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Research Articles: Therapeutics, Targets, and Development

Combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia

¹ Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital; ² Chemical Computing Group, Inc., Montreal, Quebec Canada and ³ Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada

Requests for reprints: Bertrand J. Jean-Claude, Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, M7.19, Montreal, Quebec, Canada H3A 1A1. Phone: 514-842-1231 ext. 35841; Fax: 514-843-1475. E-mail: bertrandj.jean-claude{at}mcgill.ca

Abstract

Blockade of Bcr-Abl by the inhibitor Imatinib has proven efficacious in the therapy of chronic myelogenous leukemia (CML). However resistance to the drug emerges at the advanced phases of the disease. Therefore, novel therapy models remained to be designed. We have developed a novel dual targeted agent termed "combi-molecule" designed to not only block Bcr-Abl but also damage DNA. ZRF1, the first optimized prototype of the approach, was "programmed" to degrade into another inhibitor ZRF0 plus a methyl diazonium species. It was 2-fold stronger Abl tyrosine kinase inhibitor than Imatinib and a more potent DNA-damaging agent than Temodal. In the p53 wild-type Mo7p210 cells, the potency of ZRF1 was 1,000-fold superior to that of the equieffective combinations of Imatinib plus Temodal. More importantly, its superior potency over Imatinib was more pronounced in Bcr-Abl-positive cells coexpressing wild-type p53. Studies to rationalize these results showed that, through its Bcr-Abl inhibitory function, it down-regulated p53. However, sufficient level of the latter protein was available for transactivating p21 and Bax, which are required for cell cycle arrest and apoptosis. The results suggest that, in p53 wild-type cells, apoptosis is induced not only through Bcr-Abl inhibition but also through the p53-controlled DNA-damaging pathway, leading to an additive effect that translates into enhanced cell death. The study conclusively showed that p53 is a major determinant for the cytotoxic advantages of the novel combi-molecular approach in CML, a disease in which 70% to 85% of all the cases express wild-type p53. [Mol Cancer Ther 2008;7(5):1033–43]

Grant support: Leukemia and Lymphoma Society of Canada; Fonds de Recherche et Santé du Québec scholarship (A. Katsoulas).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/13/07; revised 1/30/08; accepted 3/14/08.