Allosterically Controllable Maxizyme-Mediated Suppression of Progression of Leukemia in Mice

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Abstract
Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules2000, 1, 108−117; Kuwabara et al. Biomacromolecules2001, 2, 788−799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature2000, 406, 473−474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNAVal promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.