The effect of p53 dysfunction on purine analogue cytotoxicity in chronic lymphocytic leukaemia

Abstract

Summary. To clarify the role of p53 in the killing of chronic lymphocytic leukaemia (CLL) cells by purine analogues, we examined the cytotoxic effects of chlorodeoxyadenosine and udarabine on CLL cells that had been characterized according to their p53 functional status.Cases of CLL with p53 dysfunction (n 7) displayed slight, but signi®cant, resistance to nucleoside-induced cell killing when compared with cases with functionally intact p53 (n 12). The small difference between the two groups indicated that p53 plays a minor role in such killing.These ®ndings suggest that the poor therapeutic response to purine analogues observed in patients with p53 defects is likely to be caused by the emergence, on a background of genomic instability, of CLL-cell clones that are resistant to nucleoside-induced killing for reasons unrelated to p53.

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

“…These observations have been made in in-vitro experiments (Silber et al, 1994;Morabito et al, 1997;Pettitt et al, 1999b;Sturm et al, 2003), in retrospective clinical studies (el Rouby et al, 1993;Wattel et al, 1994;Dohner et al, 1995;Valganon et al, 2005) and most importantly in prospective clinical trials of first-line therapy (Catovsky et al, 2004;Gine et al, 2005;Stilgenbauer, 2005). In the light of these considerations, it is clear that one of the most pressing therapeutic challenges in CLL is to devise new and better ways of treating patients with p53 defects.…”

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

“…[180][181][182][183][184][185][186][187] Alterations in p53 function have been related to in vitro Leukemia resistance to NA. 68,188 p53 appears to have a specific role in resistance to NA since it possesses exonuclease activity, and may therefore be able to excise illegally DNA-incorporated NA. Recently, Feng et al reported that although the 3Ј-5Ј exonuclease of wild-type p53 (wt-p53) protein was able to bind and excise gemcitabine residues from DNA in vitro, removal of the drug molecules from cellular DNA was slow in sensitive cells containing wt-p53, and undetectable in drugresistant mut-p53 cells.…”

“…Incorporation of 2-CdATP into DNA by the repair machinery terminates the nucleotide excision repair process leading to the progressive accumulation of DNA single-strand breaks which eventually initiate apoptosis by p53-dependent or p53-independent pathways. 67,68 p53 activation subsequently regulates the levels of expression of p53-dependent proteins such as Bcl-2 and Bax leading to the activation of the caspase pathway. 69 Second, incorporation of 2-CdA into DNA may alter gene transcription with a consequent depletion of proteins required for cell survival.…”

Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells

“…Furthermore,¯udar-abine was found to be e cient in the treatment of chronic lymphoid leukaemia with low proliferative capacity, suggesting that it may also trigger apoptosis. In fact,¯udarabine induces the expression of the proapoptotic protein p53 (Chernova et al, 1995), and cells carrying an inactivating mutation of p53 have been reported to be resistant to¯udarabine (Pettitt et al, 1999;Thomas et al, 1996). Another possible target for¯udarabine is STAT1, a transcription factor that is involved in cellular responses to interferon (IFN).…”