Cell cycle effects of topotecan alone and in combination with irradiation.
OBJECTIVE
To elucidate the role of TP53 on differential effects of topoisomerase I inhibitor topotecan (Hycamtin on radiation sensitivity.


METHODS
Cell cycle distribution and protein expression of TP53, p21(WAF1/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 1 microM) and/or ionizing radiation (2 Gy).


RESULTS
Cell cycle effects varied with topotecan concentration, resulting in G1 arrest (1 microM), or S/G2/M arrest (0.05 microM), and was modified differentially in fibroblasts and in glioblastoma cells in combination with irradiation. Phosphorylation of TP53 and expression of p21(WAF1/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 1 microM topotecan generated phosphorylation of TP53 and p21(WAF1/CIP1) expression; 0.05 microM caused stabilization of cyclin B.


CONCLUSIONS
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.
Ohneseit
Petra A
PA
Section of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Germany.
Prager
Daniela
D
Kehlbach
Rainer
R
Rodemann
H Peter
HP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000166:cytology; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019772:Topotecan