Identification of 24-Hydroxylase Polymorphisms and Splicing Variants That Modulate Vitamin D Oxidative Metabolism and Serum Pharmacokinetics in Patients With Colorectal Cancer on Cholecalciferol Therapy
- To identify CYP24 single nucleotide polymorphisms (SNPs) using peripheral blood
mononuclear cell genomic DNA from patients with colorectal cancer receiving
- To evaluate the effects of these CYP24 SNPs on baseline serum vitamin D_3 metabolites
(25-D_3, 24,25-D_3, and 1,25-D_3), and parathyroid hormone levels (PTH).
- To evaluate the effects of these CYP24 SNPs on serum vitamin D_3 metabolites and PTH
levels during cholecalciferol treatment.
- To examine CYP24 splicing, protein expression, and enzyme activity at baseline and
during cholecalciferol treatment.
- To determine the relationship, if any, between serum cholecalciferol pharmacokinetic
parameters and CYP24 SNPs, splicing variants, and enzyme activity.
OUTLINE: Patients receive oral cholecalciferol 2000 IU once daily for 1 year. Patients
without response to vitamin D supplementation (serum 25-D_3 level < 32 ng/mL) by 6 months
will have their cholecalciferol dose increased to 4000 IU once daily.
Blood is collected at baseline and on days 14, 30, 60, 90, 180, 270, and 360. Peripheral
blood mononuclear cells for CYP24 genotyping, protein expression, enzyme activity, and
splicing variants are analyzed by polymerase chain reaction (PCR), western blot, high
performance liquid chromatography, and reverse transcriptase PCR, respectively. Serum is
analyzed for vitamin D_3 metabolite levels (by radioimmunoassay), calcium (to monitor for
hypercalcemia), and parathyroid hormone assays (to measure vitamin D effect).
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care
Identification of CYP24 single nucleotide polymorphisms (SNPs)
Baseline, days 14, 30, 60, 90, 180, 270, 360
Marwan Fakih, MD
Roswell Park Cancer Institute
United States: Food and Drug Administration
|Roswell Park Cancer Institute||Buffalo, New York 14263|