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R L Cysyk

Publications and source records attributed to R L Cysyk.

At least 55 records · Page 3Linked to original sources
PubMed1981

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. This conjugation product and the corresponding 9-acridinyl conjugates were formed spontaneously after incubation of 4'-(9-acridinylamino)methanesulfon-m-anisidide with glutathione, cysteine and N-acetylcysteine in sodium phosphate buffer and other aqueous media, as established by high-pressure liquid chromatography and field desorption mass spectra. The thiolytic pathway results in the release 4-amino-3-methoxymethanesulfonanilide which was identified in all in vitro experiments and in rat serum after intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide. 9(10H)-Acridone, 9-aminoacridine and other acridine derivatives which occur as minor products during the thiolytic cleavage in vitro were identified by field desorption and partially by high resolution electron impact mass spectrometry.

Aminoacridines↗
PubMed1981

Effect of inhibitors of the de novo pyrimidine biosynthetic pathway on serum uridine levels in mice.

Since C57BL X DBA F1 (hereafter called BDF1) mice possess a relatively constant concentration of serum uridine [9.7 +/- 1.3 (S.D.) nmol/ml], circulating uridine is available to cells with an intact pyrimidine salvage pathway and thus could influence the effectiveness of certain antitumor agents which inhibit de novo pyrimidine biosynthesis and whose cytotoxic properties are reversed by uridine. Three inhibitors of the de novo pyrimidine biosynthetic pathway were studied to determine their effects on circulating uridine concentration in BDF1 mice. Pyrazofurin and 6-azauridine were found to have no significant effect on serum uridine levels when administered as a single dose or on 4 consecutive days. In contrast, N-(phosphonacetyl)-L-aspartate reduced serum uridine levels by 55% when administered either as a single dose or on 4 consecutive days. This reduction could contribute to the antitumor effectiveness of N-(phosphonacetyl)-L-aspartate by limiting the rescue of cells possessing a salvage pathway. D-Galactosamine, a stimulator of the de novo pyrimidine pathway, was also studied and found to increase total liver uridine (uridine plus uracil nucleotides and uridine diphosphate esters) by 4-fold at 8 hr, returning to normal by 24 to 48 hr. However, these large effects were not reflected in the serum.

Amides↗
PubMed1981

Mechanism of resistance of variants of the Lewis lung carcinoma to N-(phosphonacetyl)-L-aspartic acid.

Variants of the Lewis lung carcinoma were selected for resistance to N-(phosphonacetyl)-L-aspartic acid (PALA) by treatment of tumor-bearing mice with repetitive subcurative doses of PALA. The specific activity of the target enzyme, L-aspartic acid transcarbamylase (ATCase), was measured in the four variants developed. Three had markedly elevated ATCase activities; however, the fourth line, LL/PALA-C, had an ATCase activity identical to that of the parent, PALA-sensitive line (LL/O). One high-ATCase variant, LL/PALA-J, and LL/PALA-C were compared with LL/O in subsequent biochemical studies on the mechanism of resistance to PALA. Enzyme activities in the salvage pathways which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be similar in all three lines. ATCase in these lines exhibits closely comparable kinetics with its natural substrates as well as with PALA. The time courses of restitution of ATCase after a single therapeutic dose of PALA show that both resistant variants recover full activity more rapidly than the parent. Additionally, inhibition of ATCase 24 hr following graded doses of PALA is lower in the resistant lines. The uptake of [14C]PALA in vitro into cell lines derived from the three Lewis lung carcinomas apparently occurs by passive diffusion and at comparable rates in both sensitive and resistant cells. Analysis of the nucleotide content of tumors reveals comparable spectrums of purine and pyrimidine nucleotide levels in the LL/O and LL/PALA-C lines, whereas the LL/PALA-J line has augmented nucleotide pools. In all three lines, 24 hr after treatment with PALA (400 mg/kg), uridine and cytidine nucleotide levels were substantially diminished (70 to 80%) while adenosine 5'-triphosphate and guanosine 5'-triphosphate levels were elevated (50 to 100%). Estimations of precursor flux through the de novo pyrimidine pathway by measuring orotate and orotidine levels in tumors of mice treated with pyrazofurin (an inhibitor of orotidine-5'-monophosphate decarboxylase) and either 0.9% NaCl solution or PALA shows that PALA treatment eliminates orotate and orotidine accumulation in LL/O but reduces it by only 75 and 50% in LL/PALA-C and LL/PALA-J, respectively. Similarly, PALA treatment (20 microM) of tumor lines in culture provokes a dramatic decrease in the incorporation of NaH14CO3 into pyrimidine intermediates and nucleotides in the LL/O cell line only. Determinations of specific activities of the other enzymes in this pathway reveal that the activity of carbamyl phosphate synthetase II, the rate-limiting step, is elevated 2- to 3-fold in both resistant lines. Since carbamyl phosphate synthetase II exists as a complex with ATCase, the suggestion is made that levels of carbamyl phosphate synthetase II are collaterally important determinants of PALA activity. An augmented pool of carbamyl phosphate in the resistant variants may serve to competitively displace PALA from ATCase, diminish enzyme inhibition, and allow pyrimidine biosynthesis to proceed despite therapy.

Amides↗
PubMed1980

m-AMSA: a new anticancer agent.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA; NSC-249992) is a new anticancer agent that has undergone extensive experimental investigation. Clinical trials have recently been initiated and current data suggest a wide spectrum of antitumor activity in human cancer.

Aminoacridines↗
PubMed1980

Serum uridine levels in patients receiving N-(phosphonacetyl)-L-aspartate.

Serum uridine levels of N-(phosphonacetyl)-L-aspartate-treated patients from Phase 1 and continuing trials receiving 1000 to 2000 mg/sq m/day were measured by reverse-phase high-pressure liquid chromatography. For the five patients studied, the predose serum levels ranged from 2.6 to 64. microM, well within the normal range of 1.9 to 8.9 microM. All serum uridine levels decreased in the first 24 hr, but the drop was quite variable (7 to 65%). Uridine levels in all five patients remained being 37 to 85% at differing time points. The only patient to show a daily decrease was the only responder and the patient with the largest decrease. N-(Phosphonacetyl)-L-aspartate appears to have a limited reductive effect on human serum uridine levels.

Antimetabolites, Antineoplastic↗
PubMed1979

m-AMSA and PALA: two new agents in cancer chemotherapy.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) and N-(phosphonacetyl)-L-aspartate (PALA) are two new anticancer agents that have been recently introduced into clinical investigation. This review summarizes the preclinical information that has accumulated with these compounds as well as the very preliminary data presently available from early clinical trials. This information indicates the promising potential of m-AMSA and PALA in the treatment of cancer.

Aminoacridines↗
PubMed1979

Synthesis and biological properties of N2-substituted spin-labeled analogues of actinomycin D.

We have synthesized N2-[4-(2,2,6,6-tetramethyl-1-piperidinyloxy)]actinomycin D And the related 1,2-diaminoethane and 1,3-diaminopropane derivatives and evaluated their biological properties. Binding studies with the spin-labeled actinomycin D analogues and DNA were carried out by using circular dichroism, electron spin resonance, and thermal denaturation. These studies have suggested that the derivatives bind to DNA and that their DNA-binding modes are similar but not identical. Spin-labeled actinomycin D derivatives were less potent in inhibiting Escherichia coli DNA-dependent RNA polymerase reaction than actinomycin D and were less toxic to L1210 cells in vitro than the parent compound. Spin-labeled actinomycin D derivatives were more common than the parent compounds against P-388 leukemia cells in vitro with little or no toxicity.

Animals↗
PubMed1979

Determination of N-(Phosphonacetyl)-L-aspartic acid (PALA) in dog serum and urine by gas chromatography and selected lon monitoring.

Methods are described for quantitating N-(phosphonacetyl)L-aspartic acid (PALA), a new antitumor agent presently undergoing clinical evaluation. These methods were developed to measure this compound in serum by gas chromatography using the selectivity of a nitrogen-phosphorus detector and in serum and urine by the gas chromatographic/mass spectrometric technique of selected ion monitoring. PALA and the internal standard, N-(phosphonacetyl)-L-glutamic acid (HOMOPALA), were analyzed as their tetramethyl derivatives. Extraction from the biologic fluids was achieved by first precipitating the protein with acetone and then drying the serum with subsequent washes of acetone and diethyl ether. PALA and HOMOPALA were than extracted from the dried serum into an anhydrous HCL/methanol/tetrahydrofuran solution. After removing the solvent, the extract was reacted with diazomethane to form the tetramethyl derivatives. The feasibility of the method was demonstrated in the dog by comparing the total radioactivity with PALA equivalents determined in blood and urine samples following iv administration of PALA-14C. The range of the analysis was 20.0--200 microgram/ml for the urine samples and 0.5--15 microgram/ml for the serum samples.

Animals↗
PubMed1979

Enhancement of bleomycin activity against Lewis lung tumors in mice by local hyperthermia.

The cytotoxicity of the drug bleomycin in vitro has previously been shown to be enhanced by hyperthermia. This report demonstrates in vivo a more than additive interaction between local tumor hyperthermia (43 degrees, 60 min) and bleomycin (15 mg/kg s.c.) against s.c.-implanted Lewis lung carcinomas in mice. Local hyperthermia was produced by the application of 2450-MHz microwaves to the region of the tumor without induction of significant whole-body hyperthermia. The combined drug and heat treatments were applied to tumors on Days 4, 7, and 10 following implantation. The response of the tumors to simultaneous treatment was a 17-day growth delay compared with controls, whereas the local hyperthermia and bleomycin individually resulted in only 3- and 4-day growth delays, respectively. If the two treatments were given either 4 or 24 hr apart only an additive effect on growth delay was observed.

Animals↗
PubMed1978

Oral absorption and selective tissue localization of 4'-(9-acridinylamino)-methanesulfon-m-anisidide.

The disposition of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (AMSA), a new antitumor agent presently undergoing clinical evaluation, was studied in mice and rats following oral administration and compared to that observed following intravenous administration. The metabolic fate of AMSA was the same with either intravenous or oral administration; however, the tissue distribution of AMSA differed significantly between the two routes of administration. Following absorption from the GI tract, AMSA was rapidly cleared from plasma by the liver and excreted in the bile as metabolites. Concentrations of AMSA in the liver were relatively high after oral administration and were sufficient to exert a cytotoxic effect on L1210 cells implanted at the site. The results indicate the use of AMSA orally to attain selective localization in the liver with decreased systemic exposure, which may prove useful against tumor metastases to the liver or primary hepatocellular carcinoma.

Absorption↗
PubMed1978

Selective localization of 4'-(9-acridinylamino)-methanesulfon-m-anisidide in B 16 melanoma.

The acridine derivative 4'-(9-acridinylamino)-methanesulfon-m-anisidide (AMSA, NSC-141549), a new antitumor agent undergoing phase I clinical evaluation, is highly active against B16 melanoma in vivo. AMSA was found to be concentrated in B16 melanoma cells in vivo and remained at high concentrations for at least 72 h. Subcellular fractionation of B16 melanoma cells revealed the drug to be bound to melanin granules. The results suggest the possible use of AMSA in human melanoma and the design of other antimelanoma agents that would exploit the affinity of the acridine nucleus for melanin.

Acridines↗
PubMed1978

Interaction of 4'-(9-acridinylamino)methanesulfon-m-anisidide with DNA and inhibition of oncornavirus reverse transcriptase and cellular nucleic acid polymerases.

4'-(9-Acridinylamino)methanesulphon-m-anisidide (AMSA) (NSC 141549), an acridine derivative with activity against a variety of laboratory tumors in vivo, is presently undergoing Phase 1 clinical evaluation. The interaction of AMSA with DNA and its effects on nucleic acid-polymerizing enzymes were examined in an attempt to define the site of cytotoxicity of AMSA. Binding of AMSA to DNA, as demonstrated by equilibrium dialysis and spectrophotometric methods, appears to be similar to other aminoacridines, in that two types of binding sites (type 1 and type 2) were observed. Fluorescence studies and thermal denaturation studies gave strong evidence that AMSA type 1 binding was by intercalation into DNA. The binding of AMSA to DNA was without marked base-pair specificity. Furthermore, the effect of AMSA on nucleic acid-polymerizing enzyme activities (mouse embryo DNA polymerase alpha, avian myeloblastosis virus reverse transcriptase, and Escherichia coli RNA polymerase) was studied. Inhibition of enzyme activity by AMSA appeared to be independent of DNA base sequence. The relatively high concentrations of AMSA required for inhibition of these enzymes as compared to the concentrations of AMSA necessary for cytotoxicity in vitro suggest that the interaction with DNA alone might not fully explain its antitumor activity.

Acridines↗
PubMed1977

Synthsis and antitumor properties of bis(quinaldine) derivatives.

A series of 7-nitro- and amino-N,'-bis(4-quinaldinyl)-alpha, omega-diaminoalkanes related to the 6-amino derivative 1 was synthesized and tested in the mouse P-388 lymphocytic leukemia screen. There of the 7-nitro derivatives (12, 14, and 15) were found to have moderate activity (T/C 140-150%), while other nitro derivatives (11 and 13) were devoid of any antitumor properties. All five 7-amino compounds (2-6) were moderately to strongly active (T/C 134-196%). In addition, binding of amino derivatives 2-6 to DNA was examined by their ability to (1) stabilize DNA to thermal denaturation and (2) inhibit the DNA-dependent RNA polymerase reaction in vitro. Tm data suggest that these compounds bind to DNA and are strong inhibitors of the polymerase reaction (I50 = 6-9 X 10(-6) M).

Animals↗