Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways
| Autor: | D A, Litvak, H T, Papaconstantinou, K O, Hwang, M, Kim, B M, Evers, C M, Townsend |
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| Rok vydání: | 1999 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male Mice Inbred BALB C Microfilament Proteins Muscle Proteins Apoptosis Adenocarcinoma Antineoplastic Agents Phytogenic Mice Proto-Oncogene Proteins c-bcl-2 Stomach Neoplasms Cyclins Tumor Cells Cultured Animals Humans Camptothecin Tumor Suppressor Protein p53 Cell Division |
| Zdroj: | Surgery. 126(2) |
| ISSN: | 0039-6060 |
| Popis: | The prognosis for gastric cancer remains dismal; novel agents that target specific molecular pathways are needed as adjuvant therapy. Camptothecin (CPT), on 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.The human gastric cancer SIIA was transplanted subcutaneously into athymic nude mice. After tumors reached approximately 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 mumol/L) and cells were counted over a time course; apoptosis was assessed by Hoechst stain and DNA laddering. Expression of p53 (a tumor suppressor), p21Waf1 and p27Kip1 (cell cycle inhibitors), and Bcl-2 and Bcl-XL (antiapoptotic proteins) was determined.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, p21Waf1, and p27Kip1 and a decrease in Bcl-2 and Bcl-XL RNA and protein levels.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, p21Waf1/Cip1, and p27Kip1 and the down-regulation of Bcl-2 and Bcl-XL. Novel agents such as CPT, which target specific molecular pathways, may prove clinically useful in the adjuvant treatment of gastric cancers. |
| Databáze: | OpenAIRE |
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