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Comparison between Molecularly Defined and Conventional Therapeutics in a Conditional BCR-ABL Cell Culture Model

2007; Mary Ann Liebert, Inc.; Volume: 17; Issue: 1 Linguagem: Inglês

10.1089/oli.2006.0054

1557-8526

Anuhar Chaturvedi, Karin Battmer, Daniel Schaefer, Arnold Ganser, Matthias Eder, Michaela Scherr,

Chronic Lymphocytic Leukemia Research

Accumulating knowledge about the molecular mechanisms causing human diseases can support the development of targeted therapies such as imatinib, a BCR-ABL-specific tyrosine kinase inhibitor to treat chronic myeloid leukemia (CML). Here, we use lentivirus-mediated RNA interference (RNAi) targeting BCR-ABL and the downstream signaling molecules SHP2, STAT5, and Gab2 to compare the efficacy and specificity of molecularly defined therapeutics with that of conventional cytotoxic drugs (cytarabine, doxorubicin, etoposide) in a conditional BCR-ABL cell culture model. IC50 values were determined for each drug in TonB cells cultured either with interleukin-3 (IL-3) or BCR-ABL, and molecularly defined therapies were studied using lentivirally expressed shRNAs. We demonstrate that conventional anti-leukemic drugs have small or no differential effects under different cell culture conditions, whereas both imatinib and specific RNAi significantly inhibit proliferation of TonB cells in the presence of BCR-ABL but not IL-3. To study molecularly defined combination therapy, we evaluated either imatinib in TonB cells with target-specific RNAi or we used lentiviral vectors to induce combinatorial RNAi through simultaneous expression of two shRNAs. These combination therapies result in increased efficacy without loss in specificity. Interestingly, combinatorial RNAi can specifically deplete TonB cell cultures in the presence of BCR-ABL, even without targeting the oncogene itself. This model provides a tool to evaluate potential therapeutic targets and to quantify efficacy and specificity preclinically of new combination therapies in BCR-ABL-positive cells.