Influence of keratinocyte growth factor on clonal growth of epithelial tumor cells, lymphoma and leukemia cells and on sensitivity of tumor cells towards 5-fluorouracil in vitro.

Abstract

RhKGF is developed for prevention and treatment of chemotherapy- and radiation-induced epithelial damage in cancer patients. Little information exists on growth modulation of malignant cells by KGF. We have tested the anchorage-independent clonal growth of 35 human tumor and 22 lymphoma and leukemia cell lines in semisolid media with or without rhKGF. Growth of the majority of cell lines was not significantly influenced by rhKGF. Growth of 5 cell lines (2 lung, 1 stomach, 1 colorectal, 1 breast) was significantly stimulated by rhKGF. The effect was dose-dependent with significant stimulation at concentrations >1-10 ng/ml. Growth modulation was amplified by serum reduction and abolished by anti-hKGF antibodies. Responding cell lines expressed KGF receptor RNA and showed specific KGF-binding. To determine whether KGF-induced higher colony numbers represented cell divisions with resulting differentiation and growth arrest or self-renewal we performed experiments on serial plating efficacy of colony-derived tumor cells with or without continued presence of rhKGF. Results revealed KGF stimulation of colony formation as representing increase of cellular self-renewal. To test possible interaction of rhKGF with activity of cytotoxic drugs in clinical protocols, we have used combination protocols with 5-fluorouracil (5-FU). Results showed that rhKGF incubation before, after (or both) addition of 5-FU did not diminish the sensitivity of tumor cells to 5-FU cytotoxicity under serum concentrations relevant for the clinical situation. In conclusion, some epithelial tumor cells have receptors for KGF signaling for clonal growth. When considered in the planning of treatment protocols, this effect is unlikely to compromise chemotherapy sensitivity.