WR-2721 reduces intestinal toxicity from concurrent gemcitabine and radiation treatment.
BACKGROUND
The nucleoside analog gemcitabine is a potent radiosensitizer of both tumor and normal mucosa, so severe toxic reactions have resulted from its combination with radiation in some clinical treatment schedules for pancreatic cancer. WR-2721 (amifostine) has been shown to reduce normal tissue toxicity produced from both radiation treatment and some chemotherapeutics. The aim of this study was to determine if WR-2721 can protect the gastrointestinal mucosa from injury by concurrent gemcitabine and radiation treatment.


METHODS
Gemcitabine was injected ip into C3Hf/Kam mice at a concentration of 33 mg/kg 24 h before whole-body irradiation. A single dose (200 mg/kg) of WR-2721 was given 30 min before the radiation treatment or 30 min before gemcitabine or at both times. A quantitative assessment of the chemotherapy/radiation-induced damage was carried out using the mouse microcolony assay for stem cell survival in the intestinal crypts.


RESULTS
WR-2721 given 30 min before gemcitabine followed 24 h later by radiation did not confer any protection to the jejunum (DMF 0.95). However, WR-2721 administered 30 min before radiation without or with prior gemcitabine produced protection factors (PF) of 1.35 and 1.42


CONCLUSIONS
WR-2721 did not directly protect the gastrointestinal mucosa from gemcitabine toxicity, but it did protect the gemcitabine-radiosensitized mucosa from acute radiation damage by a factor of 1.42. Therefore, in clinical treatment protocols using concurrent chemoradiation with gemcitabine, WR-2721 may have clinical utility in protecting against radiation-induced mucosal toxicity.
Phan
T P
TP
Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
Crane
C H
CH
Janjan
N A
NA
Vrdoljak
E
E
Milas
L
L
Mason
K A
KA
D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003841:Deoxycytidine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D007583:Jejunum / Q000187:drug effects* / Q000528:radiation effects*; D051379:Mice; D008809:Mice, Inbred C3H; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects*; D014916:Whole-Body Irradiation / Q000009:adverse effects*; D000093542:Gemcitabine
D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D004999:Amifostine; D000093542:Gemcitabine