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3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

Triapine® is a potent ribonucleotide reductase (RR) inhibitor that depletes intracellular deoxyribonculeotide pools, especially dATP. We designed a Phase I trial of Triapine followed by the adenosine analog fludarabine in adults with refractory acute leukemias and aggressive myeloproliferative disorders (MPD). Two schedules were examined: A. Triapine 105mg/m 2 /day over 4 hours followed by fludarabine daily × 5 (24 patients, fludarabine 15-30 mg/m 2 /dose); B.To whom correspondence should be addressed: Judith E. Karp, MD, Sidney Kimmel Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB Room 289, Baltimore, Maryland 21231-1000, Phone: 410-502-7726, Fax: 410-614-1005.edu. Current affiliation:Yale University School of Medicine, New Haven, CT Current affiliation: Genentech, South San Francisco, CA Contributions: J.E. Karp contributed to concept and design; performed research; collected, interpreted and analyzed data; wrote the paper; provided intellectual content and provided study material/patients. F.J. Giles, I. Gojo, and L.E. Morris performed research; collected, interpreted and analyzed data; provided intellectual content; and provided study material/patients. J. Greer and M. Thein collected and/ or assembled data. M. Sznol contributed to concept and design and provided intellectual content. J. Low contributed to data analysis and provided intellectual content.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

Although there are structures of the different domains of human immunodeficiency virus type 1 (HIV-1) integrase (IN), there is no structure of the entire protein. The recently determined crystal structures of the prototype foamy virus (PFV) IN tetramer, in complexes with viral DNA, led to the generation of models of full-length HIV-1 IN. These models were generated, in part, by superimposing the structures of the domains of HIV-1 IN onto the structure of full-length PFV IN. We developed a model for HIV-1 IN-based solely on its sequence alignment with PFV IN-that differs in several ways from the previous models. Specifically, in our model, the junction between the catalytic core domain and C-terminal domain adopts a helix-loop-helix motif that is similar to the corresponding segment of PFV IN and differs from the crystal structures of these two HIV-1 IN domains. The alignment of residues in the C-terminal domain also differs from the previous models. Our model can be used to explain the phenotype of previously published HIV-1 IN mutants. We made additional mutants, and the behavior of these new mutants provides additional support for the model.

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