PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma.
PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma.
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DOI：
10.1016/j.isci.2021.103725
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发表时间：
2022-02-18
期刊：
影响因子：
5.8
通讯作者：
Kurmasheva RT
中科院分区：
文献类型：
--
作者：
Del Pozo V;Robles AJ;Fontaine SD;Liu Q;Michalek JE;Houghton PJ;Kurmasheva RT
目前的治疗是无效的复发性和转移性尤文肉瘤（EwS），由于耐药性的发展。大分子前药潜在地导致正常组织中较低的药物暴露和降低的毒性。我们使用常规试验或单小鼠试验（SMT）评估了聚乙二醇化talazoparib（PEG talazoparib TLZ）（一种PARP 1抑制剂）单独或与DNA烷化剂替莫唑胺（TMZ）联合治疗EwS和其他儿科肿瘤的疗效。单剂量的PEG化TLZ（第0天10 μmol/kg）与5次每日剂量的TMZ（从第3/4天开始40 mg/kg）组合产生最小的毒性，并且组合在EwS和胶质母细胞瘤模型中实现维持完全反应。SMT试验中PEG-吡格列酮TLZ和TMZ之间间隔3天，在EwS和其他异种移植物中产生了客观缓解。因此，在儿科实体瘤模型中，PEG化TLZ + TMZ表现出广泛的活性。此外，与游离TLZ组合相比，PEG-TLZ + TMZ的治疗窗增加。纳米颗粒配制的药物使药物诱导的毒性最小化PEG化TLZ增强TMZ在儿科肿瘤异种移植物中的体内活性每种药物给药之间的3天间隔拓宽了治疗窗PEG化TLZ的单次IV剂量有利于治疗婴儿/幼儿肿瘤学;药理学;分子医学;
Current therapy is ineffective for relapsed and metastatic Ewing sarcoma (EwS) owing to development of drug resistance. Macromolecular prodrugs potentially lead to lower drug exposure in normal tissues and reduced toxicity. We evaluated the efficacy of PEGylated talazoparib (PEG∼TLZ), a PARP1 inhibitor, alone or in combination with the DNA-alkylating agent temozolomide (TMZ) in EwS and other pediatric tumors using conventional testing or single-mouse trial (SMT). A single dose of PEG∼TLZ (10 μmol/kg on day 0) combined with 5 daily doses of TMZ (40 mg/kg starting on day 3/4) produced minimal toxicity, and the combination achieved maintained complete response in EwS and glioblastoma models. The SMT trial with the 3-day interval between PEG∼TLZ and TMZ resulted in objective responses in EwS and other xenografts. Thus, PEG∼TLZ + TMZ demonstrated a broad range of activity in pediatric solid tumor models. Furthermore, the therapeutic window of PEG∼TLZ + TMZ was enhanced compared with the free-TLZ combination. Nanoparticle-formulated drugs minimize drug-induced toxicity PEG∼TLZ enhances in vivo activity of TMZ in pediatric tumor xenografts A 3-day interval between each drug's administration widens the therapeutic window A single IV dose of PEG∼TLZ is advantageous for treating infants/young children Oncology; Pharmacology; Molecular medicine;
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影响因子：
11.2
作者：
Murphy B;Yin H;Maris JM;Kolb EA;Gorlick R;Reynolds CP;Kang MH;Keir ST;Kurmasheva RT;Dvorchik I;Wu J;Billups CA;Boateng N;Smith MA;Lock RB;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
6.7
作者：
Caster JM;Sethi M;Kowalczyk S;Wang E;Tian X;Nabeel Hyder S;Wagner KT;Zhang YA;Kapadia C;Man Au K;Wang AZ
通讯作者：
Wang AZ
DOI：
10.1016/s0360-3016(98)00191-6
发表时间：
1998-08-01
影响因子：
7
作者：
Donaldson, SS;Torrey, M;Shuster, JJ
通讯作者：
Shuster, JJ
影响因子：
1.8
作者：
Ferrari, S;Mercuri, M;Bacci, G
通讯作者：
Bacci, G
影响因子：
3
作者：
Fontaine, Shaun D.;Hann, Byron;Santi, Daniel. V.
通讯作者：
Santi, Daniel. V.