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Biomedical subjects

G Powis

Publications and source records attributed to G Powis.

At least 181 records · Page 10Linked to original sources
PubMed1984

Metabolism and disposition of 3-amino-1,5-dihydro-5-methyl-1-beta-D-ribofuranosyl-1,4,5,6, 8-pentaazaacenaphthylene in the rat.

Tricyclic nucleoside (TCN, NSC 154020) is a 7-deazapurine nucleoside possessing antitumor activity towards certain tumor cell lines in vitro. In vivo, TCN is readily interconvertible with its 5'-monophosphate ester. The present study demonstrates that TCN is metabolized by rat liver microsomes to a ring-opened bicyclic metabolite with loss of cytotoxicity toward Chinese hamster ovary cells in culture. Metabolism is mediated by hydrogen peroxide generated by the rat liver microsomes but is not dependent on cytochrome P-450. Isolated hepatocytes prepared from rat do not form detectable amounts of the ring-opened bicyclic metabolite. Unchanged TCN and the ring-opened bicyclic metabolite are excreted in the bile of rats with a cannulated bile duct, comprising 42 and 12% of an i.v. dose of TCN in 8 hr, respectively. The ring-opened bicyclic metabolite is not formed by red blood cells in vitro and could not be detected in blood in vivo. The fact that the ring-opened bicyclic metabolite appears in bile suggests that liver cells not present or not active in isolated hepatocyte preparations might produce the metabolite. Alternatively, the metabolite might be formed directly from TCN in bile, perhaps by hydrogen peroxide excreted into bile. In vivo, 56% of radiolabel was found in the upper and lower gastrointestinal tract and the feces 24 hr after an i.p. or i.v. dose of 100 mg of [5-methyl-14C]TCN/sq m. Urinary excretion of radiolabel was 21% of the dose of [14C]TCN in 24 hr. Biliary excretion of radiolabel was 65% of the dose of [14C]TCN in 8 hr. The fraction of radioactivity undergoing enterohepatic cycling with reabsorption from the gastrointestinal tract after excretion in bile is 84%.

Animals↗
PubMed1984

Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines.

While colony formation assays provide sensitive indices of tumor cell proliferation and growth inhibition imposed by many chemotherapeutic agents, drugs which require metabolic activation lack activity in such assays. In the present study, we have utilized freshly isolated rat hepatocytes for the activation of drugs which are metabolized by hepatic microsomal as well as extra-microsomal enzymes. Hepatocytes in fluid medium are placed over soft-agarose matrix containing tumor-derived cells (e.g., A204, A549) within 35-mm culture dishes; drug and/or drug vehicle is added directly to the hepatocyte layer, and cultures are incubated for 24 hr prior to removal of the hepatocyte layer. Tumor cell colony formation is assessed following 7 to 10 days of incubation. Cyclophosphamide was used as a prototype agent to assess utility of the coculture methodology. In vivo treatment of rats with phenobarbital prior to hepatocyte isolation enhances cyclophosphamide toxicity in vitro, whereas pretreatment with carbon tetrachloride markedly reduced subsequent in vitro cyclophosphamide cytotoxicity. Hepatocyte:tumor cell cocultures provide an efficient means to detect metabolic activation and inactivation of several selected cancer chemotherapeutic agents as well. In the presence of hepatocytes, the 50% growth-inhibitory concentrations for cyclophosphamide, indicine N-oxide, and procarbazine are markedly decreased, whereas the 50% growth-inhibitory concentrations for [2,5-bis(1-aziridinyl)-3,6-diazo-1,4-cyclohexadiene-1,4-diyl]bis(c arbamic acid)diethyl ester, 1,3-bis-chloro(2-chloroethyl)-1-nitrosourea, dacarbazine, 5-fluorouracil, ftorafur, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and vincristine are significantly increased. By contrast, the 50% growth-inhibitory concentrations for actinomycin D, mitomycin C, 6-mercaptopurine, and other agents are unaffected by hepatocyte presence. Cryopreserved hepatocytes exhibit detectable levels of drug activation, although inadequate for routine use. Results suggest that hepatocyte:tumor cell cocultures may be well-suited for assessing the degree to which hepatic metabolism may activate or inactivate new anticancer drugs.

Animals↗
PubMed1983

Dose-dependent metabolism, therapeutic effect, and toxicity of anticancer drugs in man.

Dose-dependent metabolism is seen for a number of anticancer drugs, and they provide examples of several different types of dose-dependent metabolic processes. Arabinosyl cytosine and 5-fluorouracil are drugs whose catabolism is saturated at high doses. Therapeutic response to both drugs has been linked to plasma concentration of parent compound, and a nonlinear dose-response relationships might exist at high doses. L-Alanosine also appears to exhibit saturable metabolism at high doses, and this might be responsible for the rapid onset of L-alanosine toxicity as the dose is increased. Isophosphamide is a drug which requires metabolic activation to exert its biological effect, and saturation of metabolism seen at high dose could lead to a plateau in the dose-response relationship. Thymidine exhibits saturation of metabolism at high doses due in part to product inhibition of metabolism. Product inhibition of metabolism has also been suggested for arabinosyl cytosine. Plasma elimination of thymidine and possible elimination of 6-diazo-5-oxo-L-norleucine exhibit characteristics of a dose-dependent "memory" effect. Dose-dependent metabolism of methotrexate is unusual in that formation of the presumed toxic metabolite increases with increase in dose and is associated with a qualitative change in the pattern of drug toxicity at high compared to low doses of drug. The relationship between dose and toxicity of drugs and other foreign compounds is poorly understood in man. Anticancer drugs are one of the few classes of compounds where the relationship of toxicity to dose is reasonably well documented in human subjects. Saturation of metabolism leading to dose-dependent pharmacokinetics occurs with several anticancer drugs, and different types of dose-dependent metabolism have been covered in this review. An attempt has been made to show how dose-dependent metabolism of anticancer drugs might relate to their toxicity. Principles of dose-dependent toxicity seen with anticancer drugs might usefully be applied to other classes of compounds, particularly compounds exhibiting cytotoxicity but also other forms of toxicity. Dose-dependent metabolism could also be important in determining the therapeutic effect of anticancer drugs, and application of principles of dose-dependent metabolism to the development of new chemotherapeutic regimens migh lead to more effective cancer chemotherapy.

Alanine↗
PubMed1983

Disposition of bisantrene in humans and rabbits: evidence for intravascular deposition of drug as a cause of phlebitis.

The investigational antitumor agent bisantrene (9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride) causes frequent local complications of phlebitis and thromboses in patients receiving the drug by peripheral venous infusion. Bisantrene pharmacokinetics was studied in five patients. Plasma elimination was biphasic with t1/2 alpha of 65 min and t1/2 beta of 1142 min; the mean apparent volumes of distribution of the central compartment and peripheral compartments were 185 and 1662 liters/sq m, suggesting extensive uptake, binding, or deposition of drug. Total body clearance was 735 ml/min/sq m, and 11.3% of drug was excreted in urine. One hr after bisantrene (260 mg/sq m) at 1 mg/ml in 5% dextrose was infused into the marginal ear vein of a rabbit, the vein was congested with blood and contained 2.1 mg precipitated bisantrene. After 24 hr, the vein was clotted and contained 1.18 mg precipitated drug. Precipitation of bisantrene appears to be related to the low solubility of the drug at physiological pH. Maximum solubility of bisantrene in human and rabbit serum was 12.7 micrograms/ml. Intravascular precipitation of bisantrene may be responsible for phlebitis and thromboses in humans receiving the drug by i.v. infusion.

Animals↗
PubMed1982

High-performance liquid chromatographic assay of the antineoplastic agent tricyclic nucleoside 5'-phosphate and its disposition in rabbit.

Anion-exchange and reversed-phase high-performance liquid chromatographic procedures are described for the assay of the antineoplastic agent tricyclic nucleoside 5'-phosphate (TCNP) and its metabolite tricyclic nucleoside (TCN) in biological fluids. Disposition of TCNP has been studied in rabbit. TCNP is eliminated from blood and plasma with a biologic half-life of about 7.5 h. Apparent volume of distribution is 43.2 l/m2 and total body plasma TCNP clearance is 67.8 ml/min/m2. TCNP is hydrolyzed by plasma and probably other tissues to TCN which is present in blood and plasma at about one-tenth the concentration of TCNP. There is no accumulation of TCNP or TCN in blood or plasma over 2 days of administration. In 24 h 2.4% of a dose of TCNP is excreted in bile of a rabbit with a cannulated bile duct as unchanged TCNP and 30.7% as TCN. TCN is excreted in bile at an initial concentration half the maximum solubility of TCN in rabbit bile. Excretion of TCNP and TCN over 24 h in the urine of a rabbit with a cannulated bile duct is 1.5% and 5.2% of the dose, respectively.

Acenaphthenes↗
PubMed1982

Iron-EDTA stimulated reduction of indicine N-oxide by the hepatic microsomal fraction, isolated hepatocytes, and the intact rat.

Fe(III) complexes of EDTA and diethylenetriamine pentaacetic acid (DETAPAC) at low concentrations (between 1 and 100 microM) produced up to a 20-fold increase in anaerobic microsomal NADPH- and NADH-dependent reduction of indicine N-oxide. Under aerobic conditions microsomal indicine N-oxide reduction was stimulated to half the levels seen under anaerobic conditions. EDTA alone was much less effective at stimulating indicine N-oxide reduction, while FeCl3 alone had no effect on reduction. Other complexes of Fe(III) had little or no effect in stimulating microsomal indicine N-oxide reduction. Fe(III)-EDTA stimulated indicine N-oxide reduction by purified NADPH-cytochrome P-450 reductase and NADPH. It is probable that iron serves to transfer electrons between microsomal flavoprotein reductases and indicine N-oxide. The redox potential and the presence of an exchangeable ligand, such as water, in the inner ligand sphere of the iron complex are suggested to be important factors in determining which iron complexes will stimulate indicine N-oxide reduction. EDTA complexes of other transition metal ions do not stimulate indicine N-oxide reduction. Hydroxyl radicals, detected as the spin adduct of 5,5-dimethyl-1-pyroline-N-oxide, appear to be formed during Fe(II)-EDTA-dependent reduction of indicine N-oxide under anaerobic conditions. Fe(III)-EDTA at concentrations between 50 and 250 microM stimulated indicine N-oxide reduction by rat isolated hepatocytes up to 5-fold under anaerobic conditions and to half these values under aerobic conditions. By themselves, EDTA and FeCl3 at similar concentrations produced a small stimulation of indicine N-oxide reduction by hepatocytes under anaerobic conditions. Fe(III)-EDTA stimulated indicine N-oxide reduction by murine leukemia P-388 cells under aerobic conditions and by rat caecal flora under anaerobic but not aerobic conditions. Fe(III)-EDTA, EDTA or FeCl3 administered to rats produced a 3-fold increase in the 24-hr urinary excretion of indicine following an i.p. dose of indicine N-oxide.

Animals↗
PubMed1982

Effect of cyclophosphamide pretreatment on the short-term disposition and biliary excretion of adriamycin metabolites in rat.

The effect of pretreatment with cyclophosphamide 180 mg/kg upon the short-term disposition of adriamycin in anesthetized rat 4 days later was studied. There was a significant decrease in plasma adriamycin clearance, from 125 to 48 ml/min/kg, and a significant decrease in the apparent volume of the peripheral compartment of adriamycin distribution, from 51.7 to 25.6 l/kg, in cyclophosphamide-pretreated as against control rats. Biliary excretion of adriamycin over 2.5 h was increased significantly by 114% in cyclophosphamide-pretreated rats and there was a small but nonsignificant increase in biliary adriamycinol excretion and a decrease in excretion of adriamycin aglycones. Cyclophosphamide pretreatment was associated with an 83% increase in bile flow. Cyclophosphamide pretreatment had no significant effect upon the utilization of adriamycin or upon the formation of adriamycin metabolites by rat isolated hepatocytes. The results suggest that NADPH-cytochrome P-450 reductase, which is decreased 40% by cyclophosphamide pretreatment, is not rate-limiting in elimination of adriamycin. Biliary excretion of adriamycin is increased when plasma adriamycin clearance is decreased, suggesting that cyclophosphamide pretreatment affects a pathway besides biliary excretion that is responsible for the short-term removal of adriamycin from plasma.

Anesthesia↗
PubMed1982

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↗
PubMed1982

Pilot study of PALA and 5-FU in patients with advanced cancer.

A pilot study was carried out among 21 patients with advanced solid tumors to establish appropriate dose levels of PALA and 5-FU given on a 5-day schedule to produce definite but tolerable clinical toxicity. While dermatitis, diarrhea, leukopenia, and thrombocytopenia were observed, stomatitis was the dose-limiting side effect. The recommended initial dose levels for further clinical trials are 625 mg/m2 of PALA daily x 5 and 250-300 mg/m2 of 5-FU daily x 5, with courses repeated at 4-week intervals. Studies were also conducted to establish the time course of anticipated increased incorporation of 5-FU into cellular RNA following treatment with PALA. In murine P388 leukemia, PALA increased tritiated 5-FU incorporation by as much as 70%, the effect being maximal within 1 hour and maintained up to 25 hours. It was not possible to demonstrate increased tritiated 5-FU uptake into normal human leukocyte RNA from patients receiving combination chemotherapy with PALA and 5-FU, perhaps because of low rates of RNA synthesis.

Adult↗
PubMed1981

Activity of indicine N-oxide in refractory acute leukemia.

Indicine N-oxide, the first pyrrolizidine alkaloid N-oxide to be studied in the treatment of cancer in humans, was administered to ten patients: four children and two adolescents with refractory acute lymphocytic leukemia and four adults with refractory acute nonlymphocytic leukemia (three acute myelocytic, one myelomonocytic). Two patients, a 4-year-old boy with acute lymphocytic leukemia and a 22-year-old man with acute myelocytic leukemia, achieved complete remission lasting 3 and 5+ months, respectively. Another 15-year-old male with acute lymphocytic leukemia had a partial remission for four months. Toxicities included bone marrow suppression, mild anorexia and nausea, and transient elevation of liver enzymes. Jaundice and liver failure, presumably induced by drug, occurred in two patients.

Adolescent↗
PubMed1981

Factors affecting the intracellular generation of free radicals from quinones.

Isolated hepatocytes do not liberate appreciable amounts of superoxide into the external medium. Simple quinones stimulate the release of superoxide up to 15 nmol/min/10(6) hepatocytes. Superoxide release stimulated by a variety of simple quinones and more complex antitumor quinones was maximal at a quinone one-electron reduction potential of -70 mV. This was qualitatively similar to the pattern of superoxide formation seen with NADH-cytochrome b5 reductase and NADH: ubiquinone oxidoreductase. Superoxide production by NADPH-cytochrome P-450 reductase was maximal at a quinone single-electron reduction potential at -200 mV. Phenobarbital pretreatment had no effect on superoxide formation by hepatocytes suggesting that NADPH-cytochrome P-450 reductase activity is not rate limiting for quinone stimulated superoxide formation. Sulfonated stilbenes, specific inhibitors of anion exchange, had no effect on the release of superoxide by hepatocytes suggesting that superoxide is not transported through anion channels in the plasma membrane. Pretreatment of hepatocytes with 10(-5) M diethyldithiocarbamate produced over a two fold increase in the release of superoxide.

Animals↗
PubMed1981

Dose-dependent pharmacokinetics and cancer chemotherapy.

Dose-dependent pharmacokinetics have been reported more frequently for anticancer drugs than for other drugs, probably because anticancer drugs are studied over a wide range of doses during early evaluation and because of the increasing use of anticancer drugs at very high doses. Dose-dependent pharmacokinetics are reflected most commonly as an increase in the biological half-life of a drug and a greater than proportional increase in plasma concentration of the drug and in area under the drug concentration-time curve with increase in dose. Occasionally the rate of drug removal increases with increasing dose. These nonlinear changes in drug concentrations with dose may lead to increases in toxicity out of proportion to increases in dose. Appreciation of the possibility of dose-dependent pharmacokinetics is important in the clinical pharmacologic evaluation of new drugs, and may be essential for the design of effective therapeutic regimens.

Animals↗