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M MacCoss

Publications and source records attributed to M MacCoss.

54 records · Page 3Linked to original sources
PubMed1984

1-beta-D-arabinofuranosylcytosine-phospholipid conjugates as prodrugs of Ara-C.

The L-, D-, and D,L-isomers of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitin, new prodrugs of ara-C5, have been evaluated for antitumor activity in L1210 lymphoid leukemic mice. The L-isomer produced significant increase in life span (ILS), and longterm survivors among mice bearing i.p. and i.c. implanted L1210 leukemia and the maximal ILS values found were greater than 543 and greater than 374% with five and four 45-day survivors out of six mice, respectively, at the optimal single doses of 300 mg/kg and 125 mg/kg. The D- and D,L-isomers also displayed significant in vivo antitumor activity against both i.p. and i.c. implanted L1210 leukemia in mice with ILS range of 144-293% at a total dose of 125-250 mg/kg. Significant schedule dependency was not observed when the conjugates were administered i.p. once daily for 5 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. The L-isomer was found to be a more effective prodrug of ara-C than its isomers and other lipophilic prodrugs, 5'-O-palmitoyl-ara-C and N4-acyl-ara-C. Unlike the latter prodrugs, the new conjugates are water soluble by sonication method.

Animals↗
PubMed1983

Phospholipid-nucleoside conjugates. 5. The interaction of selected 1-beta-D-arabinofuranosylcytosine-5'-diphosphate-L-1,2-diacylglycerols with serum lipoproteins.

The phospholipid-nucleoside conjugates 1-beta-D-arabinofuranosylcytosine-5'-diphosphate-L-1,2-dipalmitin (1), -distearin (2), and -diolein (3) have been shown to interact rapidly with canine high density lipoprotein and with both high density and low density lipoproteins isolated from human serum. The extent of interaction with the high density lipoproteins appears to be dependent upon the characteristic gel-liquid crystalline phase transition of the conjugate's phospholipid. Since the phospholipid-nucleoside conjugates under study represent sustained release forms of the antileukemic agent 1-beta-D-arabinofuranosylcytosine, the therapeutic efficacy of these conjugates should now be considered in light of these interactions.

Animals↗
PubMed1982

Phospholipid-nucleoside conjugates. The aggregational characteristics and morphological aspects of selected 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-L-1,2-diacylglycerols.

1-beta-D-Arabinofuranosylcytosine 5'-diphosphate-1,2-diacylglycerols have previously been shown to be promising candidates as prodrugs of the clinically useful antileukemic agent 1-beta-D-arabinofuranosylcytosine. Because of the amphipathic nature of these liponucleotides and the potential that their morphological state may mediate their biological activity, it was necessary to undertake detailed studies of their aggregational and morphological characteristics. When samples of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-L-1,2-diacylglycerols (containing either dimyristoyl, dipalmitoyl or distearoyl fatty acid side chains) were prepared in buffered saline solutions using sonication methods, the morphological nature of the resulting aggregate was shown to be related to temperature and the length of the side chain. When sonicated at low temperatures all the above-mentioned derivatives gave turbid solutions containing large bilayer sheets. As the temperature was raised, a transition temperature was reached at which a stable three-dimensional cross-linked network of small interlocking bilayer stacks was formed. This turbidity transition temperature was directly related to the chain length of the fatty acid side chain. Sonication at temperatures close to this turbidity transition temperature produced small disc-shaped micellar structures. These micelles were shown to exist in another aggregational equilibrium consisting of a stacking-destacking process, the position within this equilibrium being dependent upon the concentration. In contrast, a sample of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-L-1,2-dioleoylglycerol (which contains an unsaturated carbon-carbon bond in each of the fatty acid side chains) was shown to give a multilamellar liposome structure when sonicated in buffered saline at temperatures above its turbidity transition temperature.

Antineoplastic Agents↗
PubMed1982

Phospholipid-nucleoside conjugates. 3. Syntheses and preliminary biological evaluation of 1-beta-D-arabinofuranosylcytosine 5'-monophosphate-L-1,2-dipalmitin and selected 1-beta-D-arabinofuranosylcytosine 5-diphosphate-L-1,2-diacylglycerols.

Several new phospholipid-ara-C conjugates have been prepared and tested as prodrugs of the parent ara-C. The new derivative include ara-CMP-L-dipalmitin, ara-CDP-L-distearin, ara-CDP-L dimyristin, ara-CDP-L-diolein, and the radioactively labeled derivative ara-CDP-L-di[1-14C]palmitin. In addition, the unusually stable ara-CMP-L-dipalmitin-N-phosphoryldicyclohexylurea adduct was isolated as a crystalline solid (two diastereomers) in the reaction sequence to prepare ara-CMP-L-dipalmitin. The new prodrugs were solubilized by sonication methods and tested for their antiproliferative activity in vitro against mouse myeloma MPC-11 cells and against L1210 lymphoid leukemia. Such studies demonstrated that the antiproliferative activities of the prodrugs (as determined by ED50) were less that ara-C on a molar basis. In the mouse myeloma cell line some evidence was obtained that the antiproliferative activity was related to the chain length of the fatty acid side chains in the prodrugs. In in vivo studies against L1210 lymphoid leukemia in mice, the prodrugs were shown to be much more effective than ara-C, with the overall efficacy apparently being independent of the length of the fatty acid side chain. Some evidence was obtained in the vivo studies that the ara-CDP-L-dimyristin, which bears the shortest fatty acid side chain, was more toxic at the higher dosages than the longer chain length derivatives.

Animals↗
PubMed1981

Phospholipid derivatives of nucleoside analogs as prodrugs with enhanced catabolic stability.

The nucleoside 5'-diphosphate-L-1,2-dipalmitin derivatives of 1-beta-D-arabinofuranosylcytosine (ara-C), 9-beta-D-arabinofuranosyladenine (ara-A), and tubercidin have been synthesized, and their cytotoxicity has been evaluated against a mouse myeloma cell line (MPC-11) in vitro and against L1210 lymphoid leukemia both in vitro and in vivo. Sonication methods were utilized to solubilize these lipophilic derivatives in aqueous solution in order to facilitate such biological evaluation; the ara-A derivative resisted solubilization by several techniques. The nucleoside:phospholipid conjugates of ara-C and tubercidin both were cytotoxic towards the two cell lines, and detailed experiments were cytotoxic towards the two cell lines, and detailed experiments were carried out to show that the new derivatives (a) were not degraded in the medium prior to cellular uptake and (b) acted as prodrugs or molecular depots of the parent nucleoside analog. In addition, 1-beta-D-arabinofuranosylcytosine 5'-diphosphate'5'-L-1,2-dipalmitin was not a substrate for cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5), the primary enzyme responsible for the rapid catabolism of ara-C. In in vivo studies against L1210 lymphoid leukemia in mice, the 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin showed an increased efficacy (increased life span, 260%) relative to the parent ara-C (increased life span, 89%) regardless of treatment schedule used, whereas the tubercidin 5'-diphosphate-5'-L-1,2-dipalmitin appeared extremely toxic even at low dosages. That 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin was acting as a sustained release drug in vivo was demonstrated by utilizing a single dose administered on Days -1, 0, +1, and +2 relative to inoculation of the L1210 lymphoid leukemia cells on Day 0. Again, a much increased efficacy relative to the best treatment using ara-C was apparent. The potential advantages and the biochemical rationale for the development of these novel prodrugs are discussed.

Animals↗
PubMed1980

Conformational flexibility of the 3' acceptor end of transfer ribonucleic acid.

The intimate details of the conformational features and dynamics of the trinucleoside diphosphates CpCpA and ApCpC in aqueous solution have been arrived at by the complete analysis of their proton magnetic resonance spectra. In addition to the right-handed stacked species in which the phosphodiester torsions conform to the gauche-gauche domains, sugar puckers 3E, C4'-C5 approximately equal to 60 degrees, C5'-O5' approximately 180 degrees, C3'-O3' approximately equal to 205 degrees, and chi CN approximately equal to 40 degrees, the trimers display a variety of spatial configurations, an important one being a bulged configuration in which the central nucleotide unit is bulged out, enabling stacking interactions between the end units. It is further shown that the 3' acceptor end of tRNA, CpCpA, displays considerable flexibility for the terminal adenine nucleotide unit. Theoretical NMR calculations demonstrate that the predominant solution conformation does not conform to the CCA terminus of tRNA as reported by four independent crystallographic studies of tRNAPhe. It is shown that the preferred intramolecular order of CCA in solution is such that chi 1 = chi 2 = chi 3 = 40 degrees, all the three sugars are in 3E, psi 1 = psi 2 = psi 3 = 60 degrees, phi 2 and phi 3 = 170 and 180 degrees, respectively, phi 1 = phi 2' = 205 degrees, and omega 1/omega 1 and omega 2/omega 2' = 240/205 degrees and 295/265 degrees, respectively.

Base Sequence↗
PubMed1979

Modification of the Dittmer-Lester reagent for the detection of phospholipid derivatives on thin-layer chromatograms.

A simple modification of the Dittmer-Lester reagent is described that allow the detection of phospholipid derivatives at very low concentrations on silica gel and reversed-phase thin-layer plates. This modification, which involves the addition of acetic acid to the mixture, permits the observation of sharp blue spots on a white background. The specificity and sensitivity of the spray are discussed.

Chromatography, Thin Layer↗