Cell cycle effects of topotecan alone and in combination with irradiation

• Published in: Radiotherapy and oncology 2005-05, Vol.75 (2), p.237-245
• Main Authors: Ohneseit, Petra A., Prager, Daniela, Kehlbach, Rainer, Rodemann, H. Peter
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cell cycle; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Cyclin B - biosynthesis; Cyclin B - genetics; Cyclin B - physiology; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Fibroblasts; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Ionizing radiation; Lung - cytology; Topotecan; Topotecan - pharmacology; TP53; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2005.03.025

To elucidate the role of TP53 on differential effects of topoisomerase I inhibitor topotecan (Hycamtin®) on radiation sensitivity. Cell cycle distribution and protein expression of TP53, p21WAF1/CIP1 and cyclin B was studied in CCD32 lung fibroblasts, glioblastoma cell lines U118 (mutant TP53), and U87 (wildtype TP53) after treatment with topotecan (0.05 and 1μM) and/or ionizing radiation (2Gy). Cell cycle effects varied with topotecan concentration, resulting in G1 arrest (1μM), or S/G2/M arrest (0.05μM), and was modified differentially in fibroblasts and in glioblastoma cells in combination with irradiation. Phosphorylation of TP53 and expression of p21WAF1/CIP1 was induced by IR and/or topotecan in CCD32 cells, and in U118 cells after topotecan treatment, accompanied by cyclin B degradation. In U87 cells only 1μM topotecan generated phosphorylation of TP53 and p21WAF1/CIP1 expression; 0.05μM caused stabilization of cyclin B. The antagonistic effect of combined topotecan/irradiation treatment in fibroblasts was most likely due to an immediate radiation induced G1 arrest, but was not observed in p53 wildtype glioblastoma cells. Thus, the impact of TP53 on the topotecan response remains indistinct, and is obviously influenced by other genomic alterations acquired by tumor cells.