A four-drug regimen, based on cell kinetic principles, induced complete remissions in 68 of 95 children (72%) with acute nonlymphocytic leukemia (ANLL). Patients entered remission after 2-5 weekly cycles of vincristine-daunorubicin (day 1) followed by sequential cytosine arabinoside and 6-azauridine (days 4-7). With continuation therapy of monthly vincristine-doxorubicin-cyclophosphamide, weekl...

To investigate the role of the Egr family of transcription regulatory factors in neuronal apoptosis, we examined the effect of a dominant negative Egr inhibitor construct in a well characterized in vitro paradigm, cerebellar granule cell death induced by withdrawal of depolarizing concentrations of extracellular potassium. We found that this apoptotic stimulus increases the activity of a report...

Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF-04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients...

Pretreatment of L5178Y murine leukemia cells with uracil arabinoside (ara-U) enhances the cytotoxicity of cytosine arabinoside (ara-C). This effect is mediated by the cytostatic effect of ara-U, which causes a delay of cell progression through S-phase. Consequently, the specific activity of enzymes that peak during S-phase increases, and deoxycytidine kinase increases 3.6-fold over untreated co...

We investigated the efficacy of dexamethasone plus diclofenac eye drops as prophylaxis for conjunctivitis induced by high-dose (HD) cytarabine (Ara-C). Sixty patients were randomized to receive either dexamethasone (group A, n=29) or dexamethasone plus diclofenac (group B, n=31). Conjunctivitis was experienced by 13/29 (45%) patients in group A, and 4/31 (13%) patients in group B (p<or=0.009). ...

In 14 patients with acute myeloid leukemia (AML) the plasma concentration of cytosine arabinoside (Ara-C) was determined at the start of the first course of treatment at various intervals after a bolus injection. In 10 patients plasma concentration/time data were fitted to a biexponential equation and pharmacokinetic parameters were estimated from the coefficient and exponents of such equations...

Adult neurogenesis in hippocampus is associated with behaviors such as learning. Hippocampus is involved in the regulation of prepulse inhibition (PPI), but the relationship between neurogenesis and PPI is unexplored. We conducted four experiments to determine the role of neural progenitor cell proliferation in PPI. Intracerebroventricular infusion of cytostatic cytosine arabinoside caused PPI ...

cells (4). Complete suppression of the secondary response to tetanus toxoid also was achieved in the rabbit (18). The pri mary and secondary responses in patients with neoplasia were inhibited completely, but often temporarily, by injections or infusions of ara-C (21). A high dose of ara-C, given 1 hour before injection of antigen, has been reported to produce anti body titers exceeding those o...

Patients with acute nonlymphocytic leukemia were randomized to receive remission induction therapy consisting of seven days of cytosine arabinoside and three days of daunorubicin ("7 + 3") or to receive the same regimen intensified by either the addition of 6-thioguanine or by extension of the administration of cytosine arabinoside to ten days. Additionally, all patients were randomized to rece...

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total...