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

David A. Litvak, Harry T. Papaconstantinou, Kevin O. Hwang, Kim Mimi, B. Mark Evers, Courtney M. Townsend

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-230
Number of pages8
JournalSurgery
Volume126
Issue number2
DOIs
StatePublished - Jan 1 1999

ASJC Scopus subject areas

  • Surgery

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