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Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.

Publication ,  Journal Article
Sharp, JG; Bishop, MR; Copple, B; Greiner, TC; Iversen, PL; Jackson, JD; Joshi, SS; Benner, EJ; Mann, SL; Rao, AK; Vose, JM
Published in: Leuk Lymphoma
July 2001

Oligonucleotides offer the potential to manipulate gene expression in targeted cells which might be exploitable for therapeutic benefit. The effects of combining a phosphorothioate oligonucleotide OL(1) p53, which transiently down-regulates p53 levels, with an anthracycline, Idarubicin, on the growth of wild-type p53 WMN gene-expressing lymphoma cells was evaluated. Fluorescent OL(1) p53, was used to demonstrate oligonucleotide uptake and retention by the WMN cells. Uptake was maximal at 24 hours and compared to baseline (0 hours) increasing apoptotic cells were evident in WMN cells treated with OL(1) (1 microM) alone and in combination with Idarubicin (0.2 nM) for 24 to 48 hours. In cells treated with OL(1) p53 and Idarubicin, truncated p53 message of a predicted 201 base pair length based on RNAase H cleavage of the OL(1) p53-p53 mRNA heteroduplex was detected after 7 hours of incubation. The message for p53 was transiently downregulated as detected by RT-PCR analysis at 24 hours, and protein levels transiently reduced at 36 hours, as shown by a quantitative Western blot. Corresponding to these events, the growth of WMN cells ceased after 48 hours in the concurrent presence of OL(1) p53 and Idarubicin and, the lymphoma cells were dead after 72 hours. No reduction in hematopoietic colony forming cell capacity of similarly treated hematopoietic progenitor cells harvested from cytokine-mobilized blood by apheresis was observed. Therefore, synergistic cytotoxicity of Idarubicin for lymphoma cells treated with an oligonucleotide targeting p53 message was demonstrated at oligonucleotide and Idarubicin concentrations which were minimally toxic to hematopoietic progenitor cells. This approach offers new opportunities for purging of lymphoma cells from hematopoietic harvests and systemic lymphoma therapy.

Duke Scholars

Published In

Leuk Lymphoma

DOI

ISSN

1042-8194

Publication Date

July 2001

Volume

42

Issue

3

Start / End Page

417 / 427

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Time Factors
  • Polymerase Chain Reaction
  • Oligodeoxyribonucleotides
  • Lymphoma
  • Kinetics
  • Immunology
  • Idarubicin
  • Humans
 

Citation

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Sharp, J. G., Bishop, M. R., Copple, B., Greiner, T. C., Iversen, P. L., Jackson, J. D., … Vose, J. M. (2001). Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells. Leuk Lymphoma, 42(3), 417–427. https://doi.org/10.3109/10428190109064599
Sharp, J. G., M. R. Bishop, B. Copple, T. C. Greiner, P. L. Iversen, J. D. Jackson, S. S. Joshi, et al. “Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.Leuk Lymphoma 42, no. 3 (July 2001): 417–27. https://doi.org/10.3109/10428190109064599.
Sharp JG, Bishop MR, Copple B, Greiner TC, Iversen PL, Jackson JD, et al. Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells. Leuk Lymphoma. 2001 Jul;42(3):417–27.
Sharp, J. G., et al. “Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.Leuk Lymphoma, vol. 42, no. 3, July 2001, pp. 417–27. Pubmed, doi:10.3109/10428190109064599.
Sharp JG, Bishop MR, Copple B, Greiner TC, Iversen PL, Jackson JD, Joshi SS, Benner EJ, Mann SL, Rao AK, Vose JM. Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells. Leuk Lymphoma. 2001 Jul;42(3):417–427.
Journal cover image

Published In

Leuk Lymphoma

DOI

ISSN

1042-8194

Publication Date

July 2001

Volume

42

Issue

3

Start / End Page

417 / 427

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Time Factors
  • Polymerase Chain Reaction
  • Oligodeoxyribonucleotides
  • Lymphoma
  • Kinetics
  • Immunology
  • Idarubicin
  • Humans