title: Abrogation of G(2)/M-phase block enhances the cytotoxicity of daunorubicin, melphalan and cisplatin in TP53 mutant human tumor cells.
abstract: Irradiation of human melanoma (MeWo, Be11) and squamous cell carcinoma (4451, 4197) cells induces cell cycle blocks from which the cells recover to re-enter mitosis after 40-60 h. In the TP53 mutant cell lines, MeWo and 4451, irradiation induces a G(2)-phase block, where the fraction of cells in G(2) phase reaches a maximum after 18-20 h. In the TP53 wild-type cell lines, 4197 and Be11, a G(1)- and G(2)-phase block is reached 12 and 16 h postirradiation, respectively. Addition of pentoxifylline after irradiation at the time when the number of cells in G(2) phase has reached a maximum shortens the normal recovery from G(2)-phase block to approximately 7 h. Addition of daunorubicin, melphalan and cisplatin under these conditions markedly enhanced drug toxicity. In the TP53-mutated cell lines MeWo and 4451, the survival ratio at 7 Gy measured by colony formation was 2.3-2.8, 8.6-85 and 52-74 for daunorubicin, melphalan and cisplatin, respectively. In the TP53 wild-type cell lines, the corresponding survival ratios were found to be 1.3-1.4, 2.3-3.0 and 1.2-2.6, respectively. The survival ratios are for clonogenic survival after 7 Gy and 2 mM pentoxifylline and measure the influence of drug doses that ensure 95% survival in nonirradiated controls. The results indicate that the G(2)-phase block is a crucial event in the damage response that can be manipulated to achieve a significant enhancement of drug toxicity. These effects are particularly pronounced in TP53 mutant cells and are observed at drug doses well below the clinical range.
authors.affiliation: Department of Radiation Oncology, Radiobiology Laboratory, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: A B
authors.initials: AB
authors.lastname: Binder
authors.forename: A M
authors.initials: AM
authors.lastname: Serafin
authors.forename: L J
authors.initials: LJ
authors.lastname: Bohm
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D009154:Mutation; D010431:Pentoxifylline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D008558:Melphalan; D010431:Pentoxifylline; D003630:Daunorubicin