Li K, Zhang J, Sirois P, Hu Y
Drew Medical Center, CA 90059, USA.
Curr Opin Mol Ther. 1999 Jun;1(3):393-8.
It is well known that the PKC family of enzymes is involved in the propagation of intracellular signals and is implicated in cancers, inflammatory processes, cardiovascular and endocrinological diseases. Relatively low isozyme specificity has largely limited the clinical use of PKC antagonists. The members of the PKC family differ from each other at the mRNA level and the selectivity of antisense compounds is distinguished by this feature. According to ISIS Pharmaceuticals Inc antisense compounds are highly selective inhibitors even within a family of closely-related genes [321211]. The use of these compounds could be invaluable as tools to discover the mechanisms and roles of specific PKC isozyme in normal and diseased tissues and could provide the information for better cancer treatments [226799]. The isozyme of PKC-alpha is believed to play an important role in the proliferation of several types of cancer cells [234471-323703]. Recently, ISIS Pharmaceuticals received a patent US-05885970, covering the antisense technique targeting human PKC-alpha for cancer therapy (US-0588970). In the past few years, several effective antisense oligonucleotides (AS ONs) targeting murine and human PKC-alpha isozymes have been developed and a series of positive results have been obtained in cell culture and in nude mice cancer transplantation [327453]. Phase I clinical trials have shown that relatively high doses were well tolerated with no obvious side-effects [226799]. Whether these AS ONs are beneficial to patients suffering from cancer, either alone or in combination with other chemotherapy drugs is still under evaluation in a clinical setting.
众所周知，蛋白激酶C（PKC）家族的酶参与细胞内信号的传导，并与癌症、炎症过程、心血管疾病和内分泌疾病有关。相对较低的同工酶特异性在很大程度上限制了PKC拮抗剂的临床应用。PKC家族成员在mRNA水平上彼此不同，反义化合物的选择性也由此得以区分。据ISIS制药公司称，反义化合物即使在密切相关的基因家族中也是高度选择性的抑制剂[321211]。这些化合物作为发现特定PKC同工酶在正常和患病组织中的机制和作用的工具可能具有极高的价值，并可为更好的癌症治疗提供信息[226799]。据信PKC-α同工酶在几种癌细胞的增殖中起重要作用[234471 - 323703]。最近，ISIS制药公司获得了美国专利US-05885970，涵盖用于癌症治疗的靶向人PKC-α的反义技术（US-0588970）。在过去几年中，已经开发出了几种针对小鼠和人PKC-α同工酶的有效反义寡核苷酸（AS ONs），并在细胞培养和裸鼠癌症移植中取得了一系列阳性结果[327453]。I期临床试验表明，相对高剂量的耐受性良好，没有明显的副作用[226799]。这些AS ONs单独或与其他化疗药物联合使用对癌症患者是否有益仍在临床环境中进行评估。
