Low-dose-melphalan-induced up-regulation of type-1 cytokine expression in the s.c. tumor nodule of MOPC-315 tumor bearers and the role of interferon gamma in the therapeutic outcome.
Low-dose-melphalan-induced up-regulation of type-1 cytokine expression in the s.c. tumor nodule of MOPC-315 tumor bearers and the role of interferon gamma in the therapeutic outcome.
复制标题
低剂量马法兰诱导皮下 1 型细胞因子表达上调
DOI：
10.1007/bf01526556
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Mokyr,MB
中科院分区：
文献类型：
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作者：
Gorelik,L;Mokyr,MB
我们之前已经证明了内源性肿瘤坏死因子（TNF）的产生对于低剂量美法仑（L-苯丙氨酸芥末）对携带大 MOPC-315 肿瘤的小鼠的疗效的重要性。在当前的研究中，我们证明低剂量马法兰实际上与皮下 TNFα mRNA 表达的增强有关。肿瘤结节。此外，肿瘤部位的干扰素 γ (IFNγ) 和白介素 12 (IL-12；p40) mRNA 表达也升高。然而，虽然TNFα和IFNγ的mRNA表达在化疗后24小时内明显升高，但IL-12(p40)的mRNA表达升高在化疗后72小时首先明显。此外，中和抗-IFNγ单克隆抗体，就像中和抗-TNF单克隆抗体但不中和抗-IL-12单克隆抗体一样，降低了低剂量美法仑对MOPC-315肿瘤携带者的疗效。对低剂量马法兰治疗的 MOPC-315 荷瘤小鼠中 IFNγ 介导其抗肿瘤作用机制的研究表明，MOPC-315 肿瘤细胞对 TNF 的直接抗肿瘤作用不敏感，但对高浓度 IFNγ 的抗增殖活性表现出一定的敏感性。然而，与TNFα不同，IFNγ不能促进抗MOPC-315细胞毒性T淋巴细胞活性的产生，并且事实上对CTL产生发挥抑制活性。综上所述，我们的研究表明，MOPC-315肿瘤携带者的低剂量美法仑治疗与IFNγ和TNF mRNA表达的快速升高有关，这两种细胞因子对于低剂量美法仑的疗效很重要，并且部分通过不同的机制介导其抗肿瘤作用。
We have previously shown the importance of endogenous tumor necrosis factor (TNF) production for the curative effectiveness of low-dose melphalan (L-phenylalanine mustard) for mice bearing a large MOPC-315 tumor. In the current study we demonstrate that low-dose melphalan is actually associated with enhanced expression of mRNA for TNFα in the s.c. tumor nodule. Moreover, the expression of mRNA for interferon γ (IFNγ) and interleukin-12 (IL-12; p40) is also elevated at the tumor site. However, while elevation in the expression of mRNA for TNFα and IFNγ is evident within 24 h after the chemotherapy, elevation in the expression of mRNA for IL-12(p40) is first evident 72 h after the chemotherapy. Moreover, neutralizing anti-IFNγ mAb, like neutralizing anti-TNF mAb but not neutralizing anti-IL-12 mAb, reduced the curative effectiveness of low-dose melphalan for MOPC-315 tumor bearers. Studies into the mechanism through which IFNγ mediates its antitumor effect in low-dose-melphalan-treated MOPC-315 tumor-bearing mice revealed that MOPC-315 tumor cells, which are not sensitive to the direct antitumor effects of TNF, display some sensitivity to the antiproliferative activity of high concentrations of IFNγ. However, unlike TNFα, IFNγ is unable to promote the generation of anti-MOPC-315 cytotoxic T lymphocyte activity and, in fact, exerts an inhibitory activity on CTL generation. Taken together, our studies illustrate that low-dose melphalan therapy of MOPC-315 tumor bearers is associated with the rapid elevation in the expression of mRNA for IFNγ and TNF, two cytokines which are important for the curative effectiveness of low-dose melphalan, and which mediate their antitumor effect, in part, through distinct mechanisms.