Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms

  • Authors:
    • H. Wang
    • S. Wang
    • L. Nan
    • D. Yu
    • S. Agrawal
    • R. Zhang
  • View Affiliations

  • Published online on: April 1, 2002     https://doi.org/10.3892/ijo.20.4.745
  • Pages: 745-752
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Antisense oligonucleotides have been investigated as anticancer agents administered alone or in combination with conventional chemotherapeutics. In the present study, we demonstrated synergistic effects between anti-MDM2 antisense oligonucleotides and the clinically used anticancer agent irinotecan, using nude mouse models of human colon cancers (LS174T and DLD-1). Surprisingly, a 5-base mismatch oligonucleotide also showed similar effects. To elucidate the underlying mechanisms, in vitro and in vivo pharmacokinetic and pharmacodynamic studies were performed. In LS174T cells, the antisense oligonucleotide, but not the mismatch oligonucleotide, specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p53 activation and p21 induction. In DLD-1 cells, the antisense oligonucleotide specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p21 induction although mutant p53 levels remained unchanged. Both oligonucleotides increased tissue uptake of irinotecan and the conversion of irinotecan to its active metabolite SN-38. These results suggest that oligonucleotides have a role in irinotecan metabolism and action, providing a basis for future development of antisense oligonucleotides as a sensitizer for irinotecan-based therapy.

Related Articles

Journal Cover

April 2002
Volume 20 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang H, Wang S, Nan L, Yu D, Agrawal S and Zhang R: Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms. Int J Oncol 20: 745-752, 2002
APA
Wang, H., Wang, S., Nan, L., Yu, D., Agrawal, S., & Zhang, R. (2002). Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms. International Journal of Oncology, 20, 745-752. https://doi.org/10.3892/ijo.20.4.745
MLA
Wang, H., Wang, S., Nan, L., Yu, D., Agrawal, S., Zhang, R."Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms". International Journal of Oncology 20.4 (2002): 745-752.
Chicago
Wang, H., Wang, S., Nan, L., Yu, D., Agrawal, S., Zhang, R."Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms". International Journal of Oncology 20, no. 4 (2002): 745-752. https://doi.org/10.3892/ijo.20.4.745