Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma
Chad R Schultz1, Matthew A Swanson2, Thomas C Dowling3
1Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 400 Monroe Ave, NW, Grand Rapids, MI, 49503, USA.
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 α-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-RbSer795), 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.
Insights
Combining probenecid with DFMO (eflornithine) reduces kidney clearance and enhances anti-neuroblastoma effects. This combination therapy may allow for lower doses and improved efficacy in treating this common childhood cancer.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Neuroblastoma (NB) is a common pediatric extracranial solid tumor.
- Inhibiting MYCN-activated ornithine decarboxylase (ODC) via DFMO (eflornithine) is a validated therapeutic strategy.
- DFMO faces challenges due to rapid renal clearance, necessitating frequent high dosing.
Purpose of the Study:
- To evaluate the in vivo efficacy of combining DFMO with probenecid in neuroblastoma.
- To assess pharmacokinetic and antitumorigenic effects in patient-derived xenografts (PDX).
Main Methods:
- In vivo studies using NB patient-derived xenografts (PDX) in mice.
- Analysis of blood, brain, and tumor tissues using LC-MS/MS, HPLC, and immunoblotting.
- Pharmacokinetic (PK) and molecular analyses of DFMO/probenecid treatment.
Main Results:
- Probenecid, an OAT 1/3 inhibitor, significantly reduced DFMO renal clearance and enhanced its antitumor activity in NB PDX (P < 0.02).
- DFMO/probenecid treatment decreased polyamine levels (putrescine, spermidine), reduced MYCN protein, and dephosphorylated Rb protein (p-RbSer795).
- These molecular changes suggest DFMO/probenecid induces cell cycle arrest in neuroblastoma.
Conclusions:
- Probenecid addition to DFMO therapy can decrease the required drug dose.
- Combining DFMO with probenecid shows potential for improved in vivo efficacy in neuroblastoma treatment.
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