EZN-2208 (PEG-SN38) Overcomes ABCG2-Mediated Topotecan Resistance in BRCA1-Deficient Mouse Mammary Tumors
Figure 1
Efficacy of Ko143+ topotecan combination therapy in Brca1−/−;p53−/− mammary tumors.
A, Experimental outline. Spontaneous mammary tumors from K14cre;Brca1F/F;p53F/F females were orthotopically transplanted into six- to eight-week-old Abcg2−/− syngeneic recipients. When tumors reached a volume of about 200 mm3, animals were either left untreated (control) or injected i.p. with 0.5 mg topotecan per kg body weight on days 0–4 and 14–18 resulting in elevated ABCG2 expression. When tumors doubled in size (∼400 mm3), animals were injected i.p. with either vehicle +0.5 mg topotecan or 10 mg Ko143+0.5 mg topotecan combination therapy per kg body weight on days 0–4 and 14–18. If the tumor volume shrank to less than 50% of the start volume, treatments were stopped until tumors relapsed to 100%. The experiment was terminated when tumors reached a volume of about 1500 mm3. B, Kaplan-Meier (K-M) survival curves of untreated and combination therapy-treated tumor-bearing animals. Eight individual tumors were tested, and per tumor one untreated control (blue line), two vehicle + topotecan- (green line) and two Ko143+ topotecan-treated animals (red line) were included. For the vehicle + topotecan group one tumor did not grow out after transplantation. The P value was calculated using the Log-rank test. C, Waterfall plots (upper panel) showing tumor volume change (%) after 5 days of combination therapy per individual mouse, with relative volumes normalized to the treatment start volume (i.e. about 200 mm3). Box and whiskers plots (lower panel) summarizing the waterfall plot data. Lines represent the median response, while the whiskers show the maximum and minimum values. The P values was calculated using the Mann Whitney test.