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The influence of phosphorothioate oligodeoxynucleotides on various organs in vivo
M Nieborowska-Skórska1, A P Białek, N C Nicolaides
1Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract:
To characterize the distribution and toxicity of phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) in vivo, the mice, previously injected with BV173 leukemic cells (Philadelphia chromosome-positive chronic myeloid leukemia blast-crisis), received intravenously 26-mer BCR-ABL antisense oligodeoxynucleotides (1 mg/mouse/day) for 9 consecutive days. Our investigation revealed that [S]ODNs were distributed to almost all organs except the brain with the highest level in the liver, spleen and kidneys. They were also detected in CD10+ leukemic cells isolated from spleen and bone marrow. Intracellular distribution assay showed the presence of [S]ODNs most prominently in nuclear and cytoplasmic fractions. Our data demonstrated no significant toxicity of [S]ODNs except the increase in spleen weight.
Insights
Phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) distribute widely in vivo, reaching leukemic cells but not the brain. The study found [S]ODNs safe, with only a slight spleen weight increase observed.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) are investigated for therapeutic potential.
- Chronic myeloid leukemia (CML) blast-crisis, specifically Philadelphia chromosome-positive (Ph+) CML, presents a challenging clinical scenario.
Purpose of the Study:
- To determine the in vivo distribution and toxicity of BCR-ABL antisense oligodeoxynucleotides.
- To assess the uptake of [S]ODNs in leukemic cells and their intracellular localization.
Main Methods:
- Mice with BV173 leukemic cells (Ph+ CML blast-crisis) were intravenously administered 26-mer BCR-ABL [S]ODNs.
- Organ distribution, leukemic cell detection, and intracellular localization (nuclear and cytoplasmic) of [S]ODNs were analyzed.
Main Results:
- [S]ODNs were distributed to most organs, with highest concentrations in the liver, spleen, and kidneys.
- Leukemic cells (CD10+) in spleen and bone marrow showed detectable levels of [S]ODNs.
- Intracellularly, [S]ODNs were predominantly found in nuclear and cytoplasmic fractions.
Conclusions:
- BCR-ABL [S]ODNs exhibit broad organ distribution in vivo, including target leukemic cells.
- The tested [S]ODNs demonstrated a favorable safety profile, with no significant toxicity noted apart from an increase in spleen weight.