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R L Cysyk

Publications and source records attributed to R L Cysyk.

71 records · Page 4Linked to original sources
PubMed1976

Synthesis and biological properties of some spin-labeled 9-aminoacridines.

Five spin-labeled 9-aminoacridines, each bearing either a 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) or a 3-(2,2,5,5-tetramethyl-1-pyrrolidinyloxy) moiety in the 9 position, have been synthesized and assayed for biological activity in three different test systems. Sedimentation velocity measurements indicated that the labels caused unwinding of calf thymus DNA. Those acridines which contained both 6-chloro and 2-methoxy substituents were less toxic to leukemia L1210 in static culture than the corresponding unsubstituted analogues. While the unsubstituted aminoacridines were quite good inhibitors of Escherichia coli DNA-primed RNA polymerase, the 6-chloro-2-methoxy-substituted compounds stimulated this enzyme system. In the presence of E.coliDNA, the ESR spectrum of 4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2,2,6,6-tetramethyl-1-piperidinyloxyl (12) became broad and highly asymmteric with a maximal hyperfine splitting of 57.5 G. This observation suggests that when 12 intercalates into DNA the piperidinyl moiety that bears the nitroxide group becomes highly immobilized. These results suggest that the spin-labeled 9-aminoacridines will be useful probes for nucleic acids.

Acridines↗
PubMed1976

The disposition of coralyne sulphoacetate in rodents.

1. The disposition of (14C) coralyne sulphoacetate has been examined in the mouse and rat at three dose levels. 2. In both species the major route of excretion is biliary following either intraperitoneal or intravenous administration. In rats, 18-24% of the 14C is eliminated in the bile in the first 24 h and only 1-2% in the urine. Transport into bile appears to be active and the transport system saturable at the doses employed. 3. The majority of the biliary 14C in the rats is unchanged parent compound and a minority is associated with a metabolite. The maximum amount of metabolite is 12% at 10-30 min following the administered dose. 4. The initial plasma decay of (14C) coralyne following intravenous administration is rapid. Half-life values are 12-3, 16-2 and 2-41 min after doses of 13, 26 and 52 mg/kg respectively. 5. No sex differences were found in the rat in the parameters studied.

Animals↗
PubMed1976

Protein cross-linking properties of the antitumor agent inosine dialdehyde (NSC-118994).

Inosine dialdehyde (IdA), a new antitumor agent presently undergoing clinical evaluation in man, possesses two aldehyde groups that form stable complexes with a variety of biologic molecules containing amino groups. Complex formation of IdA with lysine, glycine, histidine, or bovine serum albumin (BSA) greatly reduces the cytotoxicity of IdA against L1210 leukemia in vitro. Complexes of IdA and BSA exhibit molecular weights ranging from 69,000 to greater than 800,000 as determined by Sephadex G-200 gel filtration, indicating that both aldehyde groups of IdA are functional and can cross-link protein molecules. The cross-linking of plasma proteins and the cross-linking of glycine to BSA were also observed. No interaction of IdA with nucleic acids, nucleic acid bases, or nucleosides was detected. The dialdehyde derivatives of other nucleosides also possessed cross-linking properties.

Aldehydes↗
PubMed1976

Pharmacologic disposition of inosine dialdehyde (NSC-118994) in mice, rats, dogs, and monkeys.

The pharmacologic disposition of inosine dialdehyde (IdA) was studied in mice, rats, dogs, and monkeys. 14C-IdA was utilized to follow plasma and tissue levels and patterns of excretion. Plasma radioactivity curves were multiphasic with an initial rapid component (half-life = 12-18 mins) followed by a much slower decline (half-life = approximately 3 days). As time progressed after the injection, an increasing fraction of the total plasma radioactivity was found to be associated with plasma proteins and was trichloracetic acid (TCA) insoluble. IdA interacts extensively with proteins and small molecules both in vivo and in vitro, forming complexes that do not dissociate under physiologic conditions. The pharmacologic disposition of IdA is dependent upon the relative extent of IdA interaction with protein macromolecules versus small transportable molecules. The major route of excretion was urinary with less than 50% of the dose excreted during the first 24 hours after iv administration in all species studied. IdA was recovered in the urine as complexes with urine constituents. There was no preferential uptake of IdA by any organ. All radioactivity remaining 24 hours after IdA administration was associated with plasma and cellular proteins and was nondiayzable and TCA insoluble. IdA was not a substrate for aldehyde oxidase and did not inhibit the activity of this enzyme.

Aldehydes↗
PubMedDate not supplied

Chemical assay for the antitumor agent inosine dialdehyde (NSC-118994) in biologic fluids.

Inosine dialdehyde, an antitumor agent highly active against several murine tumors, ispresently undergoing clinical trial for potential activity in man. To aid in the clinical evaluation of this drug, a chemical assay has been developed for the determination of concentrations of inosine dialdehyde in biologic fluids. The method involves reaction of inosine dialdehyde with phenylhydrazine in an acetic acid medium, followed by extraction of the product into ether and determining its absorbance at 378 nm. The reaction is specific for free inosine dialdehyde and will quantitate amounts as low as 1.0 mug.

Aldehydes↗
PubMedDate not supplied

Enhancement of the effectiveness of daunorubicin (NSC-82151) or adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943).

The LD50 of intraperitoneally (ip) injected daunorubicin in nonleukemic mice (1.8 mg/kg, q4d times 3) can be increased several fold by the concomitant ip injection of ICRF-159. In addition, the survival of leukemic mice treated with daunorubicin and ICRF-159 on Days 1, 5, and 9 after ip inoculation of L1210 tumor cells was substantially greater than after treatment with either drug alone. This potentiation of survival with combination treatment usually occurred with doses of daunorubicin greater than the LD50 of daunorubicin alone. The LD50 of subcutaneously (sc) injected daunorubicin alone (14.0 mg/kg, q4d times 3) was not increased by concomitant ip treatment with ICRF-159. However, when leukemic mice were treated sc with daunorubicin and ip with ICRF-159 on Days 1, 5, and 9 after ip injection of L1210 leukemia cells, survival was greater than with treatment with either drug alone. The toxicity of ip injected adriamycin was not reduced by ICRF-159, but treatment of leukemic mice with this combination was more effective in prolonging survival than treatment with either drug alone. Combination treatment with daunorubicin plus ICRF-159 showed much less therapeutic enhancement against sc implanted L1210 leukemia than against the ip implanted tumor.

Animals↗
PubMedDate not supplied

The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide in mice and rats.

The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA; NSC-141549), a new antitumor agent presently under consideration for phase I evaluation in man, was studied in mice and rats with 14C-AMSA labeled in the 9-carbon of the acridine ring. Radioactivity was selectively localized in the liver where it was present mainly as metabolites of AMSA. After 2 hr, nearly 50% of the plasma radioactivity was bound to protein and did not dissociate upon Sephadex G-200 chromatography. Radioactivity was rapidly eliminated in the bile; greater than 50% of the administered dose was excreted by this route in 2 hr. Bile/plasma ratios of greater than 400:1 indicated an active transport mechanism. The biliary transport mechanism was saturable with therapeutic doses. AMSA was found to be especially vulnerable to nucleophilic attack by alkylthiols resulting in displacement of 4-amino-3-methoxymethanesulfonanilide and the formation of the corresponding 9-alkylthioether of acridine. The major radioactive biliary metabolite (accounting for 90-95% of the biliary radioactivity) possessed the same chromatographic properties as the thiolysis product of AMSA and glutathione (GSH). A 40% reduction in liver GSH and a 20% reduction of liver GSH-transferase activity occurred after AMSA administration to mice. The pharmacologic disposition of AMSA can best be explained by a nonenzymatic nucleophilic attack on the 9-carbon atom of AMSA by endogenous thiols, resulting in the formation of 9-thioethers of acridine. Such an attack by low molecular weight thiols results in a product that is eliminated in urine and bile, whereas interaction with protein-thiol groups results in prolonged retention of the acridine moiety.

Acridines↗
PubMedDate not supplied

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. A nuclear magnetic resonance (NMR) spectrum of the CID salt in D2O showed that the metabolite is the m-AMSA-glutathione conjugate in which the thioether linkage occurs at the 5'-position of the anilino ring. Synthesis of the metabolite was achieved by oxidizing m-AMSA with active MnO2 to -methanesulfonyl - - (9-acridinyl)-3'-methoxy - 2',5' - cyclohexadiene-1',4'-diimine (m-AQDI) followed by reaction of m-AQDI with glutathione. The 1H-NMR spectrum of the synthetic product proved identical with that of the isolated metabolite. The demonstration that the principal biliary metabolite on m-AMSA involves glutathione bound to the 9-anilino ring suggests that m-AMSA may be bioactivated in vivo to the quinoidal diimine, m-AQDI.

Acridines↗
PubMedDate not supplied

Distribution of adriamycin in mice under conditions of local hyperthermia which improve systemic drug therapy.

Local tumor hyperthermia (LTH) (43 degrees C for 60 minutes) enhanced the effectiveness of Adriamycin (ADR) (10 mg/kg iv) administered systemically against the 16C mouse mammary adenocarcinoma. LTH was produced by the local application of 2450 MHz microwaves to sc implanted tumors. During LTH the intratumor temperature uniformity was +/- 0.5 degrees C and the rectal temperatures were 36 degrees C--38 degrees C. The simultaneous application of LTH and ADR resulted in tumor growth delays which were greater than those expected from the addition of individual treatments. Enhanced effectiveness of these treatments did not occur if the two treatments were separated by 4 hours. Cures were observed only in the treatment groups that received drug and heat simultaneously. Measurements of the tissue distribution of ADR and its metabolites using 14C-ADR indicated that the uptake of radioactivity in the heated tumors was not increased by LTH. A greater percentage of the radioactivity in heated tumors was recovered as ADR metabolites and correspondingly less radioactivity was recovered as unchanged ADR.

Adenocarcinoma↗