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

• Published in: Surgery 1999-08, Vol.126 (2), p.223-230
• Main Authors: Litvak, David A., Papaconstantinou, Harry T., Hwang, Kevin O., Kim, Mimi, Evers, B.Mark, Townsend, Courtney M.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Adenocarcinoma - prevention & control; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Camptothecin - pharmacology; Cell Division - drug effects; Chemotherapy; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Microfilament Proteins - biosynthesis; Muscle Proteins; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - analysis; Stomach Neoplasms - pathology; Stomach Neoplasms - prevention & control; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - biosynthesis
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(99)70159-5

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 mm 2, 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. (Surgery 1999;126:223-30.)