P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models.
We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4-HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (p ≥ 0.06). Ketoconazole increased intratumoral levels of 4-HPR (p = 0.02), of the active 4-oxo-4-HPR metabolite (p = 0.04), and intratumoral apoptosis (p ≤ 0.0006), compared to 4-HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (p ≤ 0.008). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (p ≤ 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma.
Cancer Center and Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430.
Lluis
L
Lopez-Barcons
Cancer Center and Departments of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430.
Barry J
BJ
Maurer
Cancer Center and Departments of Cell Biology and Biochemistry, Internal Medicine, and Pharmacology/Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430.
Min H
MH
Kang
Cancer Center and Departments of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430.
C Patrick
0000-0002-2827-8536
CP
Reynolds
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004357:Drug Synergism; D017313:Fenretinide / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D017313:Fenretinide; D007654:Ketoconazole
4-oxo-4-HPR; fenretinide; ketoconazole; neuroblastoma