We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice.
The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-RbSer795), suggesting DFMO/probenecid-induced cell cycle arrest.
Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.
我们进行了体内药代动力学(PK),抗肿瘤性,以及在小鼠中使用NB患者衍生的异种移植物(PDX)进行DFMO/丙磺舒的分子研究。我们使用LC-MS/MS,HPLC,免疫印迹分析血液,脑组织,和从小鼠收集的PDX肿瘤组织样品。
有机阴离子转运1/3(OAT1/3)抑制剂丙磺舒可降低DFMO的肾脏清除率,并显着增加DFMO在NBPDX中的抗肿瘤活性(P<0.02)。切除的肿瘤显示DFMO/丙磺舒治疗减少多胺腐胺和亚精胺,降低MYCN蛋白水平和去磷酸化视网膜母细胞瘤(Rb)蛋白(p-RbSer795),提示DFMO/丙磺舒诱导的细胞周期阻滞。
向DFMO治疗中添加丙磺舒作为佐剂可能适合于降低总剂量并改善体内药物功效。