Quite recently, several new nucleoside analogues have been added to the anti-cancer arsenal: Gemcitabine, fludarabine, cladribine, ara G, and clofarabine (the structures of these compounds are in the appendix). Of these, ara G and clofarabine are effective in treating childhood leukemia.
Ara G
Ara G differs from ara C in the base moiety of the nucleoside. In the 1980s, while studying PNP (purine nucleoside phosphorylase) deficiencies, scientists discovered that in T-cells (but not B-cells), people who had a PNP deficiency built up dGTP to levels that killed the T-cells. The researchers thought to try ara G in T-cells in tissue culture and found that ara G did kill T-cells (but not B-cells). Eventually ara G was tested in animal and then human trials and found to be effective against T-cell leukemia.
The compound ara G is not the actual drug that is given patients. Instead, a prodrug named Nelarabine (or Compound 506U78) is administered. A prodrug is a compound that is converted to the active form inside the cell. Nelarabine is "2-amino-9-B-D-arabinofuranosyl-6-methoxy-9H-purine". Inside cells, it is converted to ara G. The ara G is phosphorylated to form ara GTP, which accumulates in the cell and acts to terminate DNA synthesis, causing the cell to die. One research group believes that ara G causes enhancement of apoptosis. [21-24]
COG is testing ara G/Nelarabine in a phase I clinical trial for T-cell childhood ALL. This trial is designated AALL00P2.
9/2005: FDA Advisory Committee Recommends Accelerated Approval of GlaxoSmithKline's Arranon (nelarabine) Injection - Orphan Drug Under Review for Children and Adults with T-cell Acute Lymphoblastic Leukemia (T-ALL) and T-cell Lymphoblastic Lymphoma (T-LBL).
10/2005: Another drug that works on the PNP pathway is entering the pipeline. It is named Fodosine TM, and is an analogue of GTP.
Clofarabine
Clofarabine was designed to incorporate the favorable properties of both fludarabine and cladribine. It differs from other nucleoside analogues in that it has 2 halogen atoms (fluorine and chlorine) in its structure. It has as the sugar not exactly arabinose, but arabinose with a fluorine molecule substituted for one of the -OH groups. The chlorine atom is on the base (adenine - so it’s an adenosine analogue). Clofarabine is also called Clolar or Ilex; the chemical name is 2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine.
The exciting news about clofarabine is that it shows promising results in bringing remission to children with refractory or relapsed ALL. In February of 2005, clofarabine was approved by the FDA as a treatment for childhood ALL (HemOnc Today). The approval was based on results of a phase II trial of 49 children with relapsed or refractory ALL [25, link to online abstract]. It was given Orphan Drug Designation for ALL in 2002.
The FDA/dockets web site has a technical, long, and complete discussion of the development of clofarabine from conception to manufacture through clinical trials and their results.
Fludarabine and cladribine are both ribonucleotide reductase (RnR) inhibitors. According to Jorge Cortes (MedScape article, you might have to log on to MedScape to view it), clofarabine is also a RnR inhibitor, but it works better because it "was engineered specifically to overcome the mechanisms of resistance, so, for example, it is insensitive to deamination by having a fluoride in the arabinoside molecule. Then we have a chloride that makes it insensitive to the purine nucleotide phosphorylase-2." [26, 27]
Corey et al report in March 2005 the complete remission following clofarabine treatment of a child with refractory JMML. This child had a stem cell transplant, relapsed, another transplant, relapsed again, they tried tipifarnib, didn’t work, then tried clofarabine for three 5-day courses and he went into remission. [28]
Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. S Jeha, PS Gaynon, BI Razzouk, J Franklin, R Kadota, V Shen, L Luchtman-Jones, M Rytting, LR Bomgaars, S Rheingold, K Ritchey, E Albano, RJ Arceci, S Goldman, T Griffin, A Altman, B Gordon, L Steinherz, S Weitman, and P Steinherz. J. Clin. Oncol., April 20, 2006; 24(12): 1917-23. Abstract.
May 2006: the European Commission granted marketing authorization for clofarabine (Evoltra, made by Bioenvision, Inc) for the treatment of relapsed or refractory pediatric ALL.
The Spring 2005 Candlelighters Newsletter has an article on Clolar/Clofarabine.
Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Stefan Faderl, Varsha Gandhi, Susan O'Brien, Peter Bonate, Jorge Cortes, Elihu Estey, Miloslav Beran, William Wierda, Guillermo Garcia-Manero, Alessandra Ferrajoli, Zeev Estrov, Francis J. Giles, Min Du, Monica Kwari, Michael Keating, William Plunkett, and Hagop Kantarjian. Blood, 1 February 2005, Vol. 105, No. 3, pp. 940-947. Abstract.
Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Justin P Kline & ?Richard A Larson. Expert Opinion on Pharmacotherapy. December 2005, Vol. 6, No. 15, Pages 2711-2718. Abstract.
This ends the current discussion of drugs inspired by spongethymidine. If and when new analogues come to my attention, I'll add them to this article.
Patty, April 2005