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

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• 作者：David A. Litvak ; Harry T. Papaconstantinou ; Kevin O. Hwang ; Mimi Kim ; B.Mark Evers ; Courtney M. Townsend Jr
• 刊名：Surgery
• 出版年：1999
• 出版时间：August 1999
• 年：1999
• 卷：126
• 期：2
• 页码：223-230
• 全文大小：202 K

文摘

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<sup>2sup>, 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<sup>Waf1sup> and p27<sup>Kip1sup> (cell cycle inhibitors), and Bcl-2 and Bcl-X<sub>Lsub> (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<sup>Waf1sup>, and p27<sup>Kip1sup> and a decrease in Bcl-2 and Bcl-X<sub>Lsub> 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<sup>Waf1/Cip1sup>, and p27<sup>Kip1sup> and the down-regulation of Bcl-2 and Bcl-X<sub>Lsub>. 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.)