Olaparib impedes growth of ATM mutant tumor cells in vivo and lengthens survival in a Granta-519 murine xenograft model. (A) Engraftment of a human tumor cell line in bone marrow and spleen of representative mice before treatment. Engraftment was demonstrated 14 days after intravenous injection or 5 days after subcutaneous injection of 3 × 106 Granta-519 cells/animal by FACS assessment of the percentage of human CD45+cells (top) and by immunohistochemistry using anti–human antibodies for B-cell lineage (CD5 and Pax5) and proliferating cells (Ki-67; bottom) in the spleen and bone marrow of mice (shown either at original magnification ×20 or ×40). Brown color indicates positive immunostaining. Organs from non-engrafted mice did not show nuclear staining for either hKi-67 or hPax5. (B) Effect of olaparib exposure on tumor burden in Granta-519–engrafted NOD/SCID mice. Representative FACS dot plots showing percentage of human CD45+ cells in murine bone marrow after treatment with olaparib or vehicle alone (top) and median percentage of human CD45+ cells in the bone marrow and spleen of mice intravenously injected with Granta-519 cells after 5 weeks treatment with olaparib (n = 8) or vehicle alone (n = 8; bottom). (C) Effect of olaparib treatment on size of subcutaneous tumors generated by localized Granta-519 injection (n = 15) compared with vehicle alone (n = 20). (D) Impact of olaparib treatment on overall survival of mice engrafted with Granta-519 cells (n = 10) compared with vehicle alone (n = 10).
