Fig. 9.

Radiosensitizing effect of MnTE-2-PyP⁵⁺ on tumor growth and on the tumor vasculature in a mouse 4T1 breast cancer study. a Sc xenograft tumor growth delay: MnTE-2-PyP⁵⁺ was given before and after radiation. Two regimes of dosing were employed where MnP was given either 1 h before each radiation dose or at 1, 13 and 25 h after the 3rd dose of radiation. Three doses of radiation were separated by 12 h. Tumors were allowed to reach approximately 200 mm³ in size, and randomized to 1 of 5 treatment groups on postimplantation day 9: (1) phosphate-buffered saline (NT), (2) MnTE-2-PyP⁵⁺ (6 mg/kg every 12 h/3), (3) radiation (RT; 5 Gy every 12 h/3), (4) MnTE-2-PyP⁵⁺ + RT (1 MnTE-2-PyP⁵⁺ dose before each fraction of radiation), or (5) RT + MnTE-2-PyP⁵⁺(3 MnTE-2-PyP⁵⁺ doses after the third fraction of radiation). The combined-treatment groups had significant, supra-additive effects on radiation-induced tumor growth delay, irrespective of sequencing. n = 5 per group. * p = 0.01 versus radiation alone [82]. b, c 4T1 window chamber model: the radiosensitizing effect of MnTE-2-PyP⁵⁺ is at least in part related to the antiangiogenic action of MnTE-2-PyP⁵⁺ as shown by the measurements of vascular density. Amifostin has no effect on vascular density. 4T1 window chamber tumors were randomized to treatment with radiation (RT) or sham-irradiation (NT) and phosphate-buffered saline or MnTE-2-PyP⁵⁺ (b) or phosphate-buffered saline or amifostine (WR-2721; c). A course of 3 fractions of radiation (5 Gy each, 12 h apart) was followed immediately by daily administration of MnTE-2-PyP⁵⁺ (6 mg/kg/day) or amifostine (100 mg/kg/day) for 3 days. Tumors were imaged immediately after radiation (0 h) and every day thereafter (24, 48 and 72 h), and these images were used to calculate the tumor vascular length densities. Combined treatment with radiation and MnTE-2-PyP⁵⁺ resulted in significant tumor devascularization between 48 and 72 h after radiation. n = 5 per group. * p = 0.05 versus tumor vascular length density at 0 h. Error bars represent standard deviations. Adapted from Moeller et al. [82].