Tortora G, Caputo R, Damiano V, Bianco R, Pepe S, Bianco A R, Jiang Z, Agrawal S, Ciardiello F
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università Federico II, Via Pansini 5, 80131 Napoli, Italy.
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12586-91. doi: 10.1073/pnas.94.23.12586.
Protein kinase A type I plays a key role in neoplastic transformation, conveying mitogenic signals of different growth factors and oncogenes. Inhibition of protein kinase A type I by antisense oligonucleotides targeting its RIalpha regulatory subunit results in cancer cell growth inhibition in vitro and in vivo. A novel mixed backbone oligonucleotide HYB 190 and its mismatched control HYB 239 were tested on soft agar growth of several human cancer cell types. HYB 190 demonstrated a dose-dependent inhibition of colony formation in all cell lines whereas the HYB 239 at the same doses caused a modest or no growth inhibition. A noninhibitory dose of each mixed backbone oligonucleotide was used in OVCAR-3 ovarian and GEO colon cancer cells to study whether any cooperative effect may occur between the antisense and a series of cytotoxic drugs acting by different mechanisms. Treatment with HYB 190 resulted in an additive growth inhibitory effect with several cytotoxic drugs when measured by soft agar colony formation. A synergistic growth inhibition, which correlated with increased apoptosis, was observed when HYB 190 was added to cancer cells treated with taxanes, platinum-based compounds, and topoisomerase II selective drugs. This synergistic effect was also observed in breast cancer cells and was obtained with other related drugs such as docetaxel and carboplatin. Combination of HYB 190 and paclitaxel resulted in an accumulation of cells in late S-G2 phases of cell cycle and marked induction of apoptosis. A cooperative effect of HYB 190 and paclitaxel was also obtained in vivo in nude mice bearing human GEO colon cancer xenografts. These results are the first report of a cooperative growth inhibitory effect obtained in a variety of human cancer cell lines by antisense mixed backbone oligonucleotide targeting protein kinase A type I-mediated mitogenic signals and specific cytotoxic drugs.
蛋白激酶 A I 型在肿瘤转化中起关键作用，传递不同生长因子和癌基因的促有丝分裂信号。通过靶向其 RIα 调节亚基的反义寡核苷酸抑制蛋白激酶 A I 型，可在体外和体内抑制癌细胞生长。一种新型混合骨架寡核苷酸 HYB 190 及其错配对照 HYB 239 在几种人类癌细胞类型的软琼脂生长实验中进行了测试。HYB 190 在所有细胞系中均表现出剂量依赖性的集落形成抑制作用，而相同剂量的 HYB 239 则仅产生适度抑制或无生长抑制作用。在 OVCAR - 3 卵巢癌细胞和 GEO 结肠癌细胞中使用各混合骨架寡核苷酸的非抑制剂量，以研究反义寡核苷酸与一系列作用机制不同的细胞毒性药物之间是否可能存在协同效应。通过软琼脂集落形成测定，用 HYB 190 处理会与几种细胞毒性药物产生相加的生长抑制作用。当将 HYB 190 添加到用紫杉烷类、铂类化合物和拓扑异构酶 II 选择性药物处理的癌细胞中时，观察到与凋亡增加相关的协同生长抑制作用。这种协同效应在乳腺癌细胞中也观察到，并且用多西他赛和卡铂等其他相关药物也能得到。HYB 190 与紫杉醇联合使用导致细胞在细胞周期的 S - G2 晚期积累，并显著诱导凋亡。在携带人 GEO 结肠癌细胞异种移植瘤的裸鼠体内也获得了 HYB 190 与紫杉醇的协同作用。这些结果是关于通过靶向蛋白激酶 A I 型介导的促有丝分裂信号的反义混合骨架寡核苷酸与特定细胞毒性药物在多种人类癌细胞系中获得协同生长抑制作用的首次报道。
