Reduction of radiochemotherapy-induced early oral mucositis by recombinant human keratinocyte growth factor (palifermin): experimental studies in mice.
OBJECTIVE
To study the effect of recombinant human keratinocyte growth factor (rHuKGF or palifermin) on oral mucositis induced by radiochemotherapy in a mouse model.


METHODS
Cis-diamminedichloroplatinum (cisplatin) and/or 5-fluorouracil were given before single dose irradiation, combined with palifermin before or after the treatment, or both. Daily fractionated irradiation for 2 weeks was followed by graded test doses. With additional chemotherapy in Week 1, palifermin was given before radiotherapy and at the end of the first week, or additionally at the end of Week 2. Radiochemotherapy in Week 2 was combined with palifermin at the end of Weeks 1 and 2, Weeks 1, 2, and 3, or additionally before radiotherapy. Ulceration of mouse tongue mucosa was analyzed as the endpoint.


RESULTS
The dose associated with ulcer induction in 50% of the mice (ED(50)) for single-dose irradiation was 11.5 +/- 0.7 Gy. Palifermin increased the ED(50) to about 19 Gy in all protocols tested. Similar values were observed when chemotherapy was added before irradiation. With fractionated irradiation, palifermin increased the ED(50) for test irradiation from 5.7 +/- 1.5 Gy to 12-15 Gy, depending on the administration protocol. With chemotherapy in Week 1, two palifermin injections had no significant effect, but a third injection increased the ED(50) to 13 Gy. With chemotherapy in Week 2, all palifermin protocols resulted in ED(50) values of 13-14 Gy.


CONCLUSIONS
A marked increase in oral mucosal radiation tolerance by palifermin was found, which was preserved in combinations with chemotherapy using cisplatin and/or 5-fluorouracil.
Dörr
Wolfgang
W
Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany. doerr@rcs.urz.tu-dresden.de
Bässler
Stefan
S
Reichel
Sandra
S
Spekl
Kathrin
K
D000818:Animals; D002945:Cisplatin / Q000009:adverse effects; D019583:Dose Fractionation, Radiation; D004353:Drug Evaluation, Preclinical; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D005472:Fluorouracil / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D023421:Models, Animal; D009061:Mouth Mucosa / Q000187:drug effects / Q000528:radiation effects; D019226:Oral Ulcer / Q000209:etiology / Q000517:prevention & control*; D011832:Radiation Injuries / Q000517:prevention & control*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D013280:Stomatitis / Q000209:etiology / Q000517:prevention & control*; D014060:Tongue Diseases / Q000209:etiology / Q000517:prevention & control*
C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D002945:Cisplatin; D005472:Fluorouracil