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

Background. The prognosis for gastric cancer remains dismal; novel agents that target specific molecular pathways are needed as adjuvant therapy. Camptothecin (CPT), an inhibitor of topoisomerase I, is effective in the treatment of certain solid tumors; its effects on gastric cancer are largely undefined. 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 ~100 mm², mice were randomized into 3 groups to receive either CPT (5 or 10 mg/kg) or vehicle (control) intraperitoneally 3 days per week for 3 weeks; tumor size was measured biweekly. To assess potential mechanisms of CPT-mediated inhibition, SIIA cells were treated with CPT (20 μmol/L and cells were counted over a time course; apoptosis was assessed by Hoechst stain and DNA laddering. Expression of p53 (a tumor suppressor), p21(Waf1) and p27(Kip1) (cell cycle inhibitors), 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 cell proliferation was associated with an increase in apoptosis. Moreover, CPT treatment resulted in induction of p53, p21(Waf1), and p27(Kip1) and a decrease in Bcl- 2 and Bcl-X(L) RNA and protein levels. Conclusions. Treatment with CPT effectively inhibited the growth of the human gastric cancer SIIA; the mechanism involved was induction of apoptosis mediated by up-regulation of p53, p21(Waf1)/(Cip1), and p27(Kip1) and the down-regulation of Bcl-2 and Bcl-X(L). Novel agents such as CPT, which target specific molecular pathways, may prove clinically useful in the adjuvant treatment of gastric cancers.