Sodium-phosphate cotransport in human red blood cells. Kinetics and role in membrane metabolism.

Orthophosphate (Pi) uptake was examined in human red blood cells at 37 degrees C in media containing physiological concentrations of Pi (1.0-1.5 mM).

Arabinosyl-5-azacytosine: a novel nucleoside entering clinical trials.

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside.

Flavone acetic acid (LM 975, NSC 347512). A novel antitumor agent.

Flavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.

Echinomycin: the first bifunctional intercalating agent in clinical trials.

Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p.

Trimetrexate: a new antifol entering clinical trials.

Trimetrexate, a 2,4-diaminoquinazoline derivative, is a new antifol recently introduced into clinical trials. It differs from methotrexate principally in its transport (not carrier-mediated), and its intracellular retention (not polyglutamylated). Trimetrexate is active against tumors which are methotrexate-resistant on the basis of impaired transport, and has a broader range of antitumor activity in preclinical models.

Metabolism of 4'-(9-acridinylamino)methanesulfon-m-anisidide by rat liver microsomes.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is metabolized by a hepatic microsomal enzyme system composed of rat liver microsomes, a reduced nicotinamide adenine dinucleotide phosphate-generating system, cytosolic protein (or glutathione), and oxygen. Omission of any one of the components, or incubation under an atmosphere of CO or N2, results in inhibition of the reaction. Also, the addition of inhibitors of microsomal metabolism (alpha-naphthoflavone, metyrapone, or SKF 525-A) decreases m-AMSA metabolism.

Tiazofurin: a new antitumor agent.

Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase.

Amiloride fluxes across erythrocyte membranes.

Amiloride is known to inhibit both the influx of Na+ and the activation of mitogenesis in many cultured cell lines. This paper describes experiments in which the permeability coefficient of amiloride was determined from measurements of tracer fluxes across human erythrocytes and resealed ghosts. From an analysis of these fluxes, a permeability coefficient of 10(-7) cm/s for the uncharged form of amiloride was deduced.

[3H]Ouabain binding and Na+, K+-ATPase in resealed human red cell ghosts.

The interaction of the cardiac glycoside [3H]ouabain with the Na+, K+ pump of resealed human erythrocyte ghosts was investigated. Binding of [3H]ouabain to high intracellular Na+ ghosts was studied in high extracellular Na+ media, a condition determined to produce maximal ouabain binding rates. Simultaneous examination of both the number of ouabain molecules bound per ghost and the corresponding inhibition of the Na+, K+-ATPase revealed that one molecule of [3H]ouabain inhibited one Na+, K+-ATPase complex.

Spiromustine: a new agent entering clinical trials.

Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also enhance alkylating activity against tumors other than brain tumors. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma.

Studies on the O-demethylation of misonidazole by rat liver microsomes.

The role of rat liver microsomes in the O-demethylation of misonidazole to desmethylmisonidazole was studied. The rate of the microsomal-dependent formation of desmethylmisonidazole was linear up to a protein concentration of 2 mg/ml and over a 10-minute interval. The metabolism was optimal in a system comprised of microsomes, O2, and NADPH.

Identification of the principal biliary metabolite of 4'-(9-acridinylamino)methanesulfon-m-anisidide in rats.

m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide] labeled in either the acridine or anilino portion was used to investigate the disposition of this antitumor agent in rats. The principal biliary metabolite, which accounts for approximately 80% of the total biliary radioactivity for 90 min after administration and greater than 50% of the administered dose by 180 min after administration, had both the acridine and the anilino portions intact. Isolation and purification of the principal metabolite was achieved by preparative thin-layer chromatography on silica gel and column chromatography on Amberlite XAD-2 resin.

Identification of conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide.

Conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide were identified primarily by high-pressure liquid chromatography in combination with field desorption mass spectrometry. The spontaneous metabolic pathway of the drug, as related to its susceptibility to nucleophilic attack by endogenous thiols at the 9-carbon atom of the acridine moiety, has been studied. Among the metabolite fraction of 4'-(9-acridinylamino)methanesulfon-m-anisidide excreted in rat bile after administration of a therapeutic dose, a conjugate was identified as the 9-acridinyl thioether of glutathione.

Induction and development of mouse liver glutathione S-transferase activity.

Mouse liver glutathione S-transferase activity at birth was 1/10 that of adults, and increased steadily with each successive week of age until adult values were reached at 8 weeks. Activity was inducible with phenobarbital; however, the percentage increase in activity was dependent upon substrate. 2 distinct peaks of transferase activity were obtained on CM-cellulose chromatography.

Ultrastructure of hemoglobin-depleted human erythrocyte resealed ghosts.

Both negative-stain and freeze-fracture electron microscopic techniques revealed that the ultrastructure of resealed white ghosts prepared at high dilution during the hemolysis step is very different from that of resealed ghosts prepared at low or moderate dilution (pink ghosts). The negative-stained resealed white ghosts showed light halo substructures on membrane surfaces and protrusions at the edge of the ghosts. Freeze-fracturing of these ghosts showed that membrane blebbing had occurred and that fragments of the membranes resealed to form small right-side-out vesicles ranging from 0.