Ukrain (R), an alkaloid thiophosphoric acid derivative of Chelidonium majus L. protects human fibroblasts but not human tumour cells in vitro againstionizing radiation

Purpose: Ukrain(R), an alkaloid thiophosphoric acid derivative of a Chelido nium majus L., has demonstrated a promising impact on chemotherapy in a var iety of malignancies. The effects of the drug on cell survival, alteration of the cell cycle and induction of apoptosis were examined without and in c ombination with ionizing radiation (IR). The TP53 status of the cell lines used was also investigated. Materials and methods: Exponentially growing human tumour cell lines MDA-MB -231 (breast), PA-TU-8902 ( pancreas), CCL-221 (colorectal), U-138MG (gliob lastoma), and human skin and lung fibroblastic cells, HSF1, HSF2 and CCD32- LU were studied by colony assay, flow cytometry (cell-cycle, annexin-V stai ning for apoptosis) and Western blotting. Ukrain was used in concentrations from 0.1 to 50 mug ml(-1) for 1, 3 and 24 h and radiation as single doses of 1-10 Gy. Combined drug-radiation exposure employed 1 mug ml(-1) Ukrain f or 24 h plus 2-8 Gy. Results: Ukrain cytotoxicity was time- and dose-dependent. The combination of Ukrain plus IR gave enhanced toxicity in CCL-221 and U-138MG cells, but not in MDA-MB-231 and PA-TU-8902 cells. Most strikingly, a radioprotective effect was found in normal human skin and lung fibroblasts. Flow-cytometry analyses supported the differential and cell line-specific cytotoxicity of Ukrain. CCL-221 and U-138MG cells accumulated in G(2) after 24-h Ukrain tre atment, whereas no alterations were detected in the other tumour cells and normal fibroblasts tested. Western blotting of TP53 demonstrated non-functi onal overexpression in all tumour cell lines without affecting p21. HSF1 pr esented wild-type TP53 and a p21 response after IR. Flowcytometric analyses of annexin-V staining showed no induction of apoptosis after Ukrain treatm ent in comparison with untreated controls. Conclusions : Differential effects of Ukrain in modulating radiation toxici ty of human cancer cell lines and its protective effect in normal human fib roblasts suggest that this alkaloid may have potential properties for clini cal radiochemotherapy.