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Determination of cellular uptake and intracellular levels of Cenersen (Aezea®, EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells
Open accessAbstract
TP53 encodes for tumor protein p53. The suppression of p53 protein results in interruption of DNA repair mechanisms in dividing malignant cells thereby increasing the DNA damage and activating p53-independent mechanisms of apoptosis. This ultimately may translate into enhanced cytotoxic effects of standard chemotherapy. Based on this rationale, Cenersen, a phosphorothioate oligonucleotide antisense to p53-mRNA was synthesized and tested in clinical trials for patients with acute myeloid leukemia (AML). An important component of Cenersen clinical development is to develop a sensitive and specific method to quantify plasma and intracellular levels of Cenersen in different biologic matrices in order to determine tissue and intracellular distribution of the parent compound and its metabolites. Ultimately, this will allow us to determine pharmacokinetic and pharmacodynamic relationship for dose-effect correlation and design effective regimen to be rapidly translate into the clinic. An ELISA-based assay was adapted for assay development and validation of Cenersen in mouse plasma and cell lysate. Cellular uptake of Cenersen was studied in MV4-11 and KASUMI-1 AML cell lines. Real-time RT-PCR was used to measure P53-mRNA expression changes in treated cells. The assay had a limit of quantification of 35pmol/L in mouse plasma. Within-day and between-day precision of <15% and accuracy nearly 100% were observed in a linear range of 10-2000pmol/L (R(2)=0.99) in AML cell lysate. The selectivity of this assay examined as cross-reactivity with its 3'N-1, 3'N-2-metabolites, was 16.8% and 0.4%, respectively, and with its mismatch and the scramble oligonucleotides was 0.06% and 0.4%, respectively. Cenersen was stable in mouse plasma up to 8h at 37°C. When exposed to 0.1-1μmol/L Cenersen, MV4-11 and KASUMI-1 cells showed intracellular concentration in the range of 9.97-45.34nmol/mg protein and 0.1-2.1nmol/mg protein, respectively. Successful downregulation of p53-mRNA expression was observed in Cenersen treated cells. This ELISA-based assay was applicable to plasma and intracellular concentration measurement of Cenersen. Assessment of achievable concentration of Cenersen in different biologic matrices will be useful to elucidate the biological and clinical activity of this promising drug and define its recommended dose in future clinical trials.
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Cenersen is a 20-mer phosphorothioate antisense oligonucleotide that acts on TP53, which encodes the undruggable tumor protein p53.
“Aezea (Cenersen) (235) is a 20-mer phosphorothioate ASO with a specific nucleotide sequence 5′-d[P-Thio] (CCCTG CTCCC CCCTG GCTCC)- 3′ that acts on TP53, which encodes for the undruggable tumor protein p53.557”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [557]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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Metadata
- Authors
- Alachkar, H., Xie, Z., Marcucci, G., & Chan, K. K.
- Affiliations
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- The Ohio State University (US)
- Corresponding author
- Chan, Kenneth K.
- Venue
- Journal of Pharmaceutical and Biomedical Analysis
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 71
- Pages
- 228-232
- ISSN
- 0731-7085 (ISSN-L)
- PMC
- PMC4201859
- OpenAlex
- W2042915950
- Cited by
- 11
- References
- 23
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2020: 2 · 2017: 2 · 2016: 1 · 2015: 1 · 2013: 1
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Pharmaceutical and Biomedical Analysis (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA135332, R21CA133879)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- acute myeloid leukemia, cellular uptake, intracellular drug levels, phosphorothioate oligonucleotides, p53 mRNA expression, MV4-11 cells, Kasumi-1 cells, ELISA validation, pharmacokinetics, pharmacodynamics
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Humans, Oligonucleotides, RNA, Messenger, Sensitivity and Specificity, Tissue Distribution, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Oligonucleotides, Antisense, K562 Cells, Cell Line, Tumor, Mice
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