A simple, rapid, and sensitive DNA assay procedure.

A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin

Walter T. Hughes, Donald Armstrong, Gerald P. Bodey, Eric J. Bow, Arthur E. Brown, Thierry Calandra, Ronald Feld, Philip A. Pizzo, Kenneth V. I. Rolston, Jerry L. Shenep, and Lowell S. Young St. Jude Children’s Research Hospital, Memphis, Tennessee; Memorial Sloan-Kettering Cancer Center, New York, New York; University of Texas M. D. Anderson Cancer Center, Houston; Harvard Medical School, Boston, Massachusetts; Stanford University School of Medicine, Palo Alto, and Kuzell Institute for Arthritis, San Francisco, California; University of Manitoba, Winnipeg, and Princess Margaret Hospital, Toronto, Canada; and Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

/pdf/2002-guidelines-for-the-use-of-antimicrobial-agents-in-2br60wthls.pdf

2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer

Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids and cell membranes, but the molecular basis for its antitumor activity is unknown. Similar to a number of intercalative antitumor drugs and nonintercalative epipodophyllotoxins (VP-16 and VM-26), adriamycin has been shown to induce single- and double-strand breaks in DNA. These strand breaks are unusual because a covalently bound protein appears to be associated with each broken phosphodiester bond. In studies in vitro, mammalian DNA topoisomerase II mediates DNA damage by adriamycin and other related antitumor drugs.

https://science.sciencemag.org/content/sci/226/4673/466.full.pdf

Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II

Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.

Qualitative and quantitative aspects of intercalator-induced DNA strand breaks.

Protein-associated DNA breaks in cells treated with adriamycin or ellipticine.

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.

https://cancerres.aacrjournals.org/content/canres/41/11_Part_1/4554.full.pdf

l-Asparaginase Pharmacokinetics and Asparagine Levels in Cerebrospinal Fluid of Rhesus Monkeys and Humans

Summary Ellipticine (NSC 71795), a plant alkaloid with antitumor activity, is a weakly basic polycyclic molecule with dimensions similar to those of proflavin. Like proflavin, ellipticine exhibits hypochromic and bathochromic changes in absorption spectrum in the presence of DNA. It binds preferentially to helical DNA by intercalation, but the strength of binding is substantially greater than that of proflavin. The evidence for intercalation is based on effects on the sedimentation and viscosity of sheared DNA fragments, removal and reversal of the supercoiling of closed circular DNA, and electric dichroism measurements. The sedimentation and viscosity changes are quantitatively similar to those produced by proflavin. The unwinding angle on binding to supercoiled DNA is estimated to be 7.9°, similar to that of proflavin. Electric dichroism shows the plane of the bound ellipticine molecule to be oriented parallel (±7°) to the plane of the bases in helical DNA. Ellipticine differs from proflavin in that it is uncharged at neutral pH and becomes protonated under mildly acid conditions. This feature may influence the intracellular distribution of the drug. Ellipticine bound to DNA is probably in its protonated form.

/pdf/intercalative-binding-of-ellipticine-to-dna-5g8kn1a7bc.pdf

Daniel Glaubiger

Papers

Qualitative and quantitative aspects of intercalator-induced DNA strand breaks.

Protein-associated DNA breaks in cells treated with adriamycin or ellipticine.

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer

l-Asparaginase Pharmacokinetics and Asparagine Levels in Cerebrospinal Fluid of Rhesus Monkeys and Humans

Intercalative binding of ellipticine to DNA.