Dataset Information

Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol.

ABSTRACT: Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0-24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32?mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0-24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32?mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed.

SUBMITTER: Schlegel A

PROVIDER: S-EPMC3411319 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol.

Schlegel Anne A Buhler Cyril C Devun Flavien F Agrario Céline C Urien Saïk S Lokiec François F Sun Jian-Sheng JS Dutreix Marie M

Molecular therapy. Nucleic acids 20120731

Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake. We report here the preclinical pharmacokin ...[more]

PMID: 23344149

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Project description:BackgroundDNA is a carrier of biological information. The hybridization process, the formation of the DNA double-helix from single-strands with complementary sequences, is important for all living cells. DNA microarrays, among other biotechnologies such as PCR, rely on DNA hybridization. However, to date the thermodynamics of hybridization is only partly understood. Here we address, experimentally and theoretically, the hybridization of oligonucleotide strands of unequal lengths, which form a bulged loop upon hybridization. For our study we use in-house synthesized DNA microarrays.ResultsWe synthesize a microarray with additional thymine bases in the probe sequence motifs so that bulged loops occur upon target hybridization. We observe a monotonic decrease of the fluorescence signal of the hybridized strands with increasing length of the bulged loop. This corresponds to a decrease in duplex binding affinity within the considered loop lengths of one to thirteen bases. By varying the position of the bulged loop along the DNA duplex, we observe a symmetric signal variation with respect to the center of the strand. We reproduce the experimental results well using a molecular zipper model at thermal equilibrium. However, binding states between both strands, which emerge through duplex opening at the position of the bulged loop, need to be taken into account.ConclusionsWe show that stable DNA duplexes with a bulged loop can form from short strands of unequal length and they contribute substantially to the fluorescence intensity from the hybridized strands on a microarray. In order to reproduce the result with the help of equilibrium thermodynamics, it is essential (and to a good approximation sufficient) to consider duplex opening not only at the ends but also at the position of the bulged loop. Although the thermodynamic parameters used in this study are taken from hybridization experiments in solution, these parameters fit our DNA microarray data well.

Dataset Information

Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol.

Publications

Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol.

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