Assessment of supra-additive effects of cytotoxic drugs and low dose rate irradiation in an in vitro model for hepatocellular carcinoma.
The use of 5-fluorouracil, topotecan, or gemcitabine was tested for enhancement of the effects of low dose rate (LDR) irradiation in an in vitro model for hepatocellular carcinoma. For comparison, all drugs were tested in combination with high dose rate (HDR) gamma-irradiation as well. Multicellular spheroids of HepG2 cells were exposed to HDR or LDR irradiation by means of external beam cobalt-60 or rhenium-188 (188Re), respectively, dissolved in the culture medium. Secondly, exposure to irradiation was combined with the cytotoxic drug. Toxicity was evaluated by means of a quantitative spheroid outgrowth assay and histology. For 5-fluorouracil, supra-additive effects were observed in combination with HDR irradiation. With 188Re, the supra-additive toxicity was only transient. For topotecan and 188Re, no supra-additive effects were seen, whereas the addition of HDR irradiation at the end of the topotecan exposure yielded lasting supra-additive effects. Incubation with gemcitabine followed by exposure to HDR irradiation, induced a synergistic toxicity on the outgrowth. No supra-additive effects were observed when HDR irradiation was added at the start of the incubation with gemcitabine or combined with LDR irradiation. For all drugs tested, supra-additive effects were observed with HDR irradiation if the timing of the irradiation was appropriate. For 188Re, no lasting supra-additive effects were observed.
Lambert
Bieke
B
Department of Nuclear Medicine, De Pintelaan 185, Ghent University Hospital, 9000 Ghent, Belgium.
De Ridder
Leo
L
De Vos
Filip
F
Slegers
Guido
G
de Gelder
Virginie
V
Van de Wiele
Christophe
C
Thierens
Hubert
H
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003037:Cobalt Radioisotopes; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D012211:Rhenium; D019772:Topotecan / Q000494:pharmacology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003037:Cobalt Radioisotopes; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D003841:Deoxycytidine; D012211:Rhenium; D019772:Topotecan; D005472:Fluorouracil; D000093542:Gemcitabine