Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms.
Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms.
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发表时间：
2001-11
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通讯作者：
Hui Wang;Li Nan;Dong Yu;S. Agrawal;Ruiwen Zhang
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作者：
Hui Wang;Li Nan;Dong Yu;S. Agrawal;Ruiwen Zhang
小鼠双微体2（MDM 2）癌基因已被建议作为癌症治疗的靶点。它在许多人类癌症中扩增或过表达，包括乳腺癌，并且MDM 2水平与几种人类癌症的预后不良相关，包括乳腺癌，卵巢癌，骨肉瘤和淋巴瘤。在本研究中，我们研究了MDM 2癌基因在乳腺癌生长中的功能，以及MDM 2作为肿瘤治疗药物靶点的潜在价值，通过特异性反义抗人MDM 2寡核苷酸（oligo）抑制MDM 2表达。在人乳腺癌模型中评价所选反义混合骨架寡核苷酸的体外和体内抗肿瘤活性：含有野生型p53的MCF-7细胞系和含有突变型p53的MDA-MB-468细胞系。在MCF-7细胞中，p53和p21水平升高，这是由于反义寡核苷酸（AS）特异性抑制MDM 2表达所致。在MDA-MB-468细胞中，抑制MDM 2表达后，p21水平升高，但p53水平保持不变。腹膜内给予反义抗MDM 2寡核苷酸后，在携带MCF-7或MDA-MB-468异种移植物的裸鼠中以剂量依赖性方式发生体内抗肿瘤活性。在这两种模型中，观察到MDM 2抑制和临床使用的癌症化疗剂伊立替康、5-氟尿嘧啶和紫杉醇（Taxol）的体内协同或相加治疗作用。这些结果表明，MDM 2通过p53依赖性和p53非依赖性机制在肿瘤生长中发挥作用。我们推测，MDM 2抑制剂，如AS，在人类乳腺癌中具有广谱的抗肿瘤活性，无论p53状态如何。本研究为今后开发抗MDM 2 AS作为单独或与常规化疗药物联合使用的癌症治疗药物提供了基础。
The mouse double minute 2 (MDM2) oncogene has been suggested as a target for cancer therapy. It is amplified or overexpressed in many human cancers, including breast cancer, and MDM2 levels are associated with poor prognosis of several human cancers, including breast cancer, ovarian cancer, osteosarcoma, and lymphoma. In the present study, we investigated the functions of MDM2 oncogene in the growth of breast cancer and the potential value of MDM2 as a drug target for cancer therapy by inhibiting MDM2 expression with a specific antisense antihuman-MDM2 oligonucleotide (oligo). The selected antisense mixed-backbone oligo was evaluated for its in vitro and in vivo antitumor activity in human breast cancer models: MCF-7 cell line containing wild-type p53 and MDA-MB-468 cell line containing mutant p53. In MCF-7 cells, p53 and p21 levels were elevated, resulting from specific inhibition of MDM2 expression by the antisense oligo (AS). In MDA-MB-468 cells, after inhibition of MDM2 expression, p21 levels were elevated, although p53 levels remained unchanged. After i.p. administration of the antisense anti-MDM2 oligo, in vivo antitumor activity occurred in a dose-dependent manner in nude mice bearing MCF-7 or MDA-MB-468 xenografts. In both models, in vivo synergistically or additive therapeutic effects of MDM2 inhibition and the clinically used cancer chemotherapeutic agents irinotecan, 5-fluorouracil, and paclitaxel (Taxol) were observed. These results suggest that MDM2 have a role in tumor growth through both p53-dependent and p53-independent mechanisms. We speculate that MDM2 inhibitors, such as ASs, have a broad spectrum of antitumor activities in human breast cancers, regardless of p53 status. This study should provide a basis for future development of anti-MDM2 ASs as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.