isotretinoin and Central-Nervous-System-Neoplasms

Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA.. Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples.. Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels.. We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Humans; Isotretinoin; Mice, Inbred BALB C; Microsomes; N-Myc Proto-Oncogene Protein; Neurites; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Receptors, Retinoic Acid; RNA, Messenger; Tandem Mass Spectrometry; Tretinoin

Successfully inducing differentiation in ectodermal diseases, retinoids harbour considerable therapeutic potential in the treatment of neuroectodermal-neuroepithelial malignancies. The principal tissue retinoid, retinoic acid, can be potently upregulated in vivo by a relatively specific catabolic inhibitor, R75251 (liarozole). Both substances have been given orally over 2 years in addition to standard treatment, and have been well tolerated. Corresponding closely to plasma retinoid levels, cutaneous side effects facilitate individual dosing. We evaluate this adjuvant retinoid approach and additional efforts to improve therapy of primary CNS malignancies, including the topical administration of retinoids in gamma linolenic acid.

Topics: Aged; Aged, 80 and over; Brain Neoplasms; Cell Differentiation; Central Nervous System Neoplasms; Combined Modality Therapy; Female; Glioblastoma; Humans; Imidazoles; Isotretinoin; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Retinoids; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Vitamin A