NCI 比较肿瘤学计划在自然发生的犬淋巴瘤中测试非喜树碱类吲哚喹啉拓扑异构酶 I 抑制剂。
NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.
机构信息
School of Veterinary Medicine, University of California Davis, Davis, California.
Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
出版信息
Clin Cancer Res. 2018 Dec 1;24(23):5830-5840. doi: 10.1158/1078-0432.CCR-18-1498. Epub 2018 Jul 30.
PURPOSE
Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.
EXPERIMENTAL DESIGN
Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.
RESULTS
The MTDs were 17.5 mg/m for LMP 776 and 100 mg/m for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744.
CONCLUSIONS
These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
目的
唯一被美国食品药品监督管理局（FDA）批准的拓扑异构酶 I（TOP1）抑制剂为喜树碱类，伊立替康和拓扑替康被广泛应用。由于其具有局限性（化学不稳定性、药物外排介导的耐药性和腹泻），因此需要新型 TOP1 抑制剂。非喜树碱类拓扑异构酶 I（TOP1）抑制剂可克服限制喜树碱使用的化学不稳定性和耐药性。在一项针对患有淋巴瘤的犬的 I 期研究中，对三种哚异喹啉类药物 LMP400（依替康）、LMP776（英地美替康）和 LMP744 进行了研究，以评估其疗效、药效学、毒理学和药代动力学的差异。
实验设计
84 只患有淋巴瘤的宠物犬被纳入每个哚异喹啉类药物的剂量递增队列中，LMP744 则进行了扩展阶段。确定了疗效、耐受性、药代动力学和靶点结合情况。
结果
LMP776 的最大耐受剂量（MTD）为 17.5mg/m，LMP744 的 MTD 为 100mg/m，骨髓毒性为剂量限制性毒性；高达 65mg/m 的 LMP400 耐受性良好，且未达到 MTD。这些药物均未引起明显腹泻。LMP744 可观察到肿瘤持续积聚；治疗后 2 小时和 6 小时可观察到 γH2AX 诱导；在所有化合物和剂量水平下，大多数淋巴瘤样本中都观察到 TOP1 蛋白减少，这与在低剂量 LMP744 时也观察到肿瘤反应的事实一致。所有哚异喹啉类药物均记录到客观缓解；LMP744 的疗效（19 只犬中有 13 只）最高。
结论
这些结果证明了哚异喹啉类 TOP1 抑制剂的作用机制，支持其进一步的临床开发。它们还强调了 NCI 比较肿瘤学计划（https://ccr.cancer.gov/Comparative-Oncology-Program）在评估免疫功能正常的宠物癌症新型治疗方法中的价值。
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