osi - 7836 DNA Calu-6和H460异种移植肿瘤。

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理查森F,黑色C,理查森K,法兰克人,井E,卡里年代,Sennello G,哈特K, Meyer D,爱默生D, E,布朗LeRay J,尼尔森C, B Tomkinson Bendele R

osi - 7836 DNA Calu-6和H460异种移植肿瘤。

癌症Chemother杂志。2005年3月,55(3):213 - 21所示。Epub 2004年11月16日。

PubMed ID

15592840 (在PubMed

]

文摘

osi - 7836 (4 ' -thio-beta-D-arabinofuranosylcytosine)是一种新型核苷模拟在第一阶段临床开发治疗癌症。与其它核苷类似物,提出的作用机制包括磷酸化三磷酸形式并入细胞DNA,从而导致细胞死亡。这个假设被测量和比较研究ara-C的合并,osi - 7836,吉西他滨(dFdC)培养细胞的DNA,通过调查脱氧胞苷激酶在osi - 7836毒性的作用。我们报告的额外研究在细胞循环的作用在osi - 7836毒性研究和整合osi - 7836异种移植肿瘤的DNA测量。细胞周期的作用是检查通过比较osi - 7836在非小细胞型肺癌A549细胞的毒性,在日志增长阶段或已达到融合。小说验证质/ MS分析了量化osi - 7836的浓度DNA Calu-6和H460人类肿瘤异种移植小鼠。结果表明,osi - 7836诱导细胞凋亡在循环细胞明显大于在汇合的环状结构细胞,尽管只有适度增加细胞内三磷酸osi - 7836浓度。质/ MS分析研发纳入DNA测量osi - 7836有一个对列检出限0.25 fmol,量化限制0.5 fmol和灵敏度约0.1 pmol osi - 7836 / micromol dThy。osi - 7836的浓度在脾脏DNA (osi - 7836 0.4 pmol / micromol dThy)平均5倍不到Calu-6平均浓度和H460异种移植DNA (osi - 7836 3.0 pmol / micromol dThy)在osi - 7836剂量400毫克/公斤。osi - 7836浓度Calu-6肿瘤DNA分离24 h后剂量的400,1000,或1600毫克osi - 7836 /公斤大约1.3,1 osi - 7836和1.3 pmol / micromol dThy,分别。 Concentrations of OSI-7836 in DNA from H460 and Calu-6 xenografts did not appear to increase during repeated administration of 400 mg OSI-7836/kg on days 1, 4, 7, and 10. The majority of OSI-7836 in DNA from Calu-6 and H460 tumors of mice dosed with 1600 mg/kg was located at internal nucleotide linkages, similar to dFdC and ara-C. In conclusion, cell cycling studies supported the hypothesis that OSI-7836 cytotoxicity is dependent upon DNA synthesis. A validated LC-MS/MS assay was developed that could quantify OSI-7836 in DNA from tissues. The assay was used to show that OSI-7836 was incorporated in internal linkages in tumor DNA in a manner that was dose-independent at the doses tested and did not appear to accumulate during repeated dosing. The results suggest that if DNA incorporation is a toxic event, the relationships between administered dose, DNA incorporation, and toxicity are complex.

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osi - 7836