In-vitro and in-vivo anti-cancer activity of a novel gemcitabine-cardiolipin conjugate
In-vitro and in-vivo anti-cancer activity of a novel gemcitabine-cardiolipin conjugate
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DOI：
10.1097/01.cad.0000185182.80227.48
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发表时间：
2006-01-01
影响因子：
2.3
通讯作者：
Ahmad, I
中科院分区：
文献类型：
--
作者：
Chen, P;Chien, PY;Ahmad, I
我们的目标是研究新型吉西他滨-心磷脂结合物 (NEO6002) 的生物活性，并与吉西他滨进行比较。使用磺罗丹明 B 测定法测定了几种对吉西他滨敏感的亲本癌细胞系和吉西他滨耐药癌细胞系的体外细胞毒性。通过常规小鼠的体重和血液学指数的变化来检查体内毒性。使用携带 P388 和 BxPC-3 肿瘤异种移植物的免疫缺陷 SCID 小鼠来评估体内治疗效果。 NEO6002 和吉西他滨均对所有测试的吉西他滨敏感细胞系显示出促凋亡和细胞毒性作用。与吉西他滨不同，NEO6002 的细胞毒性不依赖于核苷转运蛋白 (NT) 抑制剂，表明 NEO6002 具有不同的内化途径。该缀合物不仅在 NT 缺陷的吉西他滨耐药人白血病细胞系 ARAC-8C 中表现出良好的活性，而且在其他几种吉西他滨耐药细胞系中也表现出良好的活性。在体内水平上，比较毒性研究显示，吉西他滨治疗的小鼠体重显着减轻，白细胞计数减少，而 NEO6002 的影响轻微。以 27 μmol/kg 的 NEO6002 治疗使携带 P388 细胞的 CD2F1 小鼠的中位存活率提高了 73%，而相同剂量和方案的吉西他滨导致所有治疗小鼠中毒性死亡。在18μmol/kg的剂量下，NEO6002抑制BxPC-3异种移植物的生长52%，而吉西他滨仅实现32%的肿瘤抑制。我们的结论是，NEO6002 可能是一种有效的化疗药物，具有改善的耐受性，并且有可能规避 NT 缺陷、吉西他滨耐药的肿瘤。
Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 mu mol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 mu mol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.