Torben Mikkelsen - Academia.edu (original) (raw)

Papers by Torben Mikkelsen

Cancers, 2021

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment o... more Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and th...

Pediatric Blood & Cancer, 2019

BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patient... more BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine best can be used as a predictor for severely delayed MTX elimination thus a guide for therapeutic interventions to minimize renal toxicity.

The Lancet Oncology, 2016

van der Sluis, Ester Zapotocka-on behalf of the Ponte di Legno toxicity working group. Affiliatio... more van der Sluis, Ester Zapotocka-on behalf of the Ponte di Legno toxicity working group. Affiliations: Supplemental material S1. Toxicity working group members: Webappendix.

American Journal of Medical Case Reports, 2015

Malignant melanoma in childhood and adolescence is rare but incidences have been seen to rise. Pr... more Malignant melanoma in childhood and adolescence is rare but incidences have been seen to rise. Prognostic factors, risk factors and prognosis have similarities to melanoma in adulthood but paediatric melanoma presents a diagnostic challenge as it often lacks the classical features of adult pigmented malignant melanoma and histologically is difficult to diagnose. This case report describes a clinically atypical presentation of melanoma on the thigh of a 16 month old boy. Initially seen at five months old by a dermatologist were a punch biopsy of the element was made with histological diagnosis; unusual congenital nevus. The element hereafter evolved and at the time of diagnosis measured 7.5 mm in Breslow thickness. Sentinel node biopsy and full body scans were made with no sign of metastasis. Like other cases reported, the melanoma did not exhibit the classical characteristics of the ABCD criteria which may have played a part in delaying diagnosis. Studies suggest that delayed diagnosis in children is not uncommon and younger patients present with more advanced disease at the time of diagnosis. To facilitate earlier recognition of melanoma in children additions to the conventional ABCD criteria have been suggested. This report illustrates that malignant melanoma should always be taken into consideration when presented with lesions of the skin and that a high level of clinical awareness and suspicion is required in order to hasten diagnosis and maybe improve prognosis in cutaneous malignant melanoma in children and adolescents.

Journal of Clinical Oncology, 2011

Purpose To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1... more Purpose To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m2) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG1-7) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes. Methods From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m2) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG1-7 in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells). Results The 24-hour infusion resulted in significantly higher amounts of MTXPG1-7 in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/109 cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect...

Genome Research, 2011

Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic... more Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic leukemia (ALL). Inter-individual variation in clearance of methotrexate results in heterogeneous systemic exposure, clinical efficacy, and toxicity. In a genome-wide association study of children with ALL, we identified SLCO1B1 as harboring multiple common polymorphisms associated with methotrexate clearance. The extent of influence of rare versus common variants on pharmacogenomic phenotypes remains largely unexplored. We tested the hypothesis that rare variants in SLCO1B1 could affect methotrexate clearance and compared the influence of common versus rare variants in addition to clinical covariates on clearance. From deep resequencing of SLCO1B1 exons in 699 children, we identified 93 SNPs, 15 of which were non-synonymous (NS). Three of these NS SNPs were common, with a minor allele frequency (MAF) >5%, one had low frequency (MAF 1%–5%), and 11 were rare (MAF <1%). NS SNPs (comm...

Drug Resistance Updates, 2012

Members of the solute carrier family of transporters are responsible for the cellular uptake of a... more Members of the solute carrier family of transporters are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. Several of these solute carriers are known to be expressed in cancer cells or cancer cell lines, and decreased cellular uptake of drugs potentially contributes to the development of resistance. As result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. In this review article, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of solute carriers to anticancer drug uptake in tumors, the role of these carriers in regulation of anticancer drug disposition, and recent advances in attempts to evaluate these proteins as therapeutic targets.

Clinical Cancer Research, 2012

Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the ... more Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrela...

Pharmacogenetics and Genomics, 2011

CYP2J2 is a member of the cytochrome P450 (CYP) family of monooxygenases, and, in humans, is the ... more CYP2J2 is a member of the cytochrome P450 (CYP) family of monooxygenases, and, in humans, is the sole member of the CYP2J subfamily [1]. Specifically, CYP2J2 is an epoxygenasethat catalyzes epoxideformation at thesite of a carbon-carbon double bond in the substrate, as other CYP epoxygenases do, such as CYP2C8 and CYP2C9 [2]. The therapeutic agents ebastine [3], astemizole, terfenadine, diclofenac, and bufurarol are metabolized by CYP2J2 [4]. A recent study, screening 139 marketed therapeutic agents and compounds, have identified albendazole, amiodarone, cyclosporine A, danazol, mesoridazine, nabumetone, tamoxifen, and thioridazine as CYP2J2 substrates [5]. These findings show the ability of CYP2J2 to metabolize structurally diverse compounds. The substrates identified for CYP2J2 were also metabolized by CYP3A4, but with differences in regioselectivity [5]. For large compounds, CYP2J2 metabolism was more restricted to a single site, compared with CYP3A4, which metabolized substrates at multiple sites [5]. A study of microsomes from human livers and human small intestines investigated the metabolism of astemizole by CYP2J2 [6]. This study found that the CYP2J2 substrates arachidonic acid (AA) and ebastine strongly inhibited astemizole O-demethylation in microsomes from human small intestines and in in-vitro experiments with recombinant CYP2J2 [6]. A follow-up study found an inhibition of α-naphthoflavone, ketoconazole, troglitazone, tranylcypromine, ebastine, and terfenadine on the rate of astemizole Odemethylation in human small intestinal microsomes and on the rate of astemizole Odemethylation in recombinant CYP2J2 microsomes [7]. AA and linoleic acid (LA) are endogenous substrates of CYP2J2 [2,8]. CYP epoxygenases catalyze the metabolism of AA to four regioisomeric epoxyeicosatrienoic acids (EETs): 14,15-EET, 11,12-EET, 5,6-EET, and 8,9-EET [9]. EETs have been shown to possess many biologically relevant properties, such as inducing membrane hyperpolarization and vasodilation, reducing inflammation by inhibition of transcription factor nuclear factor-κB, and increasing fibrinolytic activity (reviewed in [10]). CYP2J2-derived EETs have been

Clinical pharmacology and therapeutics, 2009

Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The... more Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from severe cisplatin-induced renal tubular damage. Subsequently, we found that a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene SLC22A2 (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients. Collectively, these results indicate the critical importance of OCT2 in the renal handling and related renal toxicity of cisplatin and pr...