Wang Hui, Hang Jie, Shi Zhenqi, Li Mao, Yu Dong, Kandimalla Ekambar R, Agrawal Sudhir, Zhang Ruiwen
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Int J Oncol. 2002 Jul;21(1):73-80.
The RIalpha-subunit of cAMP-dependent protein kinase (PKA) is overexpressed in various human cancers and PKA has been suggested to be a potential target for cancer therapy. We have shown an antisense oligonucleotide with advanced chemistry (mixed-backbone oligonucleotide) targeted to PKA RIalpha-subunit (GEM231) to have anti-tumor activity in vitro and in vivo. In the present study, we demonstrated synergistic effects between the anti-PKA antisense oligonucleotide and the clinically used anticancer agent irinotecan, using nude mouse models of human cancers of colon (LS174T and DLD-1), breast (MCF-7), prostate (DU-145 and PC-3) and lung (H1299). To elucidate the underlying mechanisms, in vivo pharmacokinetics of irinotecan was determined following pre-treatment of oligo GEM 231 in CD-1 mice and nude mice bearing LS174T xenografts. GEM 231 increased tissue uptake of irinotecan. However, no significant change in host toxicity was observed following combination treatment of irinotecan and GEM231 compared with irinotecan alone. These results suggest that GEM231 have a role in irinotecan metabolism and its antitumor activity, providing a basis for future development of this oligonucleotide as a chemosensitizer for irinotecan-based therapy.
环磷酸腺苷依赖性蛋白激酶（PKA）的RIα亚基在多种人类癌症中过表达，并且PKA已被认为是癌症治疗的潜在靶点。我们已经证明，一种针对PKA RIα亚基的具有先进化学结构的反义寡核苷酸（混合骨架寡核苷酸，即GEM231）在体外和体内均具有抗肿瘤活性。在本研究中，我们使用人结肠癌（LS174T和DLD-1）、乳腺癌（MCF-7）、前列腺癌（DU-145和PC-3）和肺癌（H1299）的裸鼠模型，证明了抗PKA反义寡核苷酸与临床使用的抗癌药物伊立替康之间的协同作用。为了阐明潜在机制，在CD-1小鼠和携带LS174T异种移植物的裸鼠中，在给予寡核苷酸GEM 231预处理后，测定了伊立替康的体内药代动力学。GEM 231增加了伊立替康的组织摄取。然而，与单独使用伊立替康相比，伊立替康与GEM231联合治疗后未观察到宿主毒性有显著变化。这些结果表明，GEM231在伊立替康代谢及其抗肿瘤活性中发挥作用，为该寡核苷酸作为基于伊立替康治疗的化学增敏剂的未来开发提供了依据。
