Ormerod M G, Orr R M, O'Neill C F, Chwalinski T, Titley J C, Kelland L R, Harrap K R
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research: Royal Cancer Hospital, Sutton, UK.
Br J Cancer. 1996 Dec;74(12):1935-43. doi: 10.1038/bjc.1996.656.
We have used flow cytometry to study the mechanism of cytotoxic action of a series of ammine/amine Pt(IV) dicarboxylates [ammine diacetatodichloro(cyclohexylamine) platinum(IV), JM216; ammine dibutyratodichloro(cyclohexylamine)platinum(IV), JM221; ammine diacetatodichloro(propylamine)platinum(IV), JM223; ammine dibenzoatodichloro(propylamine)platinum(IV), JM244]. JM216 has been shown to have clinical potential and has recently entered phase II trials. All the compounds caused a slowdown in S-phase transit followed by a block in G2. Cells died either through apoptosis (largely during S-phase) or by failing to overcome the G2 block (some days after treatment). In G2, the cells either divided or enlarged and died. At equitoxic doses, JM216 showed the most apoptotic cells and had the most platinum bound to the DNA; JM244 showed the fewest apoptotic cells and had the least platinum bound to DNA. We suggest that whether apoptosis was triggered or not was governed by the total amount of Pt bound to the DNA; the type of lesion was more important in determining whether a cell became blocked in G2.
我们运用流式细胞术研究了一系列氨/胺铂（IV）二羧酸盐[氨二乙酸二氯（环己胺）铂（IV），JM216；氨二丁酸二氯（环己胺）铂（IV），JM221；氨二乙酸二氯（丙胺）铂（IV），JM223；氨二苯甲酸二氯（丙胺）铂（IV），JM244]的细胞毒性作用机制。JM216已显示出具有临床应用潜力，并且最近已进入II期试验。所有化合物均导致S期进程放缓，随后出现G2期阻滞。细胞通过凋亡死亡（主要在S期）或未能克服G2期阻滞（处理后数天）。在G2期，细胞要么分裂，要么增大并死亡。在等效毒性剂量下，JM216显示出的凋亡细胞最多，与DNA结合的铂也最多；JM244显示出的凋亡细胞最少，与DNA结合的铂也最少。我们认为，是否引发凋亡取决于与DNA结合的铂的总量；损伤类型在决定细胞是否在G2期阻滞方面更为重要。
