Enhancement of radiation-induced regrowth delay by gemcitabine in a human tumor xenograft model.
Gemcitabine, a cytidine nucleoside analogue, has schedule-dependent antitumor activity in vitro and in vivo. Gemcitabine also has dose- and time-dependent radiosensitization properties in vitro. Thus it may have therapeutic application in combination with radiation. The aims of this study were to investigate whether gemcitabine could enhance radiation-induced tumor regrowth delay in a human squamous carcinoma (FaDu) xenograft in nude mice and to examine the effect of gemcitabine on radiation-induced apoptosis in in vivo tumors. Radiation was given locally to the tumors twice daily in 2 Gy fractions over 2 weeks for 5 days/week. Significant regrowth delay enhancement was observed which was dependent on gemcitabine schedule. Effective schedules using maximum tolerated gemcitabine doses were twice weekly and once weekly, but not daily. Significant toxicity occurred with radiation plus twice weekly gemcitabine, but enhancement was seen using gemcitabine doses well below the maximum tolerated dose. Both gemcitabine and radiation led to apoptotic cell death, but this was not increased when both treatments were combined. These results indicate that gemcitabine may be of therapeutic value as a radiation enhancer in the treatment of human cancers. Preliminary studies suggest that increased apoptotic cell death is not a mechanism leading to this enhancement.
Joschko
M A
MA
Experimental Chemotherapy and Pharmacology Unit, Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Webster
L K
LK
Groves
J
J
Yuen
K
K
Palatsides
M
M
Ball
D L
DL
Millward
M J
MJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine