Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma.
Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma.
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DOI：
10.1007/s00280-011-1623-y
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发表时间：
2011-12
影响因子：
3
通讯作者：
Adamson, Peter C.
中科院分区：
文献类型：
--
作者：
Norris, Robin E.;Minturn, Jane E.;Brodeur, Garrett M.;Maris, John M.;Adamson, Peter C.
Leadetinib（CEP-701）是一种多激酶抑制剂，对受体酪氨酸激酶的Trk家族具有强效活性，已在复发性神经母细胞瘤儿童中进行了早期临床评价。我们研究了CEP-701与异维甲酸（13 cRA）和芬维A胺（4 HPR）的相互作用，这两种维甲酸已在高危神经母细胞瘤儿童中进行了研究。在体外生长抑制进行了评估后，72小时的药物暴露使用磺酰罗丹明B（SR B）测定在8个神经母细胞瘤细胞系与变量Trk B表达。适当时，使用Chou-Talalay的组合指数（CI）来表征13 cRA（非恒定比率）或4 HPR（恒定比率）与CEP-701的相互作用。CEP-701单药在所有细胞系中的中位（范围）IC 50为0.09（0.08-0.3）μM。13 cRA和CEP-701的组合导致在所研究的五种细胞系中的四种中的加性到协同相互作用。添加1或5 μM 13 cRA使CEP-701 IC 50中位数（范围）分别降低1.5倍（1.1-2.8倍）和1.7倍（1.5-1.8倍）。在10 μM 13 cRA的情况下，当与各种浓度的CEP-701组合时，少于50%的细胞存活。4 HPR和CEP-701的组合倾向于拮抗，ED 50的中位（范围）CI为1.3（1.1-1.5）。13 cRA和CEP-701的组合在一系列神经母细胞瘤细胞系中具有相加或协同作用，这表明这些药物可以在高危神经母细胞瘤儿童强化放化疗后的微小残留疾病的背景下一起研究。
Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma. In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701. The median (range) IC50 of single-agent CEP-701 across all cell lines was 0.09 (0.08–0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC50 1.5-fold (1.1–2.8-fold) and 1.7-fold (1.5–1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED50 of 1.3 (1.1–1.5). The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.
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DOI：
10.1111/j.1749-6632.1999.tb09530.x
发表时间：
1999-01-01
期刊：
CELL AND MOLECULAR BIOLOGY OF PANCREATIC CARCINOMA: RECENT DEVELOPMENTS IN RESEARCH AND EXPERIMENTAL THERAPY
影响因子：
--
作者：
Miknyoczki, SJ;Dionne, CA;Ruggeri, BA
通讯作者：
Ruggeri, BA
影响因子：
64.8
作者：
THIELE, CJ;REYNOLDS, CP;ISRAEL, MA
通讯作者：
ISRAEL, MA
影响因子：
158.5
作者：
Matthay, KK;Villablanca, JG;Reynolds, CP
通讯作者：
Reynolds, CP
影响因子：
5.3
作者：
NAKAGAWARA, A;AZAR, CG;BRODEUR, GM
通讯作者：
BRODEUR, GM
影响因子：
20.3
作者：
Knapper, Steven;Burnett, Alan K.;Small, Donald
通讯作者：
Small, Donald