Background/Objectives: Neuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk diseases is highly genotoxic. This, combined with less than 50% survival in high-risk diseases and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential.Methods: A prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wildtype mice were gavaged with 12.3–14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6–6.0 g/d arachidonic acid (ARA). At seven days,MYCN-expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10–20 d post-injection when tumors and tissues were harvested.Results: Fifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n = 8 or 10 animals. In contrast, ω6 arachidonic acid (4.6–6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days) compared to the control. The co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism.Conclusions: Sustained high-dose ω3 (weeks/months) is safe and well-tolerated in humans. These results suggest that ω3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma.
背景/目的：神经母细胞瘤是一种遗传多样性高、转移性强的儿童恶性肿瘤，其发病率仅占儿童癌症的约8%，却导致15%的儿童癌症死亡。目前针对高危神经母细胞瘤的标准治疗方案具有强基因毒性，加之高危患者生存率不足50%，复发患者生存率更是低至5%，因此开发新型、高效且低毒的治疗策略至关重要。 方法：本研究采用预防性同基因小鼠模型，探究高剂量脂质介质高度不饱和脂肪酸对肿瘤发生的影响。野生型小鼠每日灌胃给予12.3-14.6克（成人等效剂量）的ω-3脂肪酸EPA、DHA或抗氧化双烯丙位氘代DHA（D-DHA），同时辅以4.6-6.0克花生四烯酸（ARA）。灌胃7天后，皮下注射与灌胃小鼠同源的MYCN表达型鼠源神经母细胞瘤细胞（Neuro-2a）。注射后持续灌胃10-20天，随后采集肿瘤及组织样本。 结果：对照组（未灌胃）动物中50%（4/8）在约10天后形成肿瘤。高剂量DHA、D-DHA和EPA在8或10只动物中完全阻断肿瘤形成。相比之下，ω-6花生四烯酸（4.6-6.0克/日）与对照组相比，不仅促进肿瘤形成（6/10形成肿瘤），还缩短了肿瘤潜伏期（5.5至10天）。EPA与ARA联合给药可使肿瘤负荷降低至对照组水平，提示EPA直接拮抗ARA介导的肿瘤形成机制。DHA则通过非氧化机制发挥作用。 结论：长期高剂量ω-3脂肪酸（数周/数月）在人体中安全且耐受性良好。本研究结果表明，超高剂量ω-3脂肪酸DHA与EPA可能成为神经母细胞瘤的一种可行低毒性治疗方案。
肿瘤(癌症)患者之家