Potentially therapeutically relevant differences of antisense oligonucleotide uptake in CD34+ hematopoietic stem cells, leukemic blasts and cancer cells from patients.
Antisense oligonucleotide (ON) technology, e.g. against drug resistance or antiapoptotic factors, may play an important role in future cancer chemotherapy. An unanswered question in this field is the capacity for uptake of antisense molecules in normal and malignant patients' cells. Therefore, we examined the cellular uptake of FITC-labeled phosphorothioate modified ONs in: i) cells from the T-lymphoblastoid cell line CCRF-CEM, ii) CD34+ hematopoietic progenitors from healthy donors, iii) blasts from ALL or AML patients, iv) cells from the ovarian cancer cell line A2780 and v) cancer cells from malignant fluids. The cationic polymer ExGen was taken as a carrier for transfection, while FITC-ON uptake was evaluated by flow cytometry. We found marked differences between these cell types. Cancer cells from the cell line A2780 and from patients showed a distinctly enhanced uptake compared to hematopoietic progenitors and leukemic blasts. Since bone marrow toxicity substantially limits any conventional chemotherapeutic regimen, a better ON uptake in cancer cells compared to hematopoietic precursors might give an advantage for therapeutic approaches using e.g. ON-based chemosensitization.
Seitz
G
G
Department of Pediatric Hematology/Oncology, Tubingen, Germany.
Kohler
G
G
Nehmzow
M
M
Lorenz
G
G
Denzlinger
C
C
Müller
C
C
Bader
P
P
Brischwein
K
K
Beck
J F
JF
D018952:Antigens, CD34 / Q000378:metabolism*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D016376:Oligonucleotides, Antisense; D016650:Fluorescein-5-isothiocyanate