TRANSFORMING GROWTH-FACTOR-BETA-1 ENHANCES THE LETHAL EFFECTS OF DNA-DAMAGING AGENTS IN A HUMAN LUNG-CANCER CELL-LINE

In tissue culture conditions, exogeneous active transforming growth fa ctor-beta 1 (TGF-beta 1) enhances the lethal effect of DNA-damaging ag ents (UV-C, gamma rays, cisplatin, methotrexate and 5-fluorouracil) to ward human A549 cells and mink Mv1Lu cells, as detected by the loss of their capacity to give rise to colonies; both these cell lines harbor a wild-type p53, as determined by immunoprecipitation. Contrastingly, the sore effect of the cytokine used alone is to inhibit reversibly t he multiplication of the same cells without further impairing, once wi thdrawn from their environment, their capacity to divide and give rise to colonies, The lethal synergy between TGF-beta 1 and UV-C was studi ed on mink and human cell lines, and the biomodulation by TGF-beta 1 o f cell killing by cisplatin, gamma rays, 5-fluorouracil or methotrexat e was tested only on human cells, As investigated with UV-C-irradiated human A549 cells, TGF-beta 1 appears to enhance apoptosis rather than to disturb the repair of DNA photole-sions (mainly pyrimidine dimers) by the nucleotidic excision repair pathway according to results of nu cleosomal ladder and comet tests, Our data raise the possibility that, in vivo, TGF-beta 1 might affect the curative and/or undesirable seco ndary side effects of cancer therapy. (C) 1997 Wiley-Liss, Inc.