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Biomedical subjects

G Powis

Publications and source records attributed to G Powis.

At least 163 records · Page 9Linked to original sources
PubMed1987

Phase I and pharmacokinetic study of menogaril administered as a 72-hour continuous i.v. infusion.

Menogaril is a new anthracycline analog of nogalamycin. When administered as a 72-hour continuous iv infusion the dose-limiting toxic effect of menogaril was venous irritation at dose levels that cause only mild leukopenia and minimal gastrointestinal toxicity. Pharmacokinetic studies showed that the rise in plasma concentration during infusion was first-order, with a half-life of 11.9 hours. Total-body clearance of menogaril was 204 ml/minute/m2. There were no detectable metabolites of menogaril in plasma. Urinary excretion of unchanged menogaril was 17.3% of the dose and N-demethylmenogaril was 0.5% over 72 hours. Since menogaril does not appear to be metabolized, a high degree of tissue binding is likely.

Adult↗
PubMed1987

Effect of some anticancer drugs on the surface membrane electrical properties of differentiated murine neuroblastoma cells.

The effect of some anticancer agents that produce toxic effects on electrically excitable cells in vivo was studied in vitro with the use of differentiated N1E-115 murine neuroblastoma cells and single microelectrode electrical recording. In the presence of 10(-7) g/ml tetrodotoxin, following the release of 500-millisecond conditioning hyperpolarization, the cells exhibited Ca2+-dependent action potentials. Local application to N1E-115 neuroblastoma cells of cisplatin (cis-PDD) for 30 seconds from a drug-containing effusion pipette produced a dose-dependent reversible inhibition of the Ca2+-dependent action potential, with a 61% inhibition at 1.7 microM and 67% inhibition at 17 microM cis-PDD. trans-Dichlorodiammineplatinum(II) and platinic(IV) chloride, both of which lacked the growth inhibitory properties of cis-PDD against N1E-115 neuroblastoma cells, at concentrations of 170 and 120 microM produced only an 11 and 19% inhibition of the Ca2+-dependent action potential, respectively. Vincristine at a concentration of 1 microM reversibly inhibited the Ca2+-dependent action potential by 48%. 3'-Deamino-3'-(3''-cyano-4''-morpholinyl)doxorubicin, a more potent experimental antitumor agent than doxorubicin, at 10(-8) M inhibited the Ca2+-dependent action potential by 22%, similar to the inhibition previously reported for doxorubicin. None of the agents affected the cell transmembrane potential, which suggests a lack of an effect on the mechanisms responsible for maintaining the resting cell membrane potential difference. The effects of the agents on the Ca2+-dependent action potential might reflect a direct effect on a plasma membrane Ca2+ channel or on the lipid domain around the channels, or they might be produced by changes in intracellular Ca2+ homeostasis, among other mechanisms. It is not known whether a change in the membrane Ca2+ current is related to the antitumor effects of the agents, but such a change may contribute to the neurotoxicity of cis-PDD and vincristine and the cardiac toxicity of the anthracycline.

Action Potentials↗
PubMed1986

Gas chromatographic assay for the new antitumor agent pyrazine-2-diazohydroxide (diazohydroxide) and its stability in buffer, blood and plasma.

Diazohydroxide is a new antitumor agent being considered for clinical trial. A sensitive and specific assay for diazohydroxide in physiological media, plasma and blood has been developed based on conversion of diazohydroxide to 2-chloropyrazine in the presence of strong hydrochloric acid. The 2-chloropyrazine is extracted into the ethyl acetate and separated by capillary gas chromatography with nitrogen-phosphorus detection. Using 0.2 ml plasma the assay was linear up to 100 micrograms/ml diazohydroxide and had a lower limit of detectability for diazohydroxide of 50 ng/ml. The coefficient of variation of the assay at 1 micrograms/ml was 6.7%. Breakdown of diazohydroxide was rapid under mild acid conditions but slower under alkaline conditions,. The half-life of diazohydroxide in 0.1 M sodium phosphate buffer, pH 6.0, at room temperature was 5 min and at pH 8.0, 480 min. Breakdown of diazohydroxide in plasma was biphasic. In fresh mouse plasma diazohydroxide had a terminal half-life at 37 degrees C of 72 min while in fresh human plasma the terminal half-life was 23 min and in fresh blood 21 min. Diazohydroxide accumulated in red blood cells at 37 degrees C to a concentration 68% above the concentration in plasma. Diazohydroxide was 49% bound to human plasma proteins at room temperature.

Animals↗
PubMed1986

Enhanced formation of ethane and n-pentane by rat hepatocytes in the presence of dimethyl sulfoxide.

Incubation of rat hepatocytes with 14 mM dimethyl sulfoxide (DMSO) produced an increase in the formation of ethane, measured by capillary column gas chromatography, to 18.0 pmoles/hr/10(7) cells from 11.2 pmoles/hr/1-(7) cells from 5.6 pmoles/hr/10(7) cells in control hepatocytes. This was about one-third the stimulation of ethane and n-pentane formation produced by incubation of hepatocytes with 13 mM carbon tetrachloride. DMSO-stimulated ethane and n-pentane formation was inhibited up to 63% by 0.1 microM alpha-tocopherol and up to 89% by N2. Formation of dimethylsulfide from DMSO by hepatocytes was the same in air and N2. DMSO increased methane production by hepatocytes to 31.3 pmoles/hr/10(7) cells from 6.9 pmoles/hr/10(7) cells in control hepatocytes. Although DMSO apparently stimulated lipid peroxidation by hepatocytes, as measured by ethane and n-pentane formation, there was no increase in the formation of thiobarbituric acid reactive material. DMSO was not toxic to hepatocytes, measured by release of cytosolic lactate dehydrogenase, over a 2-hr incubation. Possible mechanisms for the increase in alkane formation by DMSO are discussed.

Animals↗
PubMed1986

Increased toxicity of the antitumor drug cyclophosphamide in mice in the presence of the volatile anesthetic agent halothane.

Exposure of mice to 0.5% halothane in air, which is close to a maintenance concentration in man, after an IP dose of cyclophosphamide produced an increase in the lethality of cyclophosphamide. The LD50 (30 day) for cyclophosphamide without halothane was 251 mg/kg; with 2 h subsequent exposure to halothane it was 152 mg/kg; and with 20 h subsequent exposure to halothane it was 158 mg/kg. The median survival time of mice receiving cyclophosphamide at doses between 137 and 240 mg/kg was more than 30 days in the absence of halothane, 12 days with 2 h halothane, and 10.5 days with 20 h halothane exposure. Survival of mice was decreased irrespective of whether 2 h halothane exposure preceded or followed cyclophosphamide administration. Separation of cyclophosphamide administration and preexposure to halothane by breathing air for 1 h abolished the decrease in survival. Halothane exposure for 2 h after cyclophosphamide had no effect on the antitumor activity of cyclophosphamide. Total-body clearance of cyclophosphamide in mice exposed to halothane was 60 ml/min/kg, as against 188 ml/min/kg in nonexposed mice. No change was produced by halothane in the area under the plasma concentration-time curve over 2 h for 4-hydroxycyclophosphamide following cyclophosphamide administration. The reason for the increased lethality of cyclophosphamide in the presence of halothane could not be determined. There was no increase in leukopenia caused by cyclophosphamide and no increase in bladder toxicity, in liver toxicity, in renal toxicity, or in the penetration of cyclophosphamide into the brain. The study, together with reports of increased toxicity in patients receiving cancer chemotherapy in close proximity to general anesthesia, should alert physicians and others to the possibility of an interaction between volatile anesthetic agents and chemotherapeutic drugs.

Animals↗
PubMed1986

Effects of advanced leukemia on hepatic drug-metabolizing activity in the mouse.

Mice that had received 10(6) P388 leukemia cells IV 8 days previously exhibited a decrease in the components of the hepatic microsomal mixed function oxidase, with a 58% decrease in cytochrome P-450, and up to a 60% decrease in hepatic microsomal metabolism of biphenyl. Liver weight was increased by 49% due to infiltration of the liver with leukemic cells. Changes in liver drug-metabolizing activity and liver weight were not seen 6 days after administration of P388 leukemia. There was a small increase in serum liver enzyme but no increase in total serum bilirubin in tumor-bearing mice. In vivo total-body plasma clearance of cyclophosphamide, a drug metabolized by hepatic cytochrome P-450, was decreased to 53 ml/min/kg in mice that had received P388 cells 8 days earlier, as against 97.2 ml/min/kg in control mice. Cytochrome P-450-independent metabolism of [14C]5-fluorouracil, measured by means of [14C]CO2 in the breath over 3 h, was decreased to 21% of the dose administered by 8 days after tumor cell administration, compared with 31% of the dose in control mice. P388 leukemia cells growing in the ascitic form in the intraperitoneal cavity of mice did not release an inhibitor of 5-fluorouracil metabolism into the ascitic fluid. Total-body plasma clearance of indocyanine green was decreased to 11 ml/min/kg by 8 days after P388 cell administration, compared with 36 ml/min/kg in control mice. The decrease in indocyanine green clearance might reflect a decrease in hepatic blood flow in the tumor-bearing mice. A possible explanation for the decrease in hepatic drug metabolism caused by P388 leukemia is that the hepatocytes are deprived of oxygen and nutrients by the tumor in the liver, coupled with or caused by a physical obstruction of hepatic blood flow.

Animals↗
PubMed1986

Disposition and metabolism of the antitumor glycoside phyllanthoside in mouse and beagle dog.

Phyllanthoside is a naturally occurring glycoside with activity against IP transplantable murine tumors. Phyllanthoside administered IV, to mice at a nontoxic dose of 16 mg/kg could not be detected in blood or plasma even 30 s after administration. There was rapid formation of a less polar metabolite, which disappeared with a half-life of about 10 min. When phyllanthoside was administered as an IV bolus to beagle dogs at doses of 0.1, 0.5, and 3.0 mg/kg the mean half-life of phyllanthoside elimination from plasma was 1.3 min and total body clearance 85.8 ml min-1 kg-1. A second phase of elimination was seen but could not be accurately defined. Only trace amounts of the less polar metabolite were detected in dog plasma. Infusion of phyllanthoside to beagle dogs at doses of 0.5 and 3.0 mg/kg over 70 min gave values for an initial half-life of 0.3 and 0.6 min, a terminal half-life of 99.4 and 16.5 min, and a total body clearance of 11.2 and 49.2 ml min-1 kg-1, respectively. The highest nontoxic dose of phyllanthoside in dog was 0.1 mg/kg, while doses of 0.5 mg/kg and 3.0 mg/kg resulted in ataxia and death of the dog. There was no difference in toxicity to dog according to whether phyllanthoside was given by IV bolus or continuous infusion. Isolated hepatocytes from rat metabolized phyllanthoside at a rate of 4.4 micrograms/min per 10(6) cells to form the less polar metabolite. Coculture with isolated hepatocytes decreased the cytotoxicity of phyllanthoside to A204 human rhabdomyosarcoma cell line growing in soft agarose. It is suggested that rapid metabolism of phyllanthoside in mouse as against dog might account for the lower toxicity of phyllanthoside in mouse, and might also account for the reported poor antitumor activity of IV-administered phyllanthoside in the mouse.

Animals↗
PubMed1986

Metabolic stability of experimental chemotherapeutic agents in hepatocyte:tumor cell co-cultures.

A U.S. National Cancer Institute screening program for new anticancer drugs, based on the growth of primary human tumor cells in an in vitro soft agar colony formation assay, has resulted in the identification of a number of compounds that have cytotoxic activity against primary human tumor cells in vitro but are inactive in the conventional in vivo murine P388 leukemia animal model pre-screen. To investigate whether metabolic inactivation ov the compounds might be a factor in the lack of in vivo cytotoxicity we have co-cultured rat hepatocytes with A204 rhabdomyosarcoma and murine P388 leukemia cell lines in the soft agarose colony formation assay for 24 h during exposure to the compounds. Twenty compounds with a range of in vitro activities were studied. Thirteen compounds exhibited cytotoxicity against A204 cells in culture; nine of them were less active when co-cultured with hepatocytes, two were activated by hepatocyte co-culture, and two showed no effect of hepatocyte co-culture. P388 cells were more sensitive to the antiproliferative effects of the compounds than A204 cells. Two compounds that were not active against A204 cells exhibited cytotoxicity against P388 cells. One compound was inactivated by hepatocyte co-culture and one showed no effect. Five compounds showed no cytotoxicity toward either A204 cells or P388 cells. Two of the compounds showing hepatocyte inactivation in vitro possess activity in one or more in vivo tumor models. Thus, evidence for metabolic inactivation in hepatocyte co-culture is not always an indication for lack of in vivo antitumor activity. Hepatocyte co-culture methodology provides a simple and objective means, amenable to large-scale screening, of distinguishing metabolic activation or inactivation of a given compound from other pharmacokinetic and pharmacodynamic factors with a minimum of material.

Animals↗
PubMed1986

Anthracycline-induced inhibition of a calcium action potential in differentiated murine neuroblastoma cells.

The effects of some anthracyclines on a Ca2+ -dependent action potential have been studied in differentiated murine neuroblastoma cells (N1E-115 clone). The differentiated neuroblastoma cell possesses characteristics of an electrically excitable cell and can generate propagated potential spikes in which Ca2+ is the inward charge carrier. This was shown by the fact that action potentials recorded from differentiated neuroblastoma cells in the presence of 10(-7) g of tetrodotoxin per ml, which inhibits active Na+ channels, had a spike amplitude that depended upon the extracellular Ca2+ concentration in a manner close to that predicted by the Nernst equation. The peak potential changed 28.9 mV/decade change in extracellular Ca2+. Local application to a cell of 10(-8) M doxorubicin produced inhibition of this Ca2+ -dependent action potential within 5 s of drug application and a maximum inhibition of 13% 60 s after drug application. There was almost complete recovery to the initial spike amplitude value within 10 min after removing drug. The same concentration of doxorubicin also produced complete inhibition, without recovery, of a Ca2+ -dependent after-discharge which followed the initial action potential in about half the cells studied. Increasing concentrations of doxorubicin produced dose-dependent inhibition of the initial Ca2+ -dependent action potential. Cells exposed to 10(-5) M doxorubicin showed 88% inhibition of the Ca2+ -dependent action potential with no recovery even 10 min after removing the drug. Daunomycin, 10(-6) M, produced 90% inhibition of the Ca2+ -dependent action potential. Daunomycin aglycone (10(-6) M), which lacks antitumor activity, had no significant effect on the Ca2+ -dependent action potential. The rapid onset of the drug-induced response together with the low concentrations of anthracyclines needed to inhibit voltage-dependent Ca2+ channels in the neuroblastoma cells suggest a direct effect of anthracyclines on the cell surface membrane. The findings are discussed in light of the possible role of Ca2+ in cancer cells.

Action Potentials↗
PubMed1986

Development of experimental models for meningeal neoplasia using intrathecal injection of 9L gliosarcoma and Walker 256 carcinosarcoma in the rat.

Two models for meningeal neoplasia have been developed in rats using intrathecal injection of 9L gliosarcoma and Walker 256 carcinosarcoma cells. Tumor cells were injected in unanesthetized animals through an indwelling catheter inserted at the cisterna magna to the level of the lumbar enlargement of the spinal cord. Survival of rats was dependent on the number of tumor cells injected. Spread of tumor was quantified by histology using a grading scale, and functional and behavioral changes were measured. Rats injected with 10(6) 9L gliosarcoma cells showed progressive weight loss, flaccid paralysis, and neurogenic bladder dysfunction and had a median survival of 11 days. The tumor frequently grew as a mass compressing the spinal cord. The 9L gliosarcoma tumor cells markedly invaded the Virchow-Robin spaces but exhibited only minimal invasion of the central nervous system parenchyma. The tumor reached the brain by day 10. Rats injected with 2 X 10(5) Walker 256 carcinosarcoma cells showed progressive weight loss and weakness and had a median survival of 6 days. The tumor grew within the leptomeninges in a discontinuous multifocal fashion and reached the brain by day 4. There was extensive invasion of the central nervous system parenchyma by Walker 256 tumor cells along the Virchow-Robin spaces resulting in hemorrhage and necrosis of grey and white matter. Hot plate and tail flick response times were significantly delayed only in the days immediately preceding death of animals with either 9L or Walker 256 tumor and were not good indicators of tumor progression. Loss of motor coordination and failure of the stepping and placing reflex on the other hand showed good correlation with spread of tumor measured histologically. Control animals injected with 0.9% NaCl or with lethally irradiated tumor cells showed no significant weight loss or functional or behavioral changes. The intrathecal 9L gliosarcoma and Walker 256 carcinosarcoma models show different characteristics of human meningeal carcinomatosis and will be used for studies of experimental chemotherapy with intrathecally administered antitumor drugs.

Animals↗
PubMed1986

Disposition of tricyclic nucleoside-5'-monophosphate in blood and plasma of patients during phase I and II clinical trials.

Tricyclic nucleoside-5'-monophosphate (TCN-P) and its dephosphorylated metabolite tricyclic nucleoside (TCN) have been measured in the blood and plasma of patients receiving TCN-P by rapid iv infusion in a phase I trial at daily doses of 24-55 mg/m2 for 5 days and in patients receiving TCN-P in a phase II trial at a single dose of 250 mg/m2. TCN-P was rapidly accumulated by rbcs and had an initial half-life in blood of 6.1 hours and a terminal half-life of 89.2 hours. Total-body blood clearance of TCN-P was 2.6 ml/minute/m2. The concentration of TCN-P in blood was not related to the dose of TCN-P and did not increase over 5 days' administration in the phase I patients. Plasma contained little detectable TCN-P even 5 minutes after administration. Plasma contained low concentrations of TCN, up to 0.4 microgram/ml, which were maintained over several days. TCN did not accumulate in the plasma with repeated administration of TCN-P in the phase I patients. No other metabolites of TCN-P, apart from TCN, were detected in blood or plasma. No relationship was detected between pharmacokinetics and toxic response of TCN-P in the phase II patients.

Acenaphthenes↗
PubMed1985

High-performance liquid chromatographic assay for the antitumor glycoside phyllanthoside and its stability in plasma of several species.

Phyllanthoside is a glycoside isolated from the roots of the Central American tree Phyllanthus acuminatus Vahl with antitumor activity against murine B-16 melanoma and P-388 leukemia. We report a reversed-phase high-performance liquid chromatographic assay for phyllanthoside in plasma using a 25-cm RP-18, 5-micron column with a linear 10-min gradient of 50% to 100% methanol in 0.3 M sodium acetate, pH 4.0, at a flow-rate of 1.5 ml/min. Eluting peaks were detected at 270 nm. The lower limit of sensitivity of the assay for phyllanthoside in 0.5 ml plasma following ethyl acetate extraction at pH 7.0 was 0.25 micrograms/ml and the coefficient of variation at 1 microgram/ml was +/- 7.4%. Phyllanthoside was very rapidly broken down by mouse and rat plasma in vitro to an unidentified less polar metabolite. Formation of this metabolite was completely inhibited by preheating mouse plasma to 100 degrees C for 10 min. When mouse plasma was diluted 1:50 with water the half-life of phyllanthoside disappearance at 37 degrees C was 2.0 min. Breakdown of phyllanthoside in plasma from other species was slower than in mouse and the initial half-life at 37 degrees C in dog plasma was 30 min, in monkey plasma 33 min and in human plasma 38 min. The same less polar metabolite as in mouse plasma was formed slowly by plasma of monkey and dog. Phyllanthoside did not accumulate in human red blood cells. Binding of phyllanthoside to human plasma protein determined by ultrafiltration at 4 degrees C was 70%.

Animals↗
PubMed1985

Anticancer drug pharmacodynamics.

A considerable amount of information is available on the pharmacokinetics of anticancer drugs, but much less is known of their pharmacodynamics, that is of the relationship between therapeutic or toxic response and drug concentration. Drug dosage regimens which are to achieve defined therapeutic objectives can only be designed when both the pharmacokinetic and the pharmacodynamic characteristics of a drug are known. There are a few reports in the literature of relationships in man between toxic response and pharmacokinetic parameters of anticancer drugs, and an even smaller number of reports of relationships between therapeutic response and pharmacokinetic parameters. It is suggested that the lack of pharmacodynamic information is currently limiting the application of pharmacokinetic information to cancer therapy. Ways of improving knowledge of the pharmacodynamics of anticancer drugs are suggested.

Animals↗
PubMed1985

Topical chemotherapy of intradermal Walker 256 carcinosarcoma with diaziquone and doxorubicin in the rat.

A model for metastatic skin cancer using intradermal injection of Walker 256 carcinosarcoma has been developed in the rat. Using this model, antitumor activity of topically applied doxorubicin and diaziquone in Vanicream, Plastibase, and dimethyl sulfoxide (DMSO) as vehicles was compared with intraperitoneal injection of the drugs at the same doses beginning 4 days after injection of tumor cells. Doxorubicin applied topically at 0.5 mg/day for 4 days in Vanicream or Plastibase exhibited no antitumor activity, while i.p. administered doxorubicin at 0.5 mg/day for 4 days inhibited tumor growth at day 20 by 66%. Diaziquone applied topically at 0.1 mg/day for 4 days in Vanicream, Plastibase, or DMSO inhibited tumor growth at day 20 by 66, 86, and 43%, respectively, and cured animals of the skin tumor at a dose of 0.5 mg/day. Diaziquone administered i.p. at 0.5 mg/day for 4 days was lethal to rats, and at 0.1 mg/day it produced 93% inhibition of tumor growth at day 20. Diaziquone applied topically at 0.1 mg/day for 4 days in Plastibase cured rats of advanced tumor when treatment was begun 12 days after injection of tumor cells. The area under the plasma radioactivity time curve over 5 h for a single 0.64-mg dose of topically applied [ring-14C]diaziquone in DMSO was 0.01% that of the same dose of [ring-14C]diaziquone administered i.p. in non-tumored rats. The decrease in WBC count following topical application of diaziquone at a dose of 0.1 mg/day for 4 days, compared to the same dose of diaziquone administered i.p., was 62% in Vanicream, 81% in Plastibase and 33% in DMSO. Topical diaziquone was non-toxic to normal skin in the rat and in the domestic pig. It is concluded that topical application of diaziquone offers a therapeutic advantage over systemic treatment for metastatic cancer of the skin.

Absorption↗
PubMed1984

Enzymatic and non-enzymatic reduction of N-acetyl-p-benzoquinone imine and some properties of the N-acetyl-p-benzosemiquinone imine radical.

N-Acetyl-p-benzoquinone imine (NAPQI) is the postulated hepatotoxic intermediate in acetaminophen overdosage. NAPQI was rapidly metabolized by NADPH-cytochrome P-450 reductase, with an apparent Km of 1.8 to 4.0 microM and an apparent Vmax of 29.4 mumoles per min per mg, and exhibited substrate inhibition of metabolism at NAPQI concentrations above 10 microM. NADPH was oxidized by NAPQI at a slower rate in the absence of enzyme. NAPQI did not appear to undergo redox cycling at an appreciable rate to form superoxide, and it did not stimulate oxygen utilization or superoxide release by rat isolated hepatocytes. Electron spin resonance studies failed to show formation of a free radical by chemical or enzymatic reduction of NAPQI under anaerobic conditions in aqueous media.

Animals↗
PubMed1984

Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study.

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.

Animals↗