Imatinib sensitizes CLL lymphocytes to chlorambucil

Abstract

The effect of imatinib on chlorambucil (CLB) cytotoxicity in chronic lymphocytic leukemia (CLL) lymphocytes was examined in vitro. Imatinib sensitizes the WSU and I83 human CLL cell lines, 10-and two-fold, respectively, to CLB. Furthermore, in primary cultures of malignant B-lymphocytes obtained from 12 patients with CLL (seven patients were untreated and five treated with CLB), imatinib synergistically sensitized these lymphocytes from two-to 20-fold to CLB. This synergistic effect was observed at concentrations of imatinib (p10 lM), which are achievable in patients with minimal toxicity. Moreover, the combination of both drugs results in increased apoptosis in CLL cell lines. These results suggest that imatinib should be useful in improving the therapeutic index of CLB in CLL. The mechanism of action appears to involve imatinib inhibition of c-abl kinase activity with an associated decrease in CLB-induced Rad51 phosphorylation and CLB-induced Rad51 nuclear foci, suggesting that imatinib decreases Rad51-related DNA repair of CLB-induced DNA lesions. Altogether, our results suggest that imatinib is a promising adjuvant therapy to CLB treatment of CLL.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

“…Preclinical evidence suggests that imatinib may enhance chemosensitivity by several possible mechanisms, including decreasing interstitial fluid pressure (Heuchel et al, 1999;Pietras et al, 2001Pietras et al, , 2002Pietras et al, , 2003Ostman, 2004), decreasing angiogenesis (Bergers et al, 2003;Dudley et al, 2003;Hwang et al, 2003;Uehara et al, 2003;Apte et al, 2004;Pietras and Hanahan, 2005), and by affecting DNA repair mechanisms (Aloyz et al, 2004), stromal chemokines (Ostman, 2004), and multidrug transporter activity (Houghton et al, 2004;Ozvegy-Laczka et al, 2004). However, the uptake and distribution of imatinib in the brain is limited by P-gp/BCRP-mediated efflux (Dai et al, 2003), suggesting that combination regimens with imatinib may be more effective than imatinib monotherapy.…”

Imatinib induces apoptosis in CLL lymphocytes with high expression of Par-4

“…6 In conclusion, these results support the notion that Imatinib applied in clinically achievable concentrations may sensitize The interesting results reported by Dr Chow et al are complementary to our findings, bringing insights into the possible mechanism of STI571-induced apoptosis in primary CLL lymphocytes. 1,2 The authors suggest the involvement of a new apoptotic pathway involving the caspase 3 activator, prostate apoptosis response gene 4 (Par-4). Moreover, Par-4 protein levels looks to correlate with the responsiveness to STI571 in a panel of six of CLL primary lymphocytes.…”

“…Moreover, Par-4 protein levels looks to correlate with the responsiveness to STI571 in a panel of six of CLL primary lymphocytes. 1 Interestingly, it has been proposed that caspase-3 induction is involved in chlorambucil (CLB)-induced CLL lymphocytes apoptosis. 3 In this regard, the fact that we did not find a correlation between the CLB and STI571 IC 50 when used alone suggests that the mechanisms downstream of STI571 and CLBinduced apoptosis are not identical.…”

“…3 In this regard, the fact that we did not find a correlation between the CLB and STI571 IC 50 when used alone suggests that the mechanisms downstream of STI571 and CLBinduced apoptosis are not identical. 1 Thus, it will be informative to assess the involvement of Par-4 protein levels in CLB-induced apoptosis in primary CLL lymphocytes. If STI571 induces Par-4 while CLB does not, the mechanism of action proposed by Dr …”

Reply to ‘Imatinib induces apoptosis in CLL lymphocytes with high expression of Par-4’ by Chow et al

“…1,2 The authors suggest the involvement of a new apoptotic pathway involving the caspase 3 activator, prostate apoptosis response gene 4 (Par-4). Moreover, Par-4 protein levels looks to correlate with the responsiveness to STI571 in a panel of six of CLL primary lymphocytes.…”