Abstract #2986: In vivo inhibition of colon tumor cell growth in the HT-29 xenograft model by SRI 21009: A novel sulindac derivative that potently induces apoptosis but does not inhibit cyclooxygenases Free

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promising chemopreventive activity, although toxicity resulting from cyclooxygenase (COX) inhibition and suppression of prostaglandin synthesis limits their clinical use. Previous studies have concluded that the mechanism for the tumor cell growth inhibitory activity of certain NSAIDs such as sulindac may be COX-independent and suggest the feasibility of developing safer and more efficacious derivatives that lack COX inhibitory activity. To selectively design out the COX inhibitory activity of SS, in silico modeling studies were performed, which revealed that the carboxylate moiety on sulindac sulfide (SS) is essential for COX-1 and COX-2 binding. These observations prompted the synthesis of a series of derivatives that were screened for tumor cell growth and COX inhibitory activity. A SS derivative with a N,N-dimethylethyl ammonium amide substitution referred to as SRI 21009 was selected as a prototype and found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of the human colon tumor cell lines, HT-29, SW480, and HCT116 with IC₅₀ values of 2-5 \#956;M compared with 73-85 \#956;M for SS. SRI 21009 also induced apoptosis with higher potency and magnitude compared with SS as measured by caspase activation and DNA fragmentation. Oral administration of SRI 21009 at dosages up to 300 mg/kg/day were tolerated in mice, which generated plasma levels that exceeded its in vitro IC₅₀ value. By comparison, sulindac was only tolerated up to a dosage of 50 mg/kg/day and generated plasma levels of SS that were below its in vitro IC₅₀ value to inhibit tumor cell growth. In a human HT-29 colon tumor xenograft mouse model, SRI 21009 at a dosage of 250 mg/kg (bid, p.o.) significantly inhibited tumor growth. Sulindac was appreciably less effective at a dosage of 40 mg/kg (bid, p.o). These results indicate that SRI 21009 may have safety and efficacy advantages for colon cancer chemoprevention and may also have applications for the treatment of colon cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2986.