Fig. 4.

PARP1 inhibitor interacted with CHK1 inhibitor in a greater than additive fashion in inhibiting tumor growth and in enhancing animal survival in vivo. A, BT549 cells (5 × 10⁶) were injected into the fourth mammary fat pad. Tumors were permitted to form to ∼250 mm³. Initial volumes of the tumor groups were as follows: vehicle, 256 mm³; AZD7762, 241 mm³; AZD2281, 281 mm³; and AZD7762+AZD2281, 245 mm³. Animals were injected with vehicle, AZD7762 (50 mg/kg), AZD2281 (50 mg/kg), or AZD7762+AZD2281 for 5 days. Tumors were measured with a caliper to determine tumor volume as described under Materials and Methods. The mean ± S.E.M. tumor volume for all animals in each treatment condition was plotted (n = 7 animals per group, two separate studies). *, p < 0.05, less than the vehicle control value. Top panel, tumors isolated 7 days after the start of treatment were fixed and stained with TUNEL staining to examine tumor cell death. B, animals carrying BT549 tumors in A after receiving the indicated drug treatment were monitored daily and when tumor volumes were >1.5 cm³, animals were sacrificed. Survival was plotted as a percentage of animals alive on any given day. C, BT474 cells (8 × 10⁶) were injected into the fourth mammary fat pad. Tumors were permitted to form to ∼75 mm³. Initial volumes of the tumor groups were as follows: vehicle (VEH), 81 mm³; AZD7762, 70 mm³; AZD2281, 78 mm³; and AZD7762+AZD2281, 68 mm³. Animals were injected with vehicle, AZD7762 (50 mg/kg body mass), AZD2281 (50 mg/kg body mass), or AZD7762+AZD2281 for 5 days. Tumors were measured with a caliper to determine the tumor volume as described under Materials and Methods. The mean ± S.E.M. tumor volume for all animals in each treatment condition was plotted (n = 10 animals/group). *, p < 0.05, less than vehicle control value. Results are representative of two independent studies. D, the tissues collected from BT474-derived tumors (day 15) were fixed and stained with TUNEL staining to examine tumor cell morphology and tumor cell death and with an anti-Ki67 antibody to measure the proliferative index. DAPI, 4,6-diamidino-2-phenylindole.