Litvak D A, Papaconstantinou H T, Evers B M, Townsend C M
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0527, USA.
J Gastrointest Surg. 1999 Nov-Dec;3(6):618-24. doi: 10.1016/s1091-255x(99)80084-5.
Novel chemotherapeutic agents are needed to treat gastric cancer for which the prognosis remains dismal. The antitumor alkaloid camptothecin (CPT) may be useful in the treatment of certain solid tumors; however, its effects on gastric cancer are largely undefined. The purpose of our study was to characterize the effects of CPT on human gastric tumors in vivo and to determine the cellular mechanisms involved in CPT-mediated inhibition. Two human gastric cancers, WIL and TOR, were transplanted subcutaneously into athymic nude mice. After tumors reached 50 to 100 mm(2), mice were randomized into three groups to receive injections of either low-dose CPT (5 mg/kg), high-dose CPT (10 mg/kg), or vehicle (control) intraperitoneally 3 days a week for 3 weeks. Tumors were measured and weighed, and protein levels of the cell cycle inhibitor, p21Waf1/Cip1, and the antiapoptotic protein, Bcl-2, were assessed. Both dosages of CPT significantly inhibited growth of WIL and TOR gastric tumors. CPT (10 mg/kg) reduced tumor size compared to baseline, establishing this as a tumoricidal dosage. Treatment with CPT was associated with increased levels of p21Waf1/Cip1 and decreased levels of Bcl-2. CPT effectively kills human gastric cancers associated with increased levels of p21Waf1/Cip1 and decreased levels of Bcl-2. By activating cell cycle withdrawal and cell death through induction of p21Waf1/Cip1 and downregulation of Bcl-2, CPT may be an effective agent for gastric cancer.
治疗预后仍然不佳的胃癌需要新型化疗药物。抗肿瘤生物碱喜树碱（CPT）可能对某些实体瘤的治疗有用；然而，其对胃癌的作用在很大程度上尚不明确。我们研究的目的是表征CPT在体内对人胃肿瘤的作用，并确定CPT介导的抑制作用所涉及的细胞机制。将两种人胃癌WIL和TOR皮下移植到无胸腺裸鼠体内。肿瘤长到50至100平方毫米后，将小鼠随机分为三组，每周3天腹腔注射低剂量CPT（5毫克/千克）、高剂量CPT（10毫克/千克）或赋形剂（对照），共3周。测量并称重肿瘤，评估细胞周期抑制剂p21Waf1/Cip1和抗凋亡蛋白Bcl-2的蛋白质水平。两种剂量的CPT均显著抑制WIL和TOR胃肿瘤的生长。与基线相比，CPT（10毫克/千克）减小了肿瘤大小，确定这为杀肿瘤剂量。CPT治疗与p21Waf1/Cip1水平升高和Bcl-2水平降低有关。CPT通过诱导p21Waf1/Cip1和下调Bcl-2激活细胞周期停滞和细胞死亡，可能是一种有效的胃癌治疗药物。
