Flavone-8-acetic acid inhibits ristocetin-induced platelet agglutination and prolongs bleeding time.
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Antineoplastic Agents↗
Biomedical subjects
M M Ames
Publications and source records attributed to M M Ames.
High-performance liquid chromatographic assay for the experimental anticancer agent oxantrazole.
Oxantrazole is an anthrapyrazole analogue developed as an anthracycline-like agent with potentially reduced cardiotoxicity. A reversed-phase high-performance liquid chromatographic assay was developed using a C2 column and mobile solvent system of dimethylformamide-acetonitrile-0.2 M ammonium acetate, pH 4.5 (20:5:75, v/v/v) at a flow-rate of 1 ml/min. Drug and internal standard were detected by ultraviolet absorbance at 514 nm. Isolation of drug and internal standard was afforded by elution from C18 disposable isolation columns with a mixture of methanol-glacial acetic acid-0.02 M sodium acetate, pH 4.0 (12:1:3, v/v/v). The assay was linear (r2 greater than 0.99) over concentrations of 0.025-2.5 micrograms/ml and the limit of detection was 10 ng/ml plasma. Oxantrazole was unstable in neutral and particularly alkaline aqueous solutions. Utilizing this assay, plasma pharmacokinetics were determined following intravenous infusion of oxantrazole to beagle dogs. Plasma elimination was rapid with elimination phase half-life values less than 45 min.
Animals↗
Human and rat liver phenol sulfotransferase: structure-activity relationships for phenolic substrates.
Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/Km = 0.92 (+/- 0.18)log P - 1.48 (+/- 0.38)MR'4 - 0.64 (+/- 0.41)MR3 + 1.04 (+/- 0.63)MR2 + 0.67(+/- 0.44) sigma- + 4.03 (+/- 0.42). In this equation Km is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-, 3-, and 4-positions, and sigma- is the Hammett constant. Values of log 1/Km calculated with this equation were highly correlated with log 1/Km values (r = 0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/Km values for these compounds were significantly correlated for the two isozymes of TS PST (r = 0.992, p less than 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict Km values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.
Animals↗
Phase I study of two schedules of teroxirone.
Two schedules of teroxirone, a triazine triepoxide, were evaluated in a phase I study. Twenty-six patients were treated on 1 day every 5 weeks at doses of 36-2250 mg/m2. At doses greater than or equal to 1500 mg/m2, severe thrombophlebitis was seen without cytotoxic effect, and this schedule was closed. Twenty-seven patients were treated on 5 days every 5 weeks at daily doses of 16-450 mg/m2. Mild thrombophlebitis and moderate leukopenia were encountered. For phase II studies, a dose of 375 mg/m2 X 5 every 5 weeks is recommended. Pharmacologic studies showed rapid plasma elimination, which suggests the agent's possible usefulness for regional infusion.
Antineoplastic Agents↗
Metabolic activation of the serotonergic neurotoxin para-chloroamphetamine to chemically reactive intermediates by hepatic and brain microsomal preparations.
Para-chloroamphetamine (PCA) is selectively toxic to serotonergic neurons in laboratory animals. Acute, reversible neurotoxicity is followed by long-term effects which include inactivation of tryptophan hydroxylase and destruction of neurons. We have studied the metabolic formation of reactive intermediates that might be involved in long-term PCA neurotoxicity. Incubation of [3H]PCA with rat hepatic microsomes resulted in NADPH-dependent and oxygen-dependent covalent binding of radioactivity to microsomal protein. Addition of SKF-525A and glutathione to incubation mixtures inhibited [3H]PCA covalent binding 30% and 92% respectively. No inhibition of radiolabeled covalent binding was observed in an atmosphere of carbon monoxide/oxygen (80/20). 7,8-Benzoflavone was more effective than metyrapone in inhibiting [3H]PCA covalent binding. The extent of [3H]PCA covalent binding to microsomal protein was unchanged after phenobarbital pretreatment of rats, whereas 3-methylcholanthrene pretreatment increased [3H]PCA covalent binding (175%). NADPH-dependent and oxygen-dependent covalent binding of radioactivity was also observed when [3H]PCA was incubated with rat brain microsomal preparations. Addition of SKF-525A and glutathione to incubation mixtures inhibited covalent binding 10 and 40% respectively. There were no significant differences in total, NADPH-independent or NADPH-dependent covalent binding of radiolabeled R,S(+/-)-, R(-)-, or S(+)-PCA to rat hepatic microsomal protein. Less covalent binding was observed when [3H]amphetamine was incubated with rat liver microsomal preparations as compared to results with [3H]PCA. Minimal covalent binding was observed when [3H]PCA was incubated with liver microsomal preparations from rabbits, a species resistant to PCA neurotoxicity. Results of these metabolism studies are consistent with the hypothesis that oxidative metabolic activation of PCA to reactive and toxic metabolites is related to the long-term neurotoxicity of this agent.
Amphetamine↗
Thiopurine methyltransferase: structure-activity relationships for benzoic acid inhibitors and thiophenol substrates.
Twenty-seven substituted benzoic acids have been studied as inhibitors of partially purified human renal thiopurine methyltransferase (TPMT). Quantitative structure-activity relationship (QSAR) analysis resulted in the following equation: pI50 = 1.25( +/- 0.53)pi'3 + 0.73( +/- 0.38)MR3,4 + 2.92( +/- 0.39). In this equation pI50 is the -log of the concentration of compound that inhibits the enzyme activity by 50% (IC50);pi'3 is the relative hydrophobicity of the more hydrophobic of the two meta substituents; and MR3,4 is the molar refractivity of the more hydrophobic of the two meta substituents and of the para substituent on the phenyl ring. In addition, 14 substituted thiophenols were tested as substrates for the enzyme. All 14 thiophenols tested were excellent substrates with Km constants (0.8-7.8 microM) that were at least 2 orders of magnitude lower than those of any known thiopurine substrate for TPMT. However, there was no discernible relationship between the activities of thiophenol substrates and their physicochemical parameters. These results suggest that benzoic acid inhibitors of and thiophenol substrates for TPMT may interact with different sites on the enzyme.
Benzoates↗
High-performance liquid chromatographic assay and preclinical pharmacological studies of pibenzimol (bisbenzimidazole).
A sensitive and selective high-performance liquid chromatographic assay with ultraviolet or fluorescence detection has been developed for the experimental antitumor agent pibenzimol. Drug is isolated from plasma or other aqueous solutions with reversed-phase C18 disposable extraction columns and chromatography afforded with a deactivated reversed-phase C18 column and phosphate buffer--methanol mobile phase. Plasma standard curves are linear for concentrations for pibenzimol from 0.01 to 5.0 micrograms/ml. Pibenzimol is stable in fresh human plasma and whole blood. Pibenzimol appears to bind to plasma proteins; however, drug adsorption to glass, plastic, membranes, and filters precludes accurate determination of pibenzimol plasma protein binding. Plasma concentrations of pibenzimol fall rapidly following rapid intravenous administration to rabbits, but parent drug is detectable in plasma 24 h after drug administration. The 24-h urinary recovery of pibenzimol is 10-20%.
Animals↗
High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.
It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement. On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy.
Aged↗
Effect of a hepatic activation system on the antiproliferative activity of hexamethylmelamine against human tumor cell lines.
Incubation of hexamethylmelamine for 1 h with human tumor cell lines in culture did not inhibit colony formation at concentrations up to the limit of drug solubility (200 micrograms/ml). When 1-h incubations were carried out in the presence of a 9,000 g rat liver supernatant preparation and an NADPH-generating system, hexamethylmelamine markedly reduced colony formation. Cyclophosphamide inhibition of colony formation was also dependent on the presence of a 9,000 g supernatant preparation and an NADPH-generating system in incubation mixtures. A 1-h incubation of N-methylolpentamethylmelamine (a DNA-alkylating metabolite formed during N-demethylation of hexamethylmelamine) with human tumor cell lines reduced colony formation in the absence of the liver-activating system. Substantial NADPH-dependent N-demethylation of hexamethylmelamine was observed with rat liver, lung, and kidney microsomal preparations. In contrast, little or no HMM metabolism was observed with tumor cells, tumor cell homogenates, or NADPH-fortified tumor cell microsomal preparations. NADPH-dependent formation of cytotoxic metabolites is a prerequisite for antiproliferative activity of hexamethylmelamine against these human tumor cell lines. In vivo activity of hexamethylmelamine against some tumors may require metabolism by normal cells and subsequent transport of active species to the tumor site.
Altretamine↗
High-performance liquid chromatographic resolution of enantiomers of 1-phenyl-2-aminopropanes (amphetamines) with four chiral reagents.
High-performance liquid chromatography (HPLC) was employed for resolution of enantiomers of chiral ring-substituted 1-phenyl-2- aminopropanes (amphetamines) and 1-phenylethylamine following derivatization with four chiral reagents: (R)-(+)-1-phenylethyl isocyanate ( PEIC ), (-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride ( MTPA X Cl), 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate ( GITC ), and 2,3,4-tri-O-acetyl-alpha-D- arabinopyranosyl isothiocyanate ( AITC ). Reactions were accomplished under mild conditions (25-70 degrees C) and were complete for all substrates within 60 min. Derivatization with the sugar isothiocyanates ( GITC and AITC ) and the acyl chloride ( MTPA . Cl) was carried out in methylene chloride or acetonitrile in the presence of a base catalyst while derivatization with the isocyanate ( PEIC ) was performed in methylene chloride. The diastereomeric derivatives were separated by reversed-phase HPLC (C18) with a methanol-water mobile phase. In general, HPLC resolution of the diastereomeric reaction products of GITC or AITC , and MTPA .Cl with the amine substrates was more complete (usually greater than 98% baseline separation) than HPLC resolution of the diastereomeric reaction products of PEIC .
Amphetamines↗
Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans.
Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.
Animals↗
In vitro chemotherapy sensitivity patterns of human colon carcinoma continuous cell lines.
The cells obtained from four established human colon carcinoma cell lines were cultured in soft agar in the presence of eight chemotherapeutic agents that have been used clinically in patients with metastatic colorectal carcinoma. 5-Fluorouracil, mitomycin C, adriamycin, and cis-platinum were highly cytotoxic in vitro at the concentrations employed. These findings were in marked contrast to in vitro chemotherapy sensitivity patterns previously reported by us for a large series of primary human colorectal carcinomas cultured in soft agar. The possible reasons behind these differences are discussed.
Adenocarcinoma↗
Role of N-methylolpentamethylmelamine in the metabolic activation of hexamethylmelamine.
Hexamethylmelamine (HMM) is metabolized by rat hepatic microsomal preparations to reactive species which covalently bind to microsomal protein and to calf thymus DNA added to microsomal incubation mixtures. Covalent binding to macromolecules is dependent on the presence of molecular oxygen and reduced nicotinamide adenine dinucleotide phosphate and is catalyzed by cytochrome P-450 monooxygenases. Reduced nicotinamide adenine dinucleotide-dependent covalent binding of [methyl-14C]HMM to microsomal protein is greater than that of [ring-14C]HMM. Reduced nicotinamide adenine dinucleotide phosphate-dependent covalent binding of [ring-14C]HMM and [methyl-14C]HMM to calf thymus DNA added to microsomal incubation mixtures are approximately equal. The [ring-14C]-labeled carbinolamine intermediate in HMM demethylation, N-methylolpentamethylmelamine, covalently binds to microsomal protein and, to a much greater extent, to calf thymus DNA.
Altretamine↗
Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives.
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine and thiopyrimidine drugs. If potent TPMT inhibitors were available, studies of the regulation and properties of this drug-metabolizing enzyme would be facilitated. Each of a series of benzoic acid derivatives tested was found to inhibit purified human kidney TPMT. Concentrations required to inhibit TPMT by 50% ranged from 20 microM for 3,4-dimethoxy-5-hydroxybenzoic acid to 2.1 mM for acetylsalicylic acid. Inhibition was noncompetitive or mixed with respect to both S-adenosyl-L-methionine, the methyl donor for the enzyme, and 6-mercaptopurine, the methyl acceptor substrate. Preliminary structure-activity relationship analysis demonstrated that the benzoic acid structure was important for inhibitory activity, and that inhibition was enhanced by the addition of methoxy and/or phenolic hydroxyl groups to the ring. Quantitative structure-activity relationship analysis performed with additional benzoic acid derivatives showed that inhibitory activity could be modeled well by an equation that included the normal Hammett constant and a parameter, pi', related to lipophilicity. Several nonheterocyclic aromatic thiol compounds, including thiophenol and thiosalicylic acid, were discovered to be substrates for TPMT. Apparent Km constants for some of these aromatic thiol compounds were in the nanomolar range, several orders of magnitude lower than those of the thiopurines and thiopyrimidines previously thought to be the only substrates for TPMT. These observations suggested that "aryl thiol methyltransferase" might be a better name than "thiopurine methyltransferase" for this enzyme. Discovery of new classes of inhibitors and substrates for this important drug-metabolizing enzyme has implications for drug metabolism research and for clinical medicine.
Benzoates↗
Stereochemical aspects of para-chloroamphetamine metabolism. Rabbit liver microsomal metabolism of RS-, R(-)-. and S(+)-para-chloroamphetamine.
With the aid of a chiral derivatizing reagent and a sensitive and specific nitrogen-phosphorus gas chromatographic assay, metabolism of para-chloroamphetamine (PCA) enantiomers has been studied following incubation of racemic (RS)-, R(-)- and S(+)-PCA with rabbit liver microsomal preparations. Significant metabolism of racemic PCA and the individual enantiomers was observed following incubation in rabbit liver microsomal preparations. Metabolism required viable microsomes, NADPH and Molecular oxygen, and the rate of metabolism increased following pretreatment with phenobarbital. Incubation of racemic PCA resulted in more rapid metabolism of the S(+) enantiomer than of the R(-) enantiomer. When the enantiomers were incubated individually, each enantiomer was metabolized more rapidly than when incubated as part of a racemic mixture, and the R(-) enantiomer was metabolized more rapidly than the S(+) enantiomer.
Amphetamines↗
Pharmacokinetic study of indicine N-oxide in pediatric cancer patients.
Pharmacokinetics of the experimental antitumor agent indicine N-oxide were investigated in a group of 23 pediatric cancer patients. Plasma elimination of indicine N-oxide was best described by a two-compartment open model. The mean plasma distribution phase half-life, plasma elimination phase half-life, and plasma clearance were 8 min, 84 min, and 62 ml/min/m2 (2.1 ml/min/kg), respectively. One patient with renal impairment had an abnormally long plasma elimination phase half-life (275 min) and reduced plasma clearance (17 ml/min/m2). Plasma elimination phase half-life values increased and plasma clearance values decreased with increasing age of the pediatric patients. Plasma elimination of indicine N-oxide was more rapid in this group of children than in adults who had previously received the drug.
Adolescent↗
Parenteral formulation of hexamethylmelamine potentially suitable for use in man.
We have developed a preparation of hexamethylmelamine (HMM), dissolved in a fat emulsion Intralipid 20%, that is potentially satisfactory for parenteral administration to man. Solid HMM can be dissolved in Intralipid 20% up to 5 mg/ml, with extensive agitation. Solubilization of HMM is facilitated first by dissolving the drug in ethanol or in dimethylacetamide and then by adding the solution to Intralipid 20%. The disposition of HMM in rabbits after iv administration of HMM dissolved in Intralipid 20% was similar to the disposition of the drug following iv administration of HMM dissolved in 0.1 N HCl.
Altretamine↗
Clinical and pharmacologic evaluation of split-dose intermittent therapy with dianhydrogalactitol.
Dianhydrogalactitol was administered as two 1-hr infusions separated by a 4-hr period once every 5 weeks to 21 patients with advanced solid tumors. Total doses ranged from 100 mg/m2 (50 mg/m2 twice on a single day) to 160 mg/m2 (80 mg/m2 twice on a single day). Peak concentrations of drug at the end of a 1-hr infusion ranged from 1.9 to 5.6 microgram/ml. Plasma elimination of dianhydrogalactitol was approximated best by a two-compartment open model. The alpha-half-life was 3.9 +/- 1.9 mins and the beta-half-life was 31.3 +/- 2.7 mins. Dose-limiting hematologic toxicity was encountered at a total dose of 160 mg/m2, with leukopenia occurring more frequently than thrombocytopenia. Other toxic effects included mild to moderate nausea in most patients and two instances of moderate alopecia. One patient with large cell cancer of the lung had a partial regression lasting 2 months and one patient with a carcinoid in the thymus had a partial regression lasting 7 1/2 months. A third patient with a mixed adenocarcinoma-squamous cell carcinoma of the lung had improvement (30% decrease) in his pulmonary tumor for greater than 2 months.
Adolescent↗