Jenski L J, Zerouga M, Stillwell W
Department of Biology, Indiana University-Purdue University at Indianapolis 46303-5132, USA.
Proc Soc Exp Biol Med. 1995 Dec;210(3):227-33. doi: 10.3181/00379727-210-43943.
omega-3 fatty acids are associated with reduced growth and incidence of certain cancers, and in this report we demonstrate that a fish oil diet (rich in omega-3 fatty acids) enhances the longevity of mice bearing the myeloid leukemia T27A. We have proposed that the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6 delta 4,7,10,13,16,19) may induce structural changes in tumor cell plasma membranes resulting in reduced tumor growth in vitro. Here, we test whether liposomes containing DHA (18:0, 22:6 PC) have antitumor effects in vivo, leading to enhanced longevity of the tumor-bearing host. Male BALB/c mice (6-8 weeks old) were inoculated intraperitoneally with a T27A tumor dose known to cause 100% mortality of syngeneic (BALB/c) mice in less than 2 weeks. Small unilamellar vesicles (liposomes) were prepared, composed of phosphatidylcholine (PC) with 18:0 in the sn-l position and one of the following fatty acids in the sn-2 position: 18:0, 18:1 omega 9 (oleic), 18:3 omega 3 (alpha-linolenic), 20:4 omega 6 (arachidonic), 22:6 omega 3 (docosahexaenoic). The liposomes were injected intraperitoneally into tumor-bearing mice at various times: concurrently with the tumor inoculum, at select times during tumor growth, and when the mice were moribund. Mouse survival was then charted. DHA-containing lipid vesicles (18:0, 22:6 PC) caused a statistically significant increase in survival of the tumor-bearing mice when compared with 18:0, 18:1 PC. Lipid vesicles of 18:0, 18:0 PC showed no benefit, and 18:0, 20:4 PC was not significantly different than 18:0, 18:1 PC. Lipid vesicles containing a different omega-3 fatty acid, 18:0, 18:3 PC, also effectively enhanced tumor-bearing mouse survival. The greatest benefit was achieved if either the liposome treatments were spaced throughout the tumor growth period, or if the tumor inoculum was suspended in the liposome preparation (without further liposome treatments). Neither lipid peroxidation nor prolonged inflammatory responses appeared to be pertinent, leaving membrane structural changes as a feasible mode of liposome action. With antitumor properties of their own, omega-3 fatty acid-containing lipid vesicles may offer an important new avenue in combination cancer therapies.
ω-3脂肪酸与某些癌症的生长减缓及发病率降低相关，在本报告中，我们证明鱼油饮食（富含ω-3脂肪酸）可延长患有髓系白血病T27A的小鼠的寿命。我们曾提出ω-3脂肪酸二十二碳六烯酸（DHA，22:6Δ4,7,10,13,16,19）可能会诱导肿瘤细胞质膜发生结构变化，从而在体外导致肿瘤生长减缓。在此，我们测试含有DHA（18:0, 22:6 PC）的脂质体在体内是否具有抗肿瘤作用，进而延长荷瘤宿主的寿命。雄性BALB/c小鼠（6 - 8周龄）腹腔内接种已知能在不到2周内使同基因（BALB/c）小鼠100%死亡的T27A肿瘤剂量。制备了小单层囊泡（脂质体），其由在sn-1位置含有18:0的磷脂酰胆碱（PC）和在sn-2位置含有以下脂肪酸之一组成：18:0、18:1ω9（油酸）、18:3ω3（α-亚麻酸）、20:4ω6（花生四烯酸）、22:6ω3（二十二碳六烯酸）。脂质体在不同时间腹腔内注射到荷瘤小鼠体内：与肿瘤接种物同时注射、在肿瘤生长期间的特定时间注射以及在小鼠濒死时注射。然后绘制小鼠存活情况图表。与18:0、18:1 PC相比，含DHA的脂质囊泡（18:0, 22:6 PC）使荷瘤小鼠的存活率有统计学意义的显著提高。18:0, 18:0 PC的脂质囊泡未显示出益处，18:0, 20:4 PC与18:0, 18:1 PC无显著差异。含有另一种ω-3脂肪酸18:0, 18:3 PC的脂质囊泡也有效提高了荷瘤小鼠的存活率。如果脂质体治疗在整个肿瘤生长期间间隔进行，或者如果肿瘤接种物悬浮在脂质体制剂中（无需进一步的脂质体治疗），则能获得最大益处。脂质过氧化和延长的炎症反应似乎都不相关，这使得膜结构变化成为脂质体作用的一种可行方式。含ω-3脂肪酸的脂质囊泡自身具有抗肿瘤特性，可能为联合癌症治疗提供一条重要的新途径。
