In vitro radiosensitization of breast cancer with hypoxia‐activated prodrugs

Abstract

KP167 is a novel hypoxia‐activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU‐55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER 0.01 of 1.60–3.42). KP167 induced greater radiosensitization in TNBC (SER 0.01 2.53 in MDAMB‐231, 2.28 in MDAMB‐468, 4.55 in MDAMB‐436) and luminal spheroids (SER 0.01 1.46 in MCF‐7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER 0.01 of 1.56–2.37 compared with AQ4N SER 0.01 of 1.13–1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.

Low serum albumin levels and high neutrophil counts are predictive of a poorer prognosis in patients with metastatic breast cancer

“…Neutrophils (NE) increase in production and release inflammatory factors during the inflammatory process (15). Previous studies have suggested that hypoxia, a common feature of solid tumors, targets multiple cell types in the tumor microenvironment including neutrophils by regulating the expression of multiple angiogenic genes (16)(17)(18). Expression of the immunosuppressive cytokine TGF-β is upregulated in tumors and plays a significant role in blocking immune responses and affecting tumor progression.…”