| Research theme | Inborn errors of purine and pyrimidine metabolism and biochemical aspects of pediatric oncological diseases |
|---|---|
| Principal Investigator | Dr. A.B.P. van Kuilenburg |
| Group members | Drs. R. Cuperus (PhD student) Drs. O.G. Besancon (PhD student) Ing. J. Meijer (technician) Ing. R. Meinsma (technician) Ing. R. Leen (technician) Ing. J. Hoebink (technician) Ing. A. Bramer (technician) |
Inborn errors of purine and pyrimidine metabolism are associated with a broad spectrum of clinical abnormalities. There is an increased awareness that pyrimidines play an important role in the regulation of the central nervous system and that metabolic changes affecting the levels of pyrimidines may lead to abnormal neurological activity. Patients with a defect in one of the enzymes of the pyrimidine degradation pathway often present with a neurological disorder. In addition, the same defects can lead to severe life-threatening toxicities when (partially) deficient individuals are treated with the pyrimidine analogue 5-fluorouracil. To date, the pathological mechanism underlying the various clinical abnormalities is not known. The main goal of our research is to elucidate the role of enzymes of purine and pyrimidine metabolism and the altered homeostasis of substrates and products in health and disease.
Neuroblastoma is the most common solid extracranial tumor in children. Unfortunately, the likelihood for survival for patients suffering from high risk neuroblastoma has not increased significantly over the last 15 years. Therefore; new and effective therapeutic strategies need to be developed. Fenretinide is a novel synthetic retinoic acid derivate which induces apoptosis in a variety of tumours but the precise underlying mechanism is not known. Furthermore, signal transduction pathways associated with cancer progression and chemotherapeutic resistance are increasingly being investigated as molecular targets of chemotherapy. There is now compelling evidence that the PI3K/Akt pathway plays an important role in regulating the bioavailability of key-proteins, such as N-myc in neuroblastoma. Therefore, PI3K inhibitors might increase the efficacy of chemotherapeutic drugs which are currently being used in the treatment of neuroblastoma.
Key publications
(1) Yaplito-Lee J, Pitt J, Meijer J, Zoetekouw L, Meinsma R, van Kuilenburg ABP. Beta-ureidopropionase deficiency presenting with congenital anomalies of the urogenital and colorectal systems. Mol Genet Metab, 93(2), 190-194, 2008.
(2) van Kuilenburg ABP, Meijer J, Mul ANPM, Hennekam RCM, Hoovers JMN, de Die-Smulders CEM, Weber P, Capone Mori A, Bierau J, Fowler B, Macke K, Sass JO, Meinsma R, Hennermann JB, Miny P, Zoetekouw L, Vijzelaar R, Nicolai J, Ylstra B, Rubio-Gozalbo ME. Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3). Hum Genet 125, 581-590, 2009.
(3) Cuperus R, Leen R, Tytgat GAM, Caron HN, van Kuilenburg ABP. Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma. Cell Mol Life Sci, 67, 807-816, 2010.
(4) van Kuilenburg ABP, Dobritzsch D, Meijer J, Meinsma R, Benoist JF, Assmann B, Schubert S, Hoffmann GF, Duran M, de Vries MC, Kurlemann G, Eyskens FJM, Greed L, Sass JO, Schwab KO, Sewell AC, Walter J, Hahn A, Zoetekouw L, Ribes A, Lind S, Hennekam RCM. Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. Biochim Biophys Acta 1802, 639-648, 2010.
(5) van Kuilenburg ABP, Meijer J, Mul AN, Meinsma R, Schmid V, Dobritzsch D, Hennekam RCM, Mannens MMAM, Kiechle M, Etienne-Grimaldi MC, Klümpen HJ, Maring JG, Derleyn VA, Maartense E, Milano G, Vijzelaar R, Gross E. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 128(5), 529-538, 2010.
