Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (cgp 69846a) after intravenous and subcutaneous administration

Phillips, J. A.; Craig, S. J.; Bayley, Deborah; Christian, Robin A.; Geary, Richard S.; Nicklin, Paul

doi:10.1016/s0006-2952(97)00190-1

Cited by 106 publications

(66 citation statements)

References 14 publications

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“…Herein, we showed that our assay is highly sensitive and specific toward the parent compound and its metabolites, as it detects only the 3V-end intact sequence of G3139 at a single nucleotide resolution, with little or no cross-reactivity with the putative 3V-end metabolites (33,34). In contrast, the assay was not selective toward 5V metabolites; however, 5V-end metabolism has not been considered a major pathway (34 -36).…”

Section: Discussionmentioning

confidence: 99%

Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia

Dai

Chan

Liu

et al. 2005

Clinical Cancer Research

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Purpose: Down-regulation of Bcl-2 by the antisense G3139, currently under clinical evaluations, could restore chemosensitivity in otherwise resistant malignant cells. To date, the mechanism of intracellular accumulation of G3139 following in vivo administration remains to be elucidated.This study aimed to assess whether detectable intracellular concentrations of G3139 are achievable in vivo and how these relate to Bcl-2 down-regulation. Experimental Design: Cellular uptake of G3139 was studied in leukemia myeloid cell lines and blasts collected from treated patients using a newly developed, novel, and highly sensitive ELISAbased assay. Real-time reverse transcription-PCR was used to quantify Bcl-2 mRNA changes in treated cells. Results: The assay was fully validated and showed a limit of quantification of 50 pmol/L.When exposed to 0.33 to10 Amol/L G3139, K562 cells exhibited intracellular concentrations in the range of 2.1 to 11.4 pmol/mg protein. When G3139 was delivered with cationic lipids, a 10-to 25-fold increase of the intracellular concentrations was observed. There was an accumulation of G3139 in the nuclei, and the ratio of nucleus to cytoplasm was increased 7-fold by cationic lipids. Intracellular concentrations of G3139 were correlated with Bcl-2 mRNA down-regulation. Robust intracellular concentrations of G3139 were achieved in vivo in bone marrow (range, 3.4-40.6 pmol/mg protein) and peripheral blood mononuclear cells (range, 0.47-19.4 pmol/mg protein) from acute myeloid leukemia patients treated with G3139. Conclusions:This is the first evidence that measurable intracellular levels of G3139 are achievable in vivo in acute myeloid leukemia patients and that Bcl-2 down-regulation is likely to depend on the achievable intracellular concentrations rather than on plasma concentrations.

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Section: Discussionmentioning

confidence: 99%

Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia

Dai

Chan

Liu

et al. 2005

Clinical Cancer Research

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“…dosing, compared with non-obese subjects, most likely due to the limited distribution of oligonucleotides into fat. Oligonucleotides are polar hydrophilic molecules and distribute preferentially to lean body mass (Phillips et al, 1997). Dosing on an actual weight basis did not reflect the patients' volume of distribution, which correlates with lean body weight, and resulted in higher plasma levels compared with lean subjects receiving the same 2 mg/kg dose.…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of ISIS 104838, a 2′-Methoxyethyl Modified Antisense Oligonucleotide Targeting Tumor Necrosis Factor-α

Sewell

Geary

Baker

et al. 2002

J Pharmacol Exp Ther

114

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“…The pharmacokinetics, tissue distribution, and metabolism appear to differ little among different P=S ODN sequences (13,14,33 (14). Elimination from the tissues appears to be primarily the result of metabolism via nucleases (14).…”

Section: Pharmacokinetics and Toxicodynamicsmentioning

confidence: 99%

Synthetic Oligonucleotides: The Development of Antisense Therapeutics

Monteith

Levin

1999

Toxicol Pathol

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Antisense therapeutics using synthetic oligodeoxynucleotides (ODNs) Antisense therapeutics are species specific because they are based on the genomic code. Although sequences may be relatively conserved among species, typical target regions for antisense therapeutics will differ by at least several bases between species. Therefore, to define pharmacologic effects, species-specific homologues of the human target must be identified and tested in the appropriate animal model. One exception is the use of human

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Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (cgp 69846a) after intravenous and subcutaneous administration

Cited by 106 publications

References 14 publications

Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia

Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia

Phase I Trial of ISIS 104838, a 2′-Methoxyethyl Modified Antisense Oligonucleotide Targeting Tumor Necrosis Factor-α

Synthetic Oligonucleotides: The Development of Antisense Therapeutics

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