Impact of hypoxic and acidic extracellular conditions on cytotoxicity of chemotherapeutic drugs

Abstract

In the microenvironment of solid growing tumors, pronounced hypoxia or extracellular acidosis is commonly found The aim of this study was the analysis of the cytotoxic effect of different chemotherapeutic agents (cisplatin, daunorubicin, docetaxel) under these conditions in vitro Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO 2 05 mmHg) or extracellular acidosis (pH=66) for 6h After 3h, cytotoxic drugs were added The cytotoxic effect was assessed by measuring caspase 3-activity (apoptosis), LDH release (necrosis) and repopulation of the cells after chemotherapy (cell death) Compared to aerobic control conditions, severe hypoxia over 6h per se led to a slight increase in apoptosis, necrosis and cell death With all three chemotherapeutic agents, hypoxia led to a reduced (by approx 25%) caspase 3-activity and a marked increase in necrosis However, the overall cytotoxicity of the drug was not affected by O 2 -deficiency By contrast, during extracellular acidosis, the cytotoxic effect of daunorubicin was reduced by 40%, preferentially due to a marked reduction in apoptosis With cisplatin and docetaxel no change in overall cell death was detected However, for daunorubicin the tumor-pH seems to have a strong impact on cytotoxicity With this chemotherapeutic drug the therapeutic efficacy is markedly reduced in an acidotic environment © 2008 Springer Science+Business Media, LLC.