Brunton V G, Workman P
CRC Department of Medical Oncology, University of Glasgow, Bearsden, UK.
Br J Cancer. 1993 May;67(5):989-95. doi: 10.1038/bjc.1993.181.
The novel imidazoisoquinoline SDZ 62-434, originally identified as a platelet-activating factor (PAF) antagonist, has antiproliferative activity in a range of cell lines from human solid and haematological malignancies. Using an MTT cytotoxicity assay, IC50 values of 5 microM - 111 microM were observed following a 24 h exposure. Similar results were obtained using a clonogenic assay. The HT29 colon adenocarcinoma was particularly sensitive while the MCF-7 breast carcinoma was the most resistant in our panel. Only a 2-3 fold cross-resistance was seen in the doxorubicin and cisplatin resistant variants of the A2780 ovarian carcinoma; the drug did not modulate sensitivity to doxorubicin in either parent or resistant lines. No cross-resistance to SDZ 62-434 was seen in a doxorubicin-resistant MCF-7 variant. Cytotoxicity was not due to non-specific membrane lysis. The potent PAF antagonist WEB 2086 did not modulate SDZ 62-434 cytotoxicity, indicating no role for PAF receptors. Precursor incorporation studies in A2780 cells showed that DNA synthesis was inhibited more effectively than protein synthesis while RNA synthesis was unaffected. SDZ 62-434 inhibited both bombesin and platelet-derived growth factor-induced DNA synthesis in quiescent Swiss 3T3 cells. This suggests a possible role for SDZ 62-434 as an inhibitor of signal transduction in cancer cells.
新型咪唑并异喹啉SDZ 62-434最初被鉴定为血小板活化因子（PAF）拮抗剂，对一系列源自人类实体瘤和血液系统恶性肿瘤的细胞系具有抗增殖活性。使用MTT细胞毒性试验，在24小时暴露后观察到IC50值为5 microM - 111 microM。使用克隆形成试验获得了类似的结果。在我们的实验中，HT29结肠腺癌特别敏感，而MCF-7乳腺癌最具抗性。在A2780卵巢癌的阿霉素和顺铂耐药变体中仅观察到2-3倍的交叉耐药性；该药物在亲本或耐药系中均未调节对阿霉素的敏感性。在阿霉素耐药的MCF-7变体中未观察到对SDZ 62-434的交叉耐药性。细胞毒性不是由于非特异性膜裂解。强效PAF拮抗剂WEB 2086未调节SDZ 62-434的细胞毒性，表明PAF受体无作用。对A2780细胞的前体掺入研究表明，DNA合成比蛋白质合成更有效地受到抑制，而RNA合成未受影响。SDZ 62-434抑制了蛙皮素和血小板衍生生长因子诱导的静止瑞士3T3细胞中的DNA合成。这表明SDZ 62-434可能作为癌细胞信号转导抑制剂发挥作用。
