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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4187-4193.
Prepublished online as a Blood First Edition Paper on September 5, 2006; DOI 10.1182/blood-2006-05-023259.
 Previous Article | Next Article 
Submitted November 29, 2005
Accepted July 14, 2006
Fludarabine increases oxaliplatin cytotoxicity in normal
and chronic lymphocytic leukemia lymphocytes by
suppressing interstrand DNA crosslink removal
Mazin A Moufarij, Deepa Sampath, Michael J Keating, and William Plunkett*
Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, TX, USA
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: wplunket{at}mdanderson.org.
Oxaliplatin and fludarabine have different but
potentially complementary mechanisms of action.
Previous studies have demonstrated that DNA repair is a
major target for fludarabine. We postulate that
potentiation of oxaliplatin toxicity by fludarabine
maybe due to the inhibition by fludarabine of the
activity of the DNA excision repair pathways activated
by oxaliplatin adducts. To test this, we investigated
the cytotoxic interactions between the two drugs in
normal and CLL lymphocytes. In each population, the
combination resulted in greater than additive killing.
Analysis of oxaliplatin damage revealed that fludarabine
enhanced accumulation of interstrand crosslinks (ICLs)
in specific regions of the genome in both populations,
but to a lesser extent in normal lymphocytes. The
action of fludarabine on the removal of oxaliplatin ICLs
was explored to investigate the mechanism by which
oxaliplatin toxicity was increased by fludarabine.
Lymphocytes from CLL patients have a greater capacity
for ICL unhooking compared to normal lymphocytes. In
the presence of fludarabine the extent of repair was
significantly reduced in both populations, more so in
CLL. Our findings support a role of fludarabine-
mediated DNA repair inhibition as a mechanism critical
for the cytotoxic synergy of the two drugs.
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