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ZRF4, a combi-molecule with increased efficacy as compared with the individual components in chronic lymphocytic leukemia lymphocytes in vitro

Leukemia volume 25, pages 1512–1516 (2011)Cite this article

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B-cell chronic lymphocytic leukemia (CLL) is characterized by actively dividing B-lymphocytes in the lymph nodes and bone marrow, as well as the accumulation of quiescent lymphocytes in the peripheral blood of affected patients. During treatment, the enzyme-mediated repair of DNA damage can induce resistance to chemotherapeutic drugs.1 Even if combinations of chemotherapy with immunotherapy have shown higher response rates and longer duration of responses, they can be associated with poor tolerability characterized by deterioration of immune functions leading to infections.2 More recently, bendamustine, a hybrid agent with a nitrogen mustard moiety and a purine analog, has been tested in clinical trials in CLL, demonstrating that hybrid molecules can result in increased therapeutic efficacy as compared with the nitrogen mustard analog alone.3 We have previously demonstrated that imatinib, an inhibitor of c-abl (c-abl is involved in homologous recombination repair), sensitizes B-CLL lymphocytes to chlorambucil (CLB) in vitro,4 an investigation which led to a phase I clinical trial in CLL patients in which the combination of CLB and imatinib resulted in a 45% response rate in a heavily pretreated population with minimal toxicity.5 These results encouraged us to develop the combi-molecule ZRF4, composed of a bifunctional alkylating moiety with an imatinib-like moiety, designed to degrade to an inhibitor of c-abl tyrosine kinase plus DNA-damaging species.

ZRF4 is a combi-molecule designed to target c-abl (through an imatinib moiety) and to induce DNA damage (through a nitrogen mustard-like moiety). The effects of the IC50 of ZRF4 as compared with equimolar concentrations of CLB alone or in combination with imatinib were examined at 24 h after in vitro treatment in nine available CLL lymphocyte samples. Our results indicated that CLB induced c-abl phosphorylation in the CLL lymphocytes tested (P<0.001) (Figure 1d). Moreover, imatinib has no significant effect on the basal c-abl phosphorylation (data not shown) but inhibited CLB-induced c-abl phosphorylation (P<0.001). The combi-molecule ZRF4 completely inhibits c-abl phosphorylation. ZRF4 inhibition of c-abl is significantly different from the basal (P<0.001) and CLB-stimulated (P<0.001) c-abl phosphorylation. Most importantly, ZRF4 is a more potent inhibitor of c-abl phosphorylation than imatinib in combination with CLB (P<0.05) (Figure 1d). Some combi-molecules are more potent inhibitors of the tyrosine kinase than the individual component inhibitor.7 We speculate that this property implies that after treatment of the B-CLL cells with ZRF4, c-abl was inhibited by two different molecules (the intact ZRF4 and the metabolite, which is an imatinib-like molecule) (Supplementary Figure). The effect of these two different molecules is an increase in the inhibition of c-abl as compared with imatinib plus CLB.

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Acknowledgements

We thank the Manitoba CLL tissue bank for the IgVH mutation analysis. LP and RA are members of the Quebec Clinical Research Organization in Cancer consortium. This study was supported by grants from the Leukemia Lymphoma society (RA and LP), Canadian Institutes of Health Research (LP, RA and BJC) and Leukemia Lymphoma Society (Canada) (BJC).

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Authors and Affiliations

  1. Department of Oncology, Faculty of Medicine, Segal Cancer Center and Lady Davis Institute from the Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    L Amrein, R Aloyz & L Panasci

  2. Department of Oncology, Faculty of Medicine, Cancer Drug Research Laboratory from Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada

    Z Rachid & B Jean-Claude

  3. Department of Medicine, Service of Hematology and Medical Oncology, Centre Hospitalier de l'Université de Montréal and Centre de Recherche du CHUM, Montreal, Quebec, Canada

    D Soulières

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  1. L Amrein
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  2. Z Rachid
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Correspondence to L Panasci.

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Amrein, L., Rachid, Z., Jean-Claude, B. et al. ZRF4, a combi-molecule with increased efficacy as compared with the individual components in chronic lymphocytic leukemia lymphocytes in vitro. Leukemia 25, 1512–1516 (2011). https://doi.org/10.1038/leu.2011.110

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