Makimoto Atsushi, Fang Jun, Maeda Hiroshi
Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan.
Faculty of Pharmaceutical Science, Sojo University, Kumamoto 860-0082, Japan.
Cancers (Basel). 2021 Jul 23;13(15):3698. doi: 10.3390/cancers13153698.
Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments.
大多数儿童癌症对化疗高度敏感，细胞毒性化疗一直是主要的治疗手段。蒽环类药物对大多数类型的儿童癌症，如神经母细胞瘤、肝母细胞瘤、肾母细胞瘤、横纹肌肉瘤、尤因肉瘤等都非常有效。然而，蒽环类药物使用的主要缺点之一——急性和慢性心脏毒性，限制了它们的效用和有效性。羟丙基丙烯酰胺聚合物共轭吡柔比星（P-THP）通过增强的渗透和滞留（EPR）效应高度选择性地靶向肿瘤组织，并继而将活性吡柔比星分子迅速释放到肿瘤周围的酸性环境中。不过，后者在正常组织周围的非酸性环境中很少发生。这种机制有可能将包括心脏毒性在内的急性和慢性毒性降至最低，并通过与活性分子的肿瘤靶向积累协同作用以及可能的剂量递增来最大化化疗效果。在给定方案中简单地用P-THP替代多柔比星，可以改善对蒽环类药物敏感的儿童癌症的治疗效果，且几乎没有心脏毒性等不良反应风险。由于癌症是一种动态疾病，在病程中表现出肿瘤内异质性，持续并行开发细胞毒性药物和分子靶向药物对于找到可能更有效的治疗方法是必要的。
