4.4 Article

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma

期刊

CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 88, 期 4, 页码 607-617

出版社

SPRINGER
DOI: 10.1007/s00280-021-04309-y

关键词

Probenecid; DFMO; Eflornithine; Repurposing drugs; Pediatric cancer; Renal drug clearance; Pharmacokinetics

资金

  1. St. Baldrick's Foundation [591704]

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The study examined the use of DFMO/probenecid in NB patient-derived xenografts in mice and found that probenecid, an OAT 1/3 inhibitor, reduced DFMO renal clearance and significantly increased its antitumor activity. The combination of probenecid as an adjuvant to DFMO therapy may decrease overall dose and improve drug efficacy in vivo.
Background Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor alpha-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment. Methods 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. Results 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-Rb-Ser795), suggesting DFMO/probenecid-induced cell cycle arrest. Conclusion Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.

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