Timmer-Bosscha H, Hospers G A, Meijer C, Mulder N H, Muskiet F A, Martini I A, Uges D R, de Vries E G
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
J Natl Cancer Inst. 1989 Jul 19;81(14):1069-75. doi: 10.1093/jnci/81.14.1069.
In a sensitive, human, small cell lung carcinoma cell line (GLC4) and a cisplatin (CP)-resistant subline (GLC4-CP), the effect of co-culturing with docosahexaenoic acid (DCHA) on CP cytotoxicity was studied. Cells were cultured for 4 days, with 32 microM of DCHA added on days 1 and 3. Incorporation of DCHA into the cellular phospholipids was demonstrated by fatty acid analysis. Supplementation with DCHA led to almost a threefold decrease of resistance in GLC4-CP and had no influence on CP cytotoxicity in GLC4. After culturing with DCHA, cellular platinum (Pt); total Pt bound to DNA; and Pt-GG, Pt-AG, G-Pt-G, and Pt-GMP adduct contents increased in both lines, whereas interstrand cross-link formation was elevated only in GLC4-CP. These experiments demonstrate that DCHA reduces CP resistance. Although an effect on cellular membranes resulting in an increased CP uptake apparently was present, this mechanism does not seem to be responsible for resistance modulation. Rather, an effect on nuclear, probably DNA-related, structures is likely and leads to an increased formation of interstrand cross-links in GLC4-CP.
在一种敏感的人小细胞肺癌细胞系（GLC4）和顺铂（CP）耐药亚系（GLC4-CP）中，研究了与二十二碳六烯酸（DCHA）共培养对CP细胞毒性的影响。细胞培养4天，在第1天和第3天添加32微摩尔的DCHA。通过脂肪酸分析证实DCHA掺入细胞磷脂中。补充DCHA导致GLC4-CP的耐药性几乎降低了三倍，且对GLC4的CP细胞毒性没有影响。用DCHA培养后，两株细胞中的细胞铂（Pt）、与DNA结合的总Pt以及Pt-GG、Pt-AG、G-Pt-G和Pt-GMP加合物含量均增加，而仅在GLC4-CP中链间交联形成增加。这些实验表明DCHA降低了CP耐药性。虽然对细胞膜有影响导致CP摄取增加这一情况显然存在，但该机制似乎并非耐药性调节的原因。相反，对细胞核（可能与DNA相关）结构的影响很可能存在，并导致GLC4-CP中链间交联形成增加。
