Weitman S, Barrera H, Moore R, Gonzalez C, Marty J, Hilsenbeck S, MacDonald J R, Waters S J, Von Hoff D
Institute for Drug Development, San Antonio, Texas 78245, USA.
J Pediatr Hematol Oncol. 2000 Jul-Aug;22(4):306-14. doi: 10.1097/00043426-200007000-00006.
6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the mushroom toxin illudin S that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound. The studies were conducted to evaluate the antitumor activity of MGI 114 as a single agent and in combination with topotecan against pediatric solid tumor cell lines and xenograft models.
In vitro studies were designed to determine the cytotoxic potential of MGI 114 using the MTT assay and 13 pediatric tumor cell lines. In addition, combination in vitro studies were performed with MGI 114 and topotecan to generate isoeffect plots. Single agent and combination in vivo studies were also performed using MGI 114 against rhabdomyosarcoma and neuroblastoma xenograft models.
After a 1-hour exposure to MGI 114, the mean IC50 (+/-standard error of mean) for medulloblastoma, neuroblastoma, Ewing sarcoma/primitive neuroectodermal tumor, and rhabdomyosarcoma cell lines were 1.58+/-0.51, 1.60+/-0.82, 1.18+/-0.08, and 3.99+/-1.69 microg/mL, respectively. When tumor cells were exposed concurrently to MGI 114 and topotecan, evidence of synergy was observed in 10 of 12 (83%) cell lines. Single agent and combination in vivo studies with MGI 114 showed that this agent had substantial, and at times curative, antitumor activity against rhabdomyosarcoma and neuroblastoma xenograft tumors.
These data suggest that MGI 114 has significant efficacy as a single agent in preclinical studies against pediatric tumors. In addition, based on previous reports and the results presented here, combining MGI 114 with topotecan appears to be an attractive approach to the treatment of pediatric malignancies. After completion of the pediatric phase I studies of MGI 114, consideration should be given to phase II single agent and phase I combination studies with a topoisomerase I inhibitor such as topotecan or irinotecan.
6-羟甲基酰基富烯（HMAF；MGI 114；irofulven）是蘑菇毒素鬼笔环肽S的半合成类似物，已被证明是一种有效的细胞毒性剂，与其母体化合物相比，治疗指数有所提高。进行这些研究以评估MGI 114作为单一药物以及与拓扑替康联合使用对儿科实体瘤细胞系和异种移植模型的抗肿瘤活性。
体外研究旨在使用MTT法和13种儿科肿瘤细胞系来确定MGI 114的细胞毒性潜力。此外，进行了MGI 114与拓扑替康的体外联合研究以生成等效线图。还使用MGI 114对横纹肌肉瘤和神经母细胞瘤异种移植模型进行了单一药物和联合体内研究。
在暴露于MGI 114 1小时后，髓母细胞瘤、神经母细胞瘤、尤因肉瘤/原始神经外胚层肿瘤和横纹肌肉瘤细胞系的平均IC50（±平均标准误差）分别为1.58±0.51、1.60±0.82、1.18±0.08和3.99±1.69μg/mL。当肿瘤细胞同时暴露于MGI 114和拓扑替康时，在12个细胞系中的10个（83%）观察到协同作用的证据。MGI 114的单一药物和联合体内研究表明，该药物对横纹肌肉瘤和神经母细胞瘤异种移植肿瘤具有显著的，有时甚至是治愈性的抗肿瘤活性。
这些数据表明，在针对儿科肿瘤的临床前研究中，MGI 114作为单一药物具有显著疗效。此外，基于先前的报告和此处呈现的结果，将MGI 114与拓扑替康联合使用似乎是治疗儿科恶性肿瘤的一种有吸引力的方法。在完成MGI 114的儿科I期研究后，应考虑进行II期单一药物研究以及与拓扑异构酶I抑制剂（如拓扑替康或伊立替康）的I期联合研究。
