The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.

Epigenetic therapy of cancer: past, present and future

Oligonucleotide analogs are provided having improved nuclease resistance. Modifications of selected nucleotides through substitutions on the pyrimidine ring are disclosed. Certain preferred embodiments comprise the inclusion of said modified nucleotides at a plurality of sites, especially at the 3' end of a selected oligonucleotide analog.

Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression

Chemical and biochemical transformations in ionic liquids

Uptake and Metabolism of Plasma Glutamine by the Small Intestine

The metabolism of low density lipoprotein (LDL, beta lipoprotein) was studied in 10 normal individuals and 10 patients with familial type II hyperlipoproteinemia using purified radioiodinated LDL. Over 97% of the label was bound to the protein moiety of LDL and therefore the turnover data reflect the fate and distribution of LDL-apoprotein. Comparison of the metabolic behavior of biologically screened and unscreened labeled LDL preparations in dogs as well as the analysis of the urinary excretion of radioiodide derived from labeled LDL degradation in humans indicated that no significant denaturation resulted from the isolation, purification, and labeling techniques. The plasma concentration of LDL-cholesterol in normals was 105+/-21 mg/100 ml (mean +/-1 SD) in contrast to 254+/-47 mg/100 mg in patients with type II hyperlipoproteinemia; these values corresponded to LDL-apoprotein concentrations of 63+/-13 mg/100 ml and 153+/-30 mg/100 ml, respectively. Despite these differences in concentration, the synthetic rate of LDL-apoprotein in both groups was not significantly different (14.43+/-1.75 mg/kg per day in normals vs. 15.01+/-1.71 mg/kg per day in type II) nor was there any difference in the fraction of the total exchangeable LDL which was in the intravascular space (68.4+/-4.3% vs. 73.3+/-5.2%). However, the fractional catabolic rate of LDL in normal individuals differed significantly from that of patients with type II hyperlipoproteinemia (0.462+/-0.077/day in normals vs. 0.237+/-0.044/day in type II) and correspondingly the biological half-life of LDL was significantly prolonged (3.08+/-0.35 days normals vs. 4.68+/-0.44 days in type II). These data indicate that the pathologic elevation of plasma LDL concentration in the individuals with type II hyperlipoproteinemia studied here is due to a decreased fractional rate of LDL degradation rather than to an abnormality of LDL synthesis. This defect of catabolism may be the primary defect in type II hyperlipoproteinemia or, alternatively, may be secondary to an underlying abnormality in lipid metabolism.

/pdf/the-metabolism-of-low-density-lipoprotein-in-familial-type-1i6hm5964n.pdf

The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia

Thiation of Nucleosides. II. Synthesis of 5-Methyl-2'-deoxycytidine and Related Pyrimidine Nucleosides1

This study was undertaken in order to compare the metabolic behavior of plasma cholesterol derived from the diet with that of cholesterol synthesized in vAvo from acetate (1). Cholesterol labeled with either isotopic carbon or hydrogen was administered orally to human subjects and the incorporation into plasma cholesterol was followed over an extended period. In certain instances, both endogenous and exogenous cholesterol metabolism were studied simultaneously by the use of appropriately labeled acetate and cholesterol. These techniques were also applied to an examination of the behavior of plasma cholesterol in four patients with hypercholesterolemia.

/pdf/isotopic-studies-of-plasma-cholesterol-of-endogenous-and-3n33k2ytir.pdf

Isotopic studies of plasma cholesterol of endogenous and exogenous origins.

Exposure of HeLa S-3 cells to 1-β-D-arabinofuranosylcytosine (ara-C) produced a loss of cell viability accompanied by an inhibition of deoxyribonucleic acid (DNA) synthesis. Continued synthesis of ribonucleic acid (RNA) and protein strongly suggests an “unbalanced growth” syndrome with a deficiency in the deoxycytidylate moiety analogous to thymidylate-deficient states previously reported with 5-fluorodeoxyuridine and amethopterin. Exposure to ara-C under appropriate conditions yields a partial synchronization of this mammalian cell culture.

https://cancerres.aacrjournals.org/content/canres/26/8_Part_1/1661.full.pdf

Action of 1-β-d-Arabinofuranosyl-5-fluorocytosine on the Nucleic Acid Metabolism and Viability of HeLa Cells

The fractionation of hydrogen isotopes in biological systems1

Summary The effects of 5-fluorouracil (FU), 5-fluorouradine (FUR), and 5-fluoro-2′-deoxyuridine (FUDR). on the growth of H.Ep. #1 human cell strain in a semisynthetic medium have been studied. FU, FUR, and FUDR produced complete inhibition of growth at 1.0, 0.01, and 0.01 µg/ml., respectively (8 × 10-6, 0.4 × 10-7, and 0.4 × 10-7m). The complete growth inhibition by FUDR at 4 × 10-7m is reversed by an approximately equivalent concentration of thymidine. The extent of reversal is independent of the FUDR concentration over a fivefold variation in the latter. These results strongly support the hypothesis that a block in the pathway leading to DNA-thymine (probably at the “methylation step”) is the principal cause of growth inhibition by FUDR. However, the inability of thymidine to reverse the growth inhibition by FU and FUR suggests that the latter are producing metabolic blocks at sites essential to growth in addition to the “methylation block” suggested for FUDR inhibition. The growth inhibition by FUDR is reversed by deoxyuridine at an approximately 100-fold excess. A fivefold increase in FUDR concentration increased by a corresponding factor the level of deoxyuridine needed for reversal. The inhibition of growth by FU could not be reversed by a 100-fold excess of thymidine, 5-methyldeoxycytidinc, dcoxyuridine, uridine, cytidine, uracil, thymine, and cytosine. The specific activity of the nucleic acid pyrimidines of H.Ep. #1 cells grown in the presence of FUDR plus thymidine (as reverser) was compared with cells grown in the presence of an equal concentration of thymidine alone. With labeled orotic acid, a significant depression in the specific activity of DNA-thymine was observed in the presence of FUDR, with relatively little effect on the other nucleic acid pyrimidines. With labeled thymidine, the specific activity of the DNA-thymine was increased by a factor of two to four in the presence of FUDR. These results demonstrate an enhanced utilization of exogenous thymidine under conditions in which the de novo pathway to DNA-thymine is blocked by FUDR.

https://cancerres.aacrjournals.org/content/canres/18/6/730.full.pdf

Maxwell L. Eidinoff

Papers

Thiation of Nucleosides. II. Synthesis of 5-Methyl-2'-deoxycytidine and Related Pyrimidine Nucleosides1

Isotopic studies of plasma cholesterol of endogenous and exogenous origins.

Action of 1-β-d-Arabinofuranosyl-5-fluorocytosine on the Nucleic Acid Metabolism and Viability of HeLa Cells

The fractionation of hydrogen isotopes in biological systems1

Growth inhibition of a human tumor cell strain by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine; reversal studies.