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.
journal_name
Radiat Resjournal_title
Radiation researchauthors
Binder AB,Serafin AM,Bohm LJdoi
10.1667/0033-7587(2000)154[0640:aogmpb]2.0.co;2subject
Has Abstractpub_date
2000-12-01 00:00:00pages
640-9issue
6eissn
0033-7587issn
1938-5404journal_volume
154pub_type
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