In vitro and in vivo effects of repifermin (keratinocyte growth factor-2, KGF-2) on human carcinoma cells.
OBJECTIVE
Repifermin (keratinocyte growth factor-2, KGF-2) is a growth factor that selectively induces epithelial cell proliferation, differentiation and migration. The objective of this study was to assess the effect of repifermin on in vitro tumor cell proliferation and in vivo tumor growth using a variety of human carcinoma cell lines with differing growth rates and levels of KGF receptor (KGFR) expression.


METHODS
Potential effects of repifermin on in vitro cell proliferation were evaluated by alamarBlue and/or [(3)H]-thymidine incorporation assays under a range of serum conditions. In vivo tumor growth was evaluated by implanting KGFR(+) carcinomas subcutaneously into nude mice and measuring tumor growth over time in mice injected intravenously (i.v.) or intraperitoneally (i.p.) with repifermin or placebo.


RESULTS
In vitro, none of the 30 human carcinoma cell lines tested demonstrated a substantial increase in proliferation in response to repifermin over the concentration range 0.01 to 1000 ng/ml. In vivo results showed no significant tumor growth-promoting activity when single- or multiple-cycle intravenous injections of repifermin (1 mg/kg) were given to athymic nude mice inoculated with human KGFR(+) tumors of the pharynx (Detroit 562, FaDu), colon (Caco-2), salivary gland (A-253) or tongue (SCC-25, CAL 27). In addition, repifermin (0.2 or 2 mg/kg) injected i.p. for 2 weeks had no effect on the growth of eight other human carcinomas including those of the ovary (NIH:OVCAR-3, SK-OV 3, PA-1), bladder (SCaBER), epidermis (A 431), lung (SW 900), breast (MDA-MB-231) and cervix (SiHa).


CONCLUSIONS
Repifermin had no in vitro or in vivo proliferative effects on KGFR(+) human epithelial-like tumors. This failure to stimulate tumor cell growth highlights the ability of repifermin to specifically target normal epithelial tissue. This is critical to the safety profile of repifermin, since it is currently in phase II clinical trials for the treatment of cancer patients with mucositis resulting from chemo- or radiotherapy.
Alderson
Ralph
R
Human Genome Sciences, Inc., 9410 Key West Avenue, Rockville, MD 20850, USA.
Gohari-Fritsch
Shiva
S
Olsen
Hendrik
H
Roschke
Viktor
V
Vance
Courtney
C
Connolly
Kevin
K
D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis* / Q000187:drug effects; D014407:Tumor Cells, Cultured
C496463:FGF10 protein, human; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor