Fig. 4.

Increased expression of Abcb1a and Abcb1b is associated with AZD2281 resistance in vivo. (A) RT-MLPA analysis of the ratios of Abcb1a, Abcb1b, Abcc1, Abcg2, Parp1, and Hprt1 expression in AZD2281-resistant tumors and samples from the corresponding untreated tumors. Actin-β expression was used as internal reference. The values presented are the mean ratio of 3 independent reactions. The suffix 28 indicates the 28-day schedule of AZD2281 and 100 the 100-day schedule. Error bars indicate standard deviation. For the complete dataset see Table S2. (B) Three Brca1^−/−;p53^−/− doxorubicin-resistant tumors (2 with up-regulation of Abcb1a/b and 1 without; ref. 13) were tested for their response to AZD2281. Days on which 50 mg of AZD2281 per kg were given have open squares. (C) T1–T4 and T6 were treated with a daily injection of 50 mg of AZD2281 per kg for 28 days. When tumors relapsed to 100% of their original volume, they were retreated by i.p. injection of 2 mg of tariquidar per kg every other day (light blue line) or 50 mg of AZD2281 per kg daily (red line) or both (dark blue line). Days on which animals were treated are indicated by rhombi, triangles, or squares. Graphs in B and C show relative tumor volume (RTV, ratio of tumor volume to initial size at start of treatment) as a function of time.