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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2392-2398.
Prepublished online as a Blood First Edition Paper on June 15, 2006; DOI 10.1182/blood-2006-03-007468.
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Submitted March 6, 2006
Accepted May 26, 2006
Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells
Kumudha Balakrishnan, Ramadevi Nimmanapalli, Farhad Ravandi, Michael J Keating, and Varsha Gandhi*
Experimental Therapeutics, M.D. Anderson Cancer Center
Leukemia,, M.D. Anderson Cancer Center
Leukemia,M.D. Anderson Cancer Center
Leukemia, M.D. Anderson Cancer Center
* Corresponding author; email: vgandhi{at}mdanderson.org.
Purine nucleoside phosphorylase (PNP) deficiency in humans results in T-lymphocytopenia. Forodesine, a potent inhibitor of PNP, was designed based on the transition-state structure stabilized by the enzyme. Previous studies established that forodesine in the presence of deoxyguanosine (dGuo) inhibits the proliferation of T-lymphocytes. A phase I clinical trial of forodesine in T-cell malignancies demonstrated significant antileukemic activity with an increase in intracellular dGuo triphosphate (dGTP). High accumulation of dGTP in T-cells may be dependant on the levels of deoxynucleoside kinases. Because B-cell chronic lymphocytic leukemia (B-CLL) cells have high activity of deoxycytidine kinase (dCK) we hypothesized that these lymphocytes would respond to forodesine. This postulate was tested in primary lymphocytes during in vitro investigations. Lymphocytes from 12 patients with CLL were incubated with forodesine and dGuo. These CLL cells showed a wide variation in the accumulation of intracellular dGTP without any effect on other deoxynucleotides. This was associated with DNA damage-induced p53 stabilization, phosphorylation of p53 at ser15, and activation of p21. The dGTP accumulation was related to induction of apoptosis measured by caspase activation, changes in mitochondrial membrane potential, and PARP cleavage. Based on these data a phase II clinical trial of forodesine has been initiated for CLL patients.
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