Combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia.
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 approximately 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 approximately 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.
Katsoulas
Athanasia
A
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.
Rachid
Zakaria
Z
McNamee
James P
JP
Williams
Christopher
C
Jean-Claude
Bertrand J
BJ
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle; D049109:Cell Proliferation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D016313:Genes, abl; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones; D015513:Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C414672:DNAJC2 protein, human; D018832:Molecular Chaperones; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D000077204:Temozolomide