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¹ Edinburgh Oncology Unit, Cancer Research UK, Edinburgh, United Kingdom and ² Isis Pharmaceuticals, Inc., Carlsbad, CA

Requests for Reprints:Richard L. Hayward, Edinburgh Oncology Unit, Cancer Research UK, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. Phone: 44-131-777-3558; Fax: 44-131-777-3520. E-mail: r.hayward{at}cancer.org.uk

Introduction: Oxaliplatin, licensed for colorectal cancer chemotherapy, damages DNA by generating intrastrand and interstrand cross-links and can induce apoptosis via a Bax-dependent pathway. Bcl-xl, an antiapoptotic Bcl-2 family member, regulates apoptosis and chemoresistance in several cancer models. Bcl-xl expression correlates with invasiveness in primary colorectal cancer. Bcl-xl may therefore represent a therapeutic target in this disease. We used the mismatch repair-deficient HCT116 colorectal cancer cell line (wild-type HCT116) and p53 null, Bax null, or p21/WAF1 null derivatives to identify genetic determinants of the response to oxaliplatin and tested the hypothesis that antisense-mediated Bcl-xl down-regulation would enhance the apoptotic response in a p53- or Bax-dependent manner. Results: At clinically relevant concentrations, oxaliplatin induced p53 and p53-dependent Bax, Bcl-xl, and p21/WAF1 protein accumulation. A minor degree of apoptosis resulted via a p53- and Bax-dependent pathway. The major response was a transient mixed G₁ and G₂ growth arrest. The G₁ arrest was p53 and p21/WAF1 dependent. A 2'-O-ribose methoxyethyl phosphorothioate antisense oligonucleotide reduced Bcl-xl protein expression by 90% in HCT116 (Bcl-xl knockdown). Missense controls were inactive. Prior Bcl-xl knockdown enhanced the apoptotic and the global cytotoxic effect of oxaliplatin. The extent of enhancement of apoptosis depended on the integrity of the p53- and Bax-mediated apoptotic pathway, providing genetic evidence that the desired proapoptotic antisense effect is due to specific down-regulation of the Bcl-xl target. Conclusion: The combination of oxaliplatin and Bcl-xl antisense merits testing in models of colorectal cancer in vivo.

Received 4/11/03; revised 10/23/03; accepted 11/13/03.

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