Impact of hypoxic and acidic extracellular conditions on cytotoxicity of chemotherapeutic drugs.
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 (pO2 < 0.5 mmHg) or extracellular acidosis (pH = 6.6) 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 6 h 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 O2-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.
Thews
Oliver
O
Institute of Physiology and Pathophysiology, University of Mainz, 55099 Mainz, Germany.
Gassner
Birgit
B
Kelleher
Debra K
DK
Schwerdt
Gerald
G
Gekle
Michael
M
D000138:Acidosis; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use; D003630:Daunorubicin / Q000378:metabolism / Q000627:therapeutic use; D000077143:Docetaxel; D005110:Extracellular Space / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D043823:Taxoids / Q000378:metabolism / Q000627:therapeutic use
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D003630:Daunorubicin