PNP Inhibitors and BCX-1777
BCX-1777, (1S)-1,4-dideoxy-1-C-( 4-hydroxypyrrolo[3,2-d] pyrimidin-7-yl)-1,4-imino-D-ribitol hydrochloride [1:1] is a transition state inhibitor of PNP. Inhibition of PNP results in elevated plasma 2'-deoxyguanosine (dGuo), which is converted to intracellular 2'-deoxyguanosine triphosphate (dGTP) in malignant T-cells and activated T-cells. dGTP induces cell death in these cell types.
BCX-1777 is being tested in several Phase I and Phase I/II studies. These include a Phase I/II study of intravenous BCX-1777 in refractory T-cell malignancies, a Phase I pharmacology study of BCX-1777 in refractory malignancies, a Phase I multi-center study of intravenous BCX-1777 in refractory hematologic malignancies, and a Phase I/II multi-center study of intravenous BCX-1777 in patients with refractory CTCL.
A New Study
The results of a new study entitled, "Intravenous and Oral Phamacokinetic and Pharmacodynamic Study of BCX-1777, a Novel Purine Nucleoside Phosphorylase Transition-State Inhibitor," are being presented. The work is the result of research conducted by John Michael Kilpatrick, Leigh Harman, Deborah Phillips, Jianwen Zhang, and Philip Morris, all from BioCryst Pharmaceuticals Inc., Birmingham, AL; Ronald Bukowski, from the Cleveland Clinic, Cleveland, OH; and Deborah Thomas at the M.D. Anderson Cancer Clinic, Houston, TX. The research associated with this study occurred at M.D. Anderson, Cleveland Clinic Foundation, University of Florida/Shands Hospital, University of Alabama at Birmingham, Mt. Sinai Hospital, Cornell/New York. Hospital, Tufts-New England Medical Center, and Duke University Medical Center. The authors will present their findings at the American Physiological Society's (APS) (www.the-aps.org) annual scientific conference, Experimental Biology 2003, being held April 17-21, 2004, at the Washington, D.C. Convention Center.
Methodology
This was a Phase I study, the first step in human testing of a new drug. These trials evaluate drug safety and toxicity at different dose levels in a small number of volunteers. This study consisted of intravenous five-day, twice daily dosing cycles, separated by two to four weeks in patients with cancer. The Phase I pharmacokinetic study (the movement of drugs throughout the body) consisted of a single oral dose after four to eight days of a single IV dose. This was followed by two days of IV dosing twice a day.
This investigation included a determination of drug pharmacokinetics and several markers related to drug activity or pharmacodynamics. These markers included plasma dGuo and inosine, erythrocyte PNP activity, and intracellular dGTP. BCX-1777, dGuo, and inosine were determined by high performance liquid chromatography coupled with mass spectrometry detection. PNP activity was monitored by enzymatic assay and cellular dGTP was determined by DNA polymerase assay.
Results
Intravenous IV administration of 10, 26, 40, 60, or 90 mg/m2 BCX-1777 to cancer patients results in a rapid elevation of plasma dGuo, going from ≤0.004 μM prior to dosing to 2.4—34 μM after dosing. In contrast, in normal rats, dogs, and primates the dGuo range was smaller (1.5-4.5 μM). The range of BCX-1777-dependent dGuo responses in cancer patients may be related to differences in the dGuo pools due to variation of cell turnover in these individuals. The plasma terminal half-life of BCX-1777 was 11.7 hr, but the half-life of the inhibition of erythrocyte PNP was much longer. In vitro experiments indicated that it might be as long as five days.
During and 7-10 days following the dosing periods, most treated patients have shown large and rapid increase in blood levels of deoxyguanosine, rapid accumulation of dGTP in leukemic T-cells, and a sharp drop in leukemic cell counts. Oral administration of 10 mg/m2 BCX-1777 solution to humans also produced an increase in plasma dGuo and inhibition of erythrocyte PNP with an apparent bioavailability of approximately 30 percent.
Conclusions
These preliminary data confirm the hypothesis that use of the PNP inhibitor BCX-1777 to elevate plasma dGuo results in elevation of cellular dGTP and a corresponding reduction of leukemic T-cells. An evaluation of the clinical efficacy is scheduled to be determined in several Phase II clinical trials. Additionally, these data support use of PNP inhibitors in treatment of other T-cell proliferative disorders, such as psoriasis and rhematoid arthritis.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 11,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
Editor's Note: For further information or to schedule an interview with a member of the research team, please contact Donna Krupa at 703-967-2751 (cell), 703-527-7357 (office) or at djkrupa1@aol.com. Or contact the APS newsroom at 202-249-4009 between 9:00 AM and 6:00 PM EDT April 17-21, 2004.