Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models.
Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models.
复制标题
阿霉素和紫杉醇与脂质体包埋末端修饰的 raf 反义寡核苷酸联合使用，可增强对人前列腺、肺和乳腺肿瘤模型的治疗效果。
DOI：
--
复制
发表时间：
2004
影响因子：
5.2
通讯作者：
P. Gokhale
中科院分区：
文献类型：
--
作者：
Rajshree R. Mewani;Wenhua Tang;Aquilur Rahman;A. Dritschilo;I. Ahmad;U. Kasid;P. Gokhale
Raf-1蛋白激酶在细胞生长、增殖和存活中起着重要作用。我们之前已经描述了使用脂质体包裹的反义raf寡核苷酸（LErafAON）来抑制raf -1的表达，从而导致肿瘤生长抑制和放射增敏。本研究的目的是评估leafaon联合阿霉素或紫杉醇对一组人类肿瘤异种移植物的化疗增敏效果。在前列腺癌（PC-3）、肺癌（A549）和乳腺癌（MDA-MB 231）模型中，单药给药leafaon （25.0 mg/kg静脉滴注x 10）具有显著的抗肿瘤活性（P<0.05）。阿霉素（1.0-4.0 mg/kg静脉滴注，每周x3）和紫杉醇（1.0-4.0 mg/kg静脉滴注，隔天x3）作为单一药物以无毒剂量给药，仅导致最低至中等抗肿瘤活性。然而，与单独使用leafaon或化疗药物治疗组相比，leafaon联合阿霉素或紫杉醇可显著增强所有肿瘤类型的抗肿瘤活性（PC-3， P<0.03; A549， P<0.035; MDA-MB 231， P<0.045）。这种化学致敏效应似乎是序列特异性的，因为错配控制寡核苷酸继续显示出显著的肿瘤生长。此外，错配寡核苷酸治疗对MDA-MB 231肿瘤组织中Raf-1的表达没有抑制作用。另一方面，LErafAON治疗可使肿瘤组织中Raf-1表达抑制约75%。这些临床前观察结果支持使用leafaon联合化疗药物来改善人类癌症的治疗。
Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.