Showing papers by "Garth Powis published in 1981"

Quinone-stimulated superoxide formation by subcellular fractions, isolated hepatocytes, and other cells

Abstract: Quinones can undergo enzymatic one-electron reduction to the semiquinone radical which, in the presence of molecular oxygen, can transfer an electron and form the superoxide anion radical (O2[unknown]). Isolated hepatocytes do not liberate appreciable amounts of O2[unknown]. Simple quinones, such as 2,5-dimethyl- p -benzoquinone, stimulate the formation of O2[unknown] by hepatocytes up to 15 nmoles/min/106 cells. Hepatocyte O2[unknown] formation stimulated by a variety of simple quinones and more complex antitumor quinones is maximal at a quinone one-electron reduction potential ( E 71) of -70 mV and qualitatively similar to the pattern of O2[unknown] formation seen with mitochondrial NADH:ubiquinone oxidoreductase and microsomal NADH-cytochrome b 5 reductase. O2[unknown] production by microsomal NADPH-cytochrome P-450 reductase is maximal at a quinone E 71 of -200 mV. Phenobarbital induction, which increases NADPH-cytochrome P-450 reductase, has no effect on O2[unknown]formation by hepatocytes. It is concluded that NADPH-cytochrome P-450 reductase activity is not rate-limiting for quinone-stimulated O2[unknown] formation by hepatocytes. The sulfonated stilbenes, 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid stilbene and 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene have no marked effect on the formation of O2[unknown]by hepatocytes, suggesting that O2[unknown] is not transported through anion channels in the plasma membrane. Ethanol has no effect on hepatocyte O2[unknown] formation, which suggests that intracellular NADH is not rate-limiting. Treatment of hepatocytes with diethyldithiocarbamate, which inhibits cytosolic and mitochondrial superoxide dismutase, increases O2[unknown] formation by hepatocytes over 2-fold. Feeding rats a copper-deficient diet, which also decreases hepatic cytosolic and mitochondrial superoxide dismutase, has no effect on the quinone-dependent formation of O2[unknown] by hepatocytes.

Protection against Adriamycin-induced Skin Necrosis in the Rat by Dimethyl Sulfoxide and α-Tocopherol

Abstract: Extravasation of Adriamycin during i.v. infusion can cause serious local complications. We have used a rat skin model to study the protection afforded by dimethyl sulfoxide and alpha-tocopherol (vitamin E) against Adriamycin-induced skin necrosis. Topical daily application of 1 ml dimethyl sulfoxide for 2 days produced a small decrease in ulcer diameter of up to 11% at 2 weeks. Topical daily applications of 1 ml 10% alpha-tocopherol succinate in dimethyl sulfoxide for 2 days produced a marked decrease in ulcer diameter at 2 weeks of up to 68%. Daily topical application of 1 ml 10% alpha-tocopherol succinate in dimethyl sulfoxide for 7 days offered no greater protection than 2-day application. alpha-Tocopherol acetate appeared to have activity slightly less than that of alpha-tocopherol succinate in reducing ulcer size, and both compounds were considerably more active than was alpha-tocopherol alcohol. Administration of alpha-tocopherol succinate or alpha-tocopherol acetate i.p. had no significant effect upon ulcer diameter. Topically applied dimethyl sulfoxide and alpha-tocopherol may provide an effective way of treating accidentally extravasated Adriamycin in cancer patients.

Dose-dependent pharmacokinetics and cancer chemotherapy

Abstract: 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.

Activity of indicine N-oxide in refractory acute leukemia.

Abstract: 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