Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways

Background. The prognosis for gastric cancer remains dismal; novel agents t hat target specific molecular pathways are needed as adjuvant therapy. Camp totheoin (CPT), an inhibitor of topoisomerase I, is effective in the treatm ent of certain solid tumors; its effects on gastric cancer are largely unde fined. The purpose of this study was to (1) characterize the effects of CPT on the growth of a human gastric cancer and (2) assess potential cellular mechanisms responsible for CPT-mediated growth inhibition. Methods. The human gastric cancer SIIA was transplanted subcutaneously into athymic nude mice. After tumors reached similar to 100 mm(2), mice were ra ndomized into 3 groups to receive either CPT (5 or 10 mg/kg) or vehicle (co ntrol) intraperitoneally 3 days per week for 3 weeks; tumor size was measur ed biweekly. To assess potential mechanisms of CPT-mediated inhibition, SII A cells were treated with CPT (20 mu mol/L) and cells were counted over a t ime course; apoptosis was assessed by Hoechst stain and DNA laddering. Expr ession of p53 (a tumor supressor), p21(Waf1) and p27(Kip1) (cell cycle inhi bitors), and Bcl-2 and Bcl-X-L (antiapoptotic proteins) was determined. Results, CPT (5 and 10 mg/kg) significantly inhibited tumor growth of SIIA gastric cancers compared with controls. CPT-mediated inhibition of SIIA cel l proliferation was associated with an increase in apoptosis. Moreover CPT treatment resulted in induction of p53, p21(Waf1), and p27(Kip1) and a decr ease in Bcl-2 and Bcl-X-L RNA and protein levels. Conclusions. Treatment with CPT effectively inhibited the growth of the hum an gastric cancer SIIA; the mechanism invoked was induction of apoptosis me diated by up-regulation of p53, p21(Waf1/Cip1), and p27(Kip1) and the down- regulation of Bcl-2 and Bcl-XL. Novel agents such as CPT, which target spec ific molecular pathways, mall prove clinically useful in the adjuvant treat ment of gastric cancers.