5 alpha-dihydrotestosterone (DHT) as the labelled ligand. Studies in patients with phenotypic signs of complete or partial AIS showed either absent (receptor-negative), decreased (receptor-deficient) or normal/increased (receptor-positive) specific binding of DHT to the receptor. In some mutant cell lines, there was evidence of thermolability and increased rate constant of dissociation of the androgen-receptor complex, suggesting a possible structural abnormality of the receptor protein. This simple receptor assay can be used to delineate quantitative and qualitative defects of the androgen receptor in a significant number of patients with a wide spectrum of phenotypic abnormalities associated with androgen resistance.

Adolescent↗
PubMed1983

Growth, morphology, and serial transplantation of anaplastic human gliomas in athymic mice.

Sixteen of 17 anaplastic human gliomas (AHGs) transplanted into athymic mice produced progressively growing subcutaneous nodules at the site of implantation. Thirty-four of 68 animals (50%) receiving transplanted tissue developed 500 m3 tumors in 24 to 364 days. Fourteen AHG were passed to a second animal generation, and 11 showed continued growth. Eight of these were serially passed, with one reaching a sixth animal generation, four reaching a fifth, and a three third. Once growth occurred in a second animal generation, no AHGs were lost in subsequent passages because of failure to grow. Of 234 animals receiving tumors beyond the first animal generation, 189 (80.8%) developed tumors. Average doubling times of the exponentially growing tumors in serial passage ranged from 3.0 to 19.1 days. This growth rate tended to increase and stabilize in early animal passages. The tumors growing in animals contained cell types which were present in the original human tumors, including fibrillary and protoplasmic astrocytes, small anaplastic cells, gemistocytes, anaplastic spindle cells, and multinucleate giant cells. Glial fibrillary acidic protein (GFAP) was detected in 15 of 17 biopsy specimens and in 12 of 14 AHGs in animals. These data illustrate the value of the athymic mouse system for the investigation of human brain tumors by demonstrating a high rate of successful transplantation, quantitative growth data on serially passed tumors, and morphological and immunochemical resemblance of the tumors in mice to the original human tumors.

Animals↗