sodium-bicarbonate and Leukemia

Hyperleukocytosis secondary to acute leukemia is a medical emergency. Intracranial hemorrhage often leads to death in this setting. Early efforts to prevent this serious complication have included emergent cranial irradiation, with its associated morbidity when used in the young child. Currently, exchange transfusion and/or leukapheresis are employed to acutely lower the peripheral leukocyte count.. We report three infants with acute leukemia and hyperleukocytosis in whom intravenous hydration, alkalinization, and allopurinol therapy alone produced rapid and dramatic decreases in the peripheral leukocyte count.. The maximal decrease in leukocyte count averaged 88% within 70 h of starting conservative management. A fall in leukocyte count to < 100 x 10(9)/L was noted at an average of 15 h following hospitalization. No patient developed complications.. When comparing this approach to exchange transfusion and leukapheresis we find it to be both safe and effective. Children with hyperleukocytosis in association with acute lymphocytic leukemia who present without life-threatening complications of an extremely high leukocyte count can be safely and effectively managed with intravenous hydration, alkalinization, and allopurinol therapy.

Topics: Allopurinol; Bicarbonates; Female; Fluid Therapy; Humans; Infant; Leukemia; Leukocytosis; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sodium; Sodium Bicarbonate

A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L-dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors.

Topics: Antineoplastic Agents; Aspartic Acid; Biphenyl Compounds; Breast Neoplasms; Carbolines; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Colonic Neoplasms; Dihydroorotate Dehydrogenase; Enzyme Inhibitors; Female; Humans; Kidney Neoplasms; Kinetics; Leukemia; Lung Neoplasms; Male; Melanoma; Mitochondria; Orotic Acid; Ovarian Neoplasms; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Prostatic Neoplasms; Ribonucleotides; Sodium Bicarbonate; Software; Tumor Cells, Cultured

Topics: Animals; Carbon; Carbon Radioisotopes; Death; Leukemia; Mice; Sodium Bicarbonate