TRANSFORMING GROWTH FACTOR-BETA-3 PROTECTION OF EPITHELIAL-CELLS FROMCYCLE-SELECTIVE CHEMOTHERAPY IN-VITRO

The transforming growth factor-beta (TGF-beta) family of regulatory gr owth factors can reversibly arrest cell division in the G(1) phase of the cell cycle. Previously, TGF-beta 3 was shown to protect epithelial cells and hematopoietic cells from cytotoxic damage in vitro and in v ivo, and to reduce the severity and duration of oral mucositis induced by 5-fluorouracil (5-FU) in vivo. In the present study, we tested whe ther TGF-beta 3 can protect epithelial cells from a range of chemother apy drugs with differing mechanisms of action, using the CCL64 cell li ne as a model system. We report that preincubation of cells with TGF-b eta 3 for 24 hr resulted in enhanced clonogenicity following exposure to vinblastine, vincristine, etoposide, taxol, ara-C, methotrexate, or 5-FU. Protection was measured in colony forming assays, which demonst rated that the protected cells could re-enter the cell cycle and under go multiple rounds of cell division. At high cytotoxic drug concentrat ions, absolute colony counts were increased for the cultures prearrest ed by TGF-beta 3, as compared with the proliferating control cultures. The effects of TGF-beta 3 were reduced for cisplatin and doxorubicin, drugs that are toxic to cells throughout the cell cycle. Thus, TGF-be ta 3 can effectively reduce the cytotoxicity of anticancer drugs that act predominantly in S or M phase of the cell cycle. (C) 1997 Elsevier Science Inc.