Summary
Seventeen patients with CLL were treated with oral 2-chloro-2′-deoxyadenosine (cladribine, CdA, 10 mg/m2) on 3 consecutive days and the pharmacokinetic parameters of CdA in patient plasma and its intracellular nucleotides (CdAMP, CdATP) in circulating leukemic cells were studied after the last dose intake and up to 72 h thereafter. The median terminal half life (t1/2) of CdA in plasma was 21.1 h and the area under the curve (AUC) was median 1.2 μMh. The median t1/2 was 14.6 h for CdAMP and 9.7 h for CdATP. The AUC of CdATP in leukemic cells is lower than the AUC of CdAMP (median ratio 0.60). There was no correlation between cellular CdATP and plasma CdA concentrations or dCK activity. The clinical response was related to higher Cmax values for plasma CdA (p=0.05) and higher products of dCK activity and CdA Cmax of plasma (p=0.02). The activity of dCK alone was not related to the clinical outcome in this patient group. The results suggest that further steps in the mechanism of action of CdA beyond its bioactivation may be more important, e.g. the extent of DNA fragmentation or the ability of the leukemic cell to go into apoptosis, than the concentration of CdA nucleotides alone.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Beutler, E., Sipe, J. C., Romine, J. S., Koziol, J. A., Mcmillan, R., and Zyroff, J. Proceedings of the National Academy of Sciences of the United States of America. 93: 1716–1720, 1996.
Piro, L. D., Ellison, D. J., and Saven, A, Leuk Lymph. 1: 121–5, 1994.
Carson, D. A., Wasson, D. B., Kaye, J., Ullman, B., Martin, D. J., Robins, R. K., and Montgomery, J. A. Proceedings of the National Academy of Sciences of the United States of America. 77: 6865–9, 1980.
Wang, L., Karlsson, A., Arner, E. S., and Eriksson, S. J Biol Chem. 268: 22847–52, 1993.
Talbot, D., Orr, R., Serafimowski, P., and Karrap, K. Proc. Am. Assoc. Cancer Res. 34: 305, 1993.
Albertioni, F., Reichelova, B., Pettersson, B., Eriksson, S., and Liliemark, J. Proc Annu Meet Am Assoc Cancer Res. 37: 316, 1996.
Arner, E. S., Spasokoukotskaja, T., Juliusson, G., Liliemark, J., and Eriksson, S. Br J Haematol. 87: 715–8, 1994.
Cheson, B. D., Bennett, J. M., Rai, K. R., Grever, M. R., Kay, N. E., Schiffer, C. A., Oken, M. M., Keating, M. J., Boldt, D. H., Kempin, S. J., and et, a. 1. Am J Hematol. 29: 152–63, 1988.
Albertioni, F., Pettersson, B., Reichelova, V., Juliusson, G., and Liliemark, J. Ther Drug Monit. 16: 413–8, 1994.
Reichelova, V., Albertioni, F., and Liliemark, J. J Chromatogr B: Biomed Appl. 682: 115–23, 1996.
Avery, T. L., Regh, J. E., Lumm, W. C., Harwood, F. C., Santana, V. M., and Baker, R. L. Cancer Res. 49: 4972–8, 1989.
Szondy, Z. Biochem J. 311: 585–8, 1995.
Mathews, C. K. Progress in Nucleic Acid Research & Molecular Biology. 44: 167–203, 1993.
Xu, Y. Z., Huang, P., and Plunkett, W. J Biol Chem. 270: 631–7, 1995.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Albertioni, F., Lindemalm, S., Eriksson, S., Juliusson, G., Liliemark, J. (1998). Relationship Between Cladribine (CDA) Plasma, Intracellular Cda-5′-Triphosphate (CDATP) Concentration, Deoxycytidine Kinase (DCK), and Chemotherapeutic Activity in Chronic Lymphocytic Leukemia (CLL). In: Griesmacher, A., Müller, M.M., Chiba, P. (eds) Purine and Pyrimidine Metabolism in Man IX. Advances in Experimental Medicine and Biology, vol 431. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5381-6_134
Download citation
DOI: https://doi.org/10.1007/978-1-4615-5381-6_134
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7456-5
Online ISBN: 978-1-4615-5381-6
eBook Packages: Springer Book Archive