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 Townsend

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 - 1999

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Camptothecin
Stomach Neoplasms
Apoptosis
bcl-X Protein
Neoplasms
Growth
Nude Mice
Topoisomerase I Inhibitors
Cell Cycle
Coloring Agents
Up-Regulation
Down-Regulation
Cell Proliferation
RNA

ASJC Scopus subject areas

  • Surgery

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Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways. / Litvak, David A.; Papaconstantinou, Harry T.; Hwang, Kevin O.; Mimi, Kim; Evers, B. Mark; Townsend, Courtney.

In: Surgery, Vol. 126, No. 2, 1999, p. 223-230.

Research output: Contribution to journalArticle

Litvak, David A. ; Papaconstantinou, Harry T. ; Hwang, Kevin O. ; Mimi, Kim ; Evers, B. Mark ; Townsend, Courtney. / Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways. In: Surgery. 1999 ; Vol. 126, No. 2. pp. 223-230.
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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.",
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AU - Litvak, David A.

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AU - Mimi, Kim

AU - Evers, B. Mark

AU - Townsend, Courtney

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N2 - 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.

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