A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders

Abstract

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

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

“…3-AP, however, may be useful as an anticancer agent in combination with other treatment modalities, such as radiation [39], or in the treatment of advanced hematologic malignancies [40,41]. …”

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

“…16 On the basis of these data, we conducted a phase I clinical trial of triapine followed by escalating doses of fludarabine in adults with relapsed and refractory acute leukemias, high-risk myelodysplastic syndrome, or transformed MPN including CMML. 31 We tested two schedules: schedule A, consisting of daily doses of triapine at 105 mg/m 2 over 4 h for 5 days followed by a 30-min infusion of fludarabine within 1 h of completion of triapine, and schedule B, consisting of triapine at 200 mg/m 2 over 24 h followed by fludarabine for 5 days. There were no dose-limiting toxicities in this study; however, the dose of fludarabine (30 mg/m 2 daily) was not further escalated due to concern about neurotoxicity.…”

Synthesis and Anticancer Evaluation of Benzyloxyurea Derivatives

“…Crucial for rapidly dividing cells, RR is an attractive therapeutic target of cancer, and over the past years, many chemotherapeutics inhibiting different subunits of RR have been developed and tested clinically for their anticancer activities and anti-HIV activities. [10][11][12][13] HU is the first RR inhibitor applied to the clinic, and is utilized for the therapeutic of neoplasms because of its influences on the DNA replication of cancer cells. 1,14) To overcome the drawbacks of HU, numerous medicinal chemistry efforts have been made to design and synthesize novel HU derivatives.…”