Inhibition of progression to androgen-independence by combined adjuvant treatment with antisense BCL-XL and antisense Bcl-2 oligonucleotides plus taxol after castration in the Shionogi tumor model.

Abstract

We have reported that antisense Bcl-2 oligodeoxynucleotide (ODN) delays progression to androgen independence in the androgen-dependent (AD) mouse Shionogi tumor model. Here, we characterize changes in bcl-xL, another important anti-apoptotic gene, and test the efficacy of adjuvant antisense Bcl-xL ODN therapy either alone or in combination with antisense Bcl-2 ODN and chemotherapy after castration in the Shionogi tumor model. Bcl-xL mRNA levels increased up to 3-fold postcastration and remained 1. 5-fold higher in androgen-independent (AI) recurrent tumors compared with AD tumors before castration. Treatment of Shionogi cells with antisense Bcl-xL ODN inhibited Bcl-xL expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-xL ODN in mice bearing Shionogi tumors after castration delayed emergence of AI recurrent tumors. We then examined whether combined adjuvant antisense Bcl-xL and/or Bcl-2 ODNs plus taxol (paclitaxel) therapy further delays time to AI progression. Combined treatment of Shionogi cells with antisense Bcl-xL and Bcl-2 ODNs significantly enhanced taxol chemosensitivity compared with either agent alone, reducing the IC(50) of taxol by more than 1 log. Apoptotic DNA laddering and cleavage of poly(ADP-ribose) polymerase were more substantial after treatment with combined antisense Bcl-2 and Bcl-xL ODNs plus taxol than that with either 2 agents. Adjuvant administration of antisense Bcl-xL and Bcl-2 ODNs plus micellar taxol resulted in a significantly delayed time to AI recurrence compared with administration of either 2 agents. Our findings suggest that Bcl-xL represents a suitable molecular target for antisense ODN strategy and illustrate the potential additive effects of multi-target pharmacology for cancer therapy.

• Authors: H Miyake, B P Monia, M E Gleave
• Journal: International journal of cancer (Int J Cancer) Vol. 86 Issue 6 Pg. 855-62 (Jun 15 2000) ISSN: 0020-7136 [Print] United States
• PMID: 10842201 (Publication Type: Journal Article)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• Androgens
• Bcl2l1 protein, mouse
• Oligonucleotides, Antisense
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• Paclitaxel

Topics

• Androgens (physiology)
• Animals
• Apoptosis (drug effects)
• Castration
• Combined Modality Therapy
• Female
• Male
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Mice
• Oligonucleotides, Antisense (therapeutic use)
• Paclitaxel (therapeutic use)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics)
• bcl-X Protein