Targeting molecular pathways with camptothecin as novel therapy for gastric cancer

Novel chemotherapeutic agents are needed to treat gastric cancer for which the prognosis remains dismal. The antitumor alkaloid camptothecin (CPT) may be useful in the treatment of certain solid tumors; however, its effects o n gastric cancer are largely undefined. The purpose of our study was to cha racterize the effects of CPT on human gastric tumors in vivo and to determi ne the cellular mechanisms involved in CPT-mediated inhibition. Two human g astric cancers, WIL and TOR, were transplanted subcutaneously into athymic nude mice. After tumors reached 50 to 100 mm(2), mice were randomized into three groups to receive injections of either low-dose CPT (5 mg/kg), high-d ose CPT (10 mg/kg), or vehicle (control) intraperitoneally 3 days a week fo r 3 weeks. Tumors were measured and weighed, and protein levels of the cell cycle inhibitor, p21(Waf1/Cip1), and the antiapoptotic protein, Bcl-2, wer e assessed. Both dosages of CPT significantly inhibited growth of WIL and T OR gastric tumors. CPT (10 mg/kg) reduced tumor size compared to baseline, establishing this as a tumoricidal dosage. Treatment with CPT was associate d with increased levels of p21(Waf1/Cip1) and decreased levels of Bcl-2. CP T effectively kills human gastric cancers associated with increased levels of p21(Waf1/Cip1) and decreased levels of Bcl-2. By activating cell cycle w ithdrawal and cell death through induction of p21(Waf1/Cip1) and downregula tion of Bcl-2, CPT may be an effective agent for gastric cancer.