Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo
Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo
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TZT-1027 增强体内分泌 TNF-α 或 IL-6 的 Lewis 肺癌的抗肿瘤活性
DOI：
10.1007/s00280-001-0388-0
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发表时间：
2001
影响因子：
3
通讯作者：
K. Nishio
中科院分区：
文献类型：
--
作者：
T. Natsume;Y. Koh;M. Kobayashi;H. Fukumoto;F. Takahashi;Takashi Nakamura;Y. Ohe;N. Saijo;K. Nishio
目的：TZT-1027是一种抑制微管蛋白聚合的抗微管剂，在多种体内可移植肿瘤模型中显示出有效的抗肿瘤活性。TZT-1027的高抗肿瘤活性促使我们推测该化合物可能具有除抗微管和抗有丝分裂活性之外的作用模式。为了阐明TZT-1027与抗肿瘤细胞因子在体内肿瘤中的相互作用，我们检测了TZT-1027对接种于C57 BL/6小鼠的各种细胞因子基因转染的刘易斯肺癌（LLC）细胞的抗肿瘤活性。用抗CD 31抗体免疫组化法检测肿瘤组织中血管的状态。结果：TZT-1027在3 mg/kg剂量下，对小鼠LLC-Neo细胞具有较强的抗肿瘤活性，T/C%值为16%。3 mg/kg TZT-1027在LLC-TNF细胞和LLC-IL 6细胞中显示出更强的抗肿瘤活性，T/C%值分别为4%和3%。TZT-1027处理破坏了肿瘤脉管系统以及用TZT-1027处理的小鼠的LLC-TNF和LLC-IL 6组织中的肿瘤细胞。TZT-1027处理小鼠的LLC-TNF和LLC-IL 6组织共同具有非组蛋白染色体蛋白HMG-14和热休克基因转录因子1的独立改变。关注与血管生成相关的基因调控，在转录因子，如ets家族基因和同源盒家族基因的改变是显着的Conclusions：这些因素的候选人作为决定因素的增强TZT-1027抗肿瘤活性与这些细胞因子。
Purpose:TZT-1027, an antimicrotubule agent that inhibits the polymerization of tubulin, shows potent antitumor activity in various transplantable tumor models in vivo. The high antitumor activity of TZT-1027 prompted us to speculate that this compound may have a mode of action other than its antimicrotubule and antimitotic activities. To elucidate the interaction of antitumor cytokines with TZT-1027 in tumors in vivo, we examined the antitumor activity of this agent against various cytokine gene-transfected Lewis lung carcinoma (LLC) cells inoculated into C57BL/6 mice.Methods:In vitro growth inhibition was evaluated using the MTT assay, and in vivo activity was evaluated in subcutaneous models in C57BL/6 mice. The status of the vasculature in tumor tissues was evaluated immunohistochemically using anti-CD31 antibody. We used a cDNA macroarray to examine the gene expression profiles in tumor tissues removed from mice.Results:TZT-1027 at 3 mg/kg showed potent antitumor activity in Mock (LLC-Neo cells) inoculated mice with a T/C% value of 16%. TZT-1027 at 3 mg/kg showed more potent antitumor activity in LLC-TNF cells and LLC-IL6 cells with T/C% values of 4% and 3%, respectively. TZT-1027 treatment destroyed the tumor vasculature as well as tumor cells in LLC-TNF and LLC-IL6 tissues of mice treated with TZT-1027. The LLC-TNF and LLC-IL6 tissues of mice treated with TZT-1027 had in common the independent alteration of the non-histone chromosomal protein HMG-14 and transcription factor 1 for heat shock gene. Focusing on the gene regulation related to angiogenesis, the alteration in transcriptional factors such as ets family genes and homeobox family genes was remarkable.Conclusions:These factors are candidates as determinants of the enhanced TZT-1027 antitumor activity in relation to these cytokines.