Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer.
Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer.
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腺病毒介导的p53基因疗法和紫杉醇在人类头颈癌、卵巢癌、前列腺癌和乳腺癌模型中具有协同功效。
作者：
L. Nielsen;P. Lipari;J. Dell;M. Gurnani;G. Hajian
两种化学制剂之间的协同作用（或拮抗作用）是一种体外经验现象，其中观察到的联合作用的效果大于（或小于）每种制剂单独作用的效果。虽然数学上的协同作用在临床环境中不能直接证明，但当两种治疗方法在体内联合使用时，它确实预测了一个有利的结果，并强烈表明存在体内协同作用。相反，公开的对抗是对未来问题的警告。在一组人类肿瘤细胞系中，使用复杂的三维统计模型来评估腺病毒（Ad）介导的p53基因治疗（p53 Ad）和紫杉醇（Taxol）之间存在的协同、加性或拮抗作用。细胞或在p53 Ad前24小时用紫杉醇预处理，或同时用两种药物处理。3 d后检测细胞增殖情况。紫杉醇与p53基因治疗有增效或加效作用。在任何情况下，这种相互作用都不是对抗性的。细胞周期分析表明，p53 Ad在凋亡细胞死亡前阻滞G0/G1期细胞，而紫杉醇在凋亡细胞死亡前阻滞G2-M期细胞。当联合使用时，每种药物的相对浓度决定了显性细胞反应。这些结果分别与先前报道的p53或紫杉醇的细胞周期效应一致；然而，这些数据无法解释观察到的药物协同作用。我们发现，低浓度紫杉醇（1-14 nM）以剂量依赖的方式使重组Ad转导的细胞数量增加了3-35%，这是观察到的协同作用的一种可能机制。特别值得注意的是，导致Ad转导增加的紫杉醇浓度低于微管凝聚所需的浓度。并对联合治疗的体内疗效进行了评价。在p53null SK-OV-3卵巢癌异种移植模型中，p53 Ad的给药方案本身对肿瘤负荷的影响相对较小（16%），但当与紫杉醇联合使用时，肿瘤负荷的降低幅度要大得多（55%）。在p53mut DU-145前列腺、p53mut MDA-MB-468乳腺和p53mut MDA-MB-231乳腺癌异种移植体内模型中也观察到更大的联合疗效。综上所述，p53 Ad联合紫杉醇治疗癌症的疗效增强。这种组合被推荐用于临床癌症试验。
Synergy (or antagonism) between two chemical agents is an in vitro empirical phenomenon, in which the observed effect of the combination is more (or less) than what would be predicted from the effects of each agent working alone. Although mathematical synergy is not directly provable in the clinical setting, it does predict a favorable outcome when the two therapeutics are combined in vivo and strongly suggests the presence of in vivo synergy. In contrast, overt antagonism warns of future problems. Sophisticated three-dimensional statistical modeling was used to evaluate the presence of synergistic, additive, or antagonistic efficacy between adenovirus (Ad)-mediated p53 gene therapy (p53 Ad) and paclitaxel (Taxol) in a panel of human tumor cell lines. Cells were either pretreated with paclitaxel 24 h before p53 Ad or treated with both agents simultaneously. Cell proliferation was measured 3 days later. Paclitaxel had synergistic or additive efficacy with p53 gene therapy. In no case was the interaction antagonistic. Cell cycle analysis demonstrated that p53 Ad arrested cells in G0/G1 prior to apoptotic cell death, whereas paclitaxel arrested cells in G2-M prior to apoptotic cell death. When combined, the relative concentration of each agent determined the dominant cellular response. These results are consistent with the previously reported cell cycle effects of p53 or paclitaxel, respectively; however, these data fail to explain the observed drug synergy. We found that low concentrations of paclitaxel (1-14 nM) increased the number of cells transduced by recombinant Ad 3-35% in a dose-dependent manner, which is one possible mechanism for the observed synergy. Of particular note, the concentrations of paclitaxel responsible for increased Ad transduction were lower than the concentrations required for microtubule condensation. The efficacy of combination therapy was also evaluated in vivo. In the p53null SK-OV-3 xenograft model of ovarian cancer, a dosing schedule of p53 Ad that, by itself, had a relatively minimal effect on tumor burden (16%) caused a much greater decrease in tumor burden (55%) when combined with paclitaxel. Greater combined efficacy was also observed in the p53mut DU-145 prostate, p53mut MDA-MB-468 breast, and p53mut MDA-MB-231 breast cancer xenograft models in vivo. In summary, p53 Ad for cancer shows enhanced efficacy when combined with paclitaxel. This combination is recommended for clinical cancer trials.
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影响因子：
11.2
作者：
T. Fujiwara;E. A. Grimm;T. Mukhopadhyay;Wei-wei Zhang;Laurie B. Owen-Schaub;J. Roth
通讯作者：
T. Fujiwara;E. A. Grimm;T. Mukhopadhyay;Wei-wei Zhang;Laurie B. Owen-Schaub;J. Roth
影响因子：
21.1
作者：
W. Greco;G. Bravo;J. C. Parsons
通讯作者：
W. Greco;G. Bravo;J. C. Parsons
DOI：
10.1073/pnas.90.20.9552
发表时间：
1993-10-15
影响因子：
11.1
作者：
JORDAN, MA;TOSO, RJ;WILSON, L
通讯作者：
WILSON, L
影响因子：
2.9
作者：
DERRY, WB;WILSON, L;JORDAN, MA
通讯作者：
JORDAN, MA
DOI：
10.1016/0964-1955(94)90036-1
发表时间：
1994-09-01
期刊：
ORAL ONCOLOGY-EUROPEAN JOURNAL OF CANCER PART B
影响因子：
--
作者：
MIN, BM;BAEK, JH;PARK, NH
通讯作者：
PARK, NH