Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity

  • Authors:
    • H. Wang
    • J. Hang
    • Z. Shi
    • M. Li
    • D. Yu
    • E. R. Kandimalla
    • S. Agrawal
    • R. Zhang
  • View Affiliations

  • Published online on: July 1, 2002     https://doi.org/10.3892/ijo.21.1.73
  • Pages: 73-80
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Abstract

The RIα-subunit of cAMP-dependent protein kinase (PKA) is overexpressed in various human cancers and PKA has been suggested to be a potential target for cancer therapy. We have shown an antisense oligonucleotide with advanced chemistry (mixed-backbone oligonucleotide) targeted to PKA RIα-subunit (GEM231) to have anti-tumor activity in vitro and in vivo. In the present study, we demonstrated synergistic effects between the anti-PKA antisense oligonucleotide and the clinically used anticancer agent irinotecan, using nude mouse models of human cancers of colon (LS174T and DLD-1), breast (MCF-7), prostate (DU-145 and PC-3) and lung (H1299). To elucidate the underlying mechanisms, in vivo pharmacokinetics of irinotecan was determined following pre-treatment of oligo GEM 231 in CD-1 mice and nude mice bearing LS174T xenografts. GEM 231 increased tissue uptake of irinotecan. However, no significant change in host toxicity was observed following combination treatment of irinotecan and GEM231 compared with irinotecan alone. These results suggest that GEM231 have a role in irinotecan metabolism and its antitumor activity, providing a basis for future development of this oligonucleotide as a chemosensitizer for irinotecan-based therapy.

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July 2002
Volume 21 Issue 1

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

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Spandidos Publications style
Wang H, Hang J, Shi Z, Li M, Yu D, Kandimalla ER, Agrawal S and Zhang R: Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity. Int J Oncol 21: 73-80, 2002
APA
Wang, H., Hang, J., Shi, Z., Li, M., Yu, D., Kandimalla, E.R. ... Zhang, R. (2002). Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity. International Journal of Oncology, 21, 73-80. https://doi.org/10.3892/ijo.21.1.73
MLA
Wang, H., Hang, J., Shi, Z., Li, M., Yu, D., Kandimalla, E. R., Agrawal, S., Zhang, R."Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity". International Journal of Oncology 21.1 (2002): 73-80.
Chicago
Wang, H., Hang, J., Shi, Z., Li, M., Yu, D., Kandimalla, E. R., Agrawal, S., Zhang, R."Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity". International Journal of Oncology 21, no. 1 (2002): 73-80. https://doi.org/10.3892/ijo.21.1.73