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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
Author(s) -
Miyake Hideaki,
Monia Brett P.,
Gleave Martin E.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000615)86:6<855::aid-ijc15>3.0.co;2-8
Subject(s) - bcl xl , antisense therapy , apoptosis , paclitaxel , adjuvant , medicine , biology , cancer research , endocrinology , chemotherapy , oligonucleotide , programmed cell death , gene , biochemistry , locked nucleic acid
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. Int. J. Cancer 86:855–862, 2000. © 2000 Wiley‐Liss, Inc.