![]() The development of innovative agents to replace previous standard therapies for leukemia using phenotype-based screening has not advanced for more than 30 years, suggesting the limitations of cell line-based screening and existing libraries for drug development. Most anti-cancer agents used in standard therapy for leukemia were developed by the 1970s. In this method, library compounds are added to the culture media of cell lines and selected based on their growth inhibitory effects on the cell lines. Phenotype-based screening using cell lines as cancer models have widely been used in the development of anti-tumor drugs. Clonal evolution by the T315I mutation in BCR-ABL represents a severe obstacle for Ph + ALL therapy. Even when the target molecule is successfully inhibited, anti-tumor effects may not be obtained due to the activation of an escape signal or evolution of resistant clones with drug-resistant mutations. This is a powerful method that is currently being used to develop many tyrosine kinase inhibitors including ABL kinase inhibitors however, difficulties have been associated with identifying the true molecular targets of diseases in many cases, and inhibition of the target molecule does not always lead to anti-tumor effects. Their effects on cell lines and mouse models are then investigated. Compounds are screened by evaluating their inhibitory effects on the enzymatic activity of the target molecule in vitro. In target-based screening, the target molecule of a certain disease, such as a particular kinase, is initially selected based on its knowledge of molecular pathology. Target-based screening and phenotype-based screening represent the two major ways to develop drugs. Therefore, there are still unmet medical needs for Ph + ALL. The only way to currently achieve a cure is to undergo allogeneic-stem cell transplantation (allo-SCT) during remission however, the therapy-related death rate of allo-SCT is high, and Ph + ALL is common among the elderly, who cannot receive allo-SCT. ABL kinase inhibitors keep CML in the chronic phase for a long period of time and markedly increase the complete remission rate of Ph + ALL however, the relapse of Ph + ALL is almost inevitable. These results indicated the potential of verteporfin as a new anti-leukemic reagent.ĪBL kinase inhibitors are highly effective for BCR-ABL-positive leukemias such as chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Furthermore, it exhibited synergistic effects with dasatinib, an ABL kinase inhibitor. Although verteporfin is a photosensitizer activated by photoirradiation, its cytotoxic effects were mediated by the light-independent production of reactive oxygen species therefore, its anti-leukemic effects were also exerted in vivo without photoirradiation. In the validation assay, its GI 50 was 228 nM, 395 nM, and 538 nM in three PDX cells and 3.93 μM, 2.11 μM, and 5.61 μM in three cell lines. We found that verteporfin, an FDA-approved drug, exhibited strong PDX cell-specific cytotoxicity. The profiles of drugs selected by PDX-cell screening were markedly different from those by screening using the Ph + ALL cell line. We established four Ph + ALL PDX mice and performed high-throughput screening of 3440 compounds using leukemia cells from the PDX mice (PDX-cell screening). We developed a high-throughput drug screening system using PDX cells and performed drug screening using the PDX cells of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). ![]() Patient-derived xenografts (PDX) are established by the transfer of primary tumor cells directly from patients into immunodeficient mice and can provide primary-like tumor cells of the amount needed at the desired time. Cell lines have been used for drug discovery as useful models of cancers however, they do not recapitulate cancers faithfully, particularly from the viewpoints of microenvironmental independence.
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