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Pediatric oncology. folate metabolism. anti-folates. clinical pharmacology and drug developmentFolate is a vitamin required for synthesis of nucleic acids and some amino acids. It is so critical in normal cell development. that on the surface. there is a medical paradox. A folate deficiency leads to abnormal methylation of DNA bases and/or fraudulent bases incorporated into DNA (e.g. deoxyuridine for thymidine) as well as increases in a toxic amino acid. homocysteine. Thus. a folate deficiency is associated with increased for cancer and there are chemoprevention trials in progress to determine the protective effects of supplemental folate. As an aside. the importance of adequate folate is also associated with normal development. i.e. a folate deficiency is causative in increased risk for neural tube defects. These birth defects may also be related to endothelial damage associated with increased homocysteine. However. the importance of folate in cell replication is so critical. that interfering with folate metabolism or folate-mediated reactions have proved successful as anti-neoplastic and anti-microbial agents. In other words. to prevent cancer. take folate. but if you develop cancer. take anti-folates. The goal of our work is to more completely understand folate homeostasis and as noted earlier. our theme is to relate normal. physiological folate metabolism to the pharmacology of anti-folates. This will allow us to increase the efficacy of treatment by identifying mechanisms of toxicity and/or resistance to the drugs. Our basic and clinical studies are interrelated. The laboratory is "driven" by questions we defined at the bedside and the bedside (patients) will hopefully benefit by clinical protocols based upon the laboratory results. Examples of our translational work include the use of dextromethorphan as a treatment and prevention of methotrexate neurotoxicity and the use of aminopterin in patients with relapsed leukemia and high risk leukemia at diagnosis. We are currently studying the basic cell biology of the folate receptor. a GPI anchored protein with increased expression in selected normal cells (choroid plexus epithelial cells. proximal tubule of kidneys and placenta) and markedly overexpressed in many carcinomas. These studies have implications for using the receptor as a marker (imaging) as well as a target for delivery of cytotoxic agents. Selected PublicationsCole PD, Drachtman RA, Masterson M, Smith AK, Glod J, Zebala JA, Lisi S, Drapala DA, Kamen BA. (2008) Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 62(1):65-75. Cole PD, Drachtman RA, Masterson M, Smith AK, Glod J, Zebala JA, Lisi S, Drapala DA, Kamen BA. (2008) Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 62(1):65-75. Kamen BA, Strair R. (2007) What is learned from an acronym? Convergence of treatments and/or diseases? J Pediatr Hematol Oncol. 29(5):277-8. Kamen BA. (2007) Megadose methylprednisolone therapy: 2 decades of experience and empiric success in need of explanation, validation, and exploitation. J Pediatr Hematol Oncol. Apr;29(4):211-2. Cole PD, Kamen BA. (2006) Delayed neurotoxicity associated with therapy for children with acute lymphoblastic leukemia. Ment Retard Dev Disabil Res Rev. 12(3):174-83. Review. Kamen BA. (2006) Marker turned target? A case to review neprilysin in ALL (or lessons learned at the American Association for Cancer Research Meetings. 2006). J Pediatr Hematol Oncol. 28(4):201-2. Cole PD. Drachtman RA. Smith AK. Cate S. Larson RA. Hawkins DS. Holcenberg J. Kelly K. Kamen BA. (2005) Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res. 11(22):8089-96. Kamen BA. Metronomic therapy: it makes sense and is patient friendly. J Pediatr Hematol Oncol. (2005) 27(11):571-2. Hochhauser CJ. Lewis M. Kamen BA. Cole PD. (2005) Steroid-induced alterations of mood and behavior in children during treatment for acute lymphoblastic leukemia. Support Care Cancer. 13(12):967-74. Cole PD. Alcaraz MJ. Smith AK. Tan J. Kamen BA. (2006) Pharmacodynamic properties of methotrexate and Aminotrexate during weekly therapy. Cancer Chemother Pharmacol. 57(6):826-34. Kamen BA. (2005) Food for thought: homage to a versatile vitamin: lessons learned from nature and your mother "eat your spinach!". J Pediatr Hematol Oncol. 27(7):347-8. Mantadakis E. Cole PD. Kamen BA. (2005) High-dose methotrexate in acute lymphoblastic leukemia: where is the evidence for its continued use? Pharmacotherapy. 25(5):748-55. Kamen BA. (2005) L-asparaginase: old dog. more tricks and leukemia: not simply a liquid tumor. J Pediatr Hematol Oncol. 27(5):243. Kamen BA. (2005) Prologue to ignorance is the greatest risk. J Pediatr Hematol Oncol. 27(3):121. Kamen BA. (2005) In the future: when is a rose is a rose is a rose? J Pediatr Hematol Oncol. 27(1):1-2. Kamen BA. Glod J. (2004) What is the price of an erythrocyte and neutrophil? J Pediatr Hematol Oncol. 26(11):699-700. Kerbel RS. Kamen BA. (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 4(6):423-36. Review. Kamen BA. (2004) High-dose methotrexate and asparaginase for the treatment of children with acute lymphoblastic leukemia: why and how? J Pediatr Hematol Oncol. 26(6):333-5. Kamen BA. Smith AK. (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 56(8):1085-97. Kamen BA. (2004) A tribute to and celebration of life. J Pediatr Hematol Oncol. 26(4):215-6. Kaufman Y. Drori S. Cole PD. Kamen BA. Sirota J. Ifergan I. Weyl Ben Arush M. Elhasid R. Sahar D. Kaspers GJL. Jansen G. Matherly LH. Rechavi G. Toren A. Assaraf YG. (2004). Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia. Cancer 100: 773-782. Kamen BA. Smith AK. (2004). A review of folate receptor alpha cycling and 5-methyltetra-hydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 56:1085-97. Bostrom BC. Erdmann GR and Kamen BA. (2003). Systemic Methotrexate exposure Is greater after intrathecal vs. oral administration. J Ped Hem Oncol 25:114-117. Winter-Vann AM. Kamen BA. Bergo MO. Young SG. Melnyk S. James SJ and Casey PJ. (2003). Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate. Proc Nat Acad Sci 100:6529-6534. Frost P and Kamen BA. (2003). The bullseye of cancer therapy: a moving target. Current Opinions in Pharmacology 3:335-337. DiPaola R. Durivage H and Kamen BA. (2003). High time for low dose prospective clinical trials. Cancer 98:1559-1561. Cole. PD and Kamen BA. (2003). "Beriberi" interesting! J Pediatr Hematol Oncol 25:924-6. |
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