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Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay.
- Source :
-
Cancer research [Cancer Res] 1995 Apr 15; Vol. 55 (8), pp. 1643-8. - Publication Year :
- 1995
-
Abstract
- Most drug discovery efforts have focused on finding new DNA-damaging agents to kill tumor cells preferentially. An alternative approach is to find ways to increase tumor-specific killing by modifying tumor-specific responses to that damage. In this report, we ask whether cells lacking the G1-S arrest in response to X-rays are more sensitive to X-ray damage when treated with agents that override G2-M arrest. Mouse embryonic fibroblasts genetically matched to be (+) or (-) p53 and rat embryonic fibroblasts (+) or (-) for wild-type p53 function were irradiated with and without caffeine, a known checkpoint inhibitor. At low doses (500 microM), caffeine caused selective radiosensitization in the p53(-) cells. At this low dose (where no effect was seen in p53(+) cells), the p53(-) cells showed a 50% reduction in the size of the G2-M arrest. At higher doses (2 mM caffeine), where sensitization was seen in both p53(+) and p53(-) cells, the radiosensitization and the G2-M override were more pronounced in the p53(-) cells. The greater caffeine-induced radiosensitization in p53(-) cells suggests that p53, already shown to control the G1-S checkpoint, may also influence aspects of G2-M arrest. These data indicate an opportunity for therapeutic gain by combining DNA-damaging agents with compounds that disrupt G2-M arrest in tumors lacking functional p53.
- Subjects :
- Animals
Cell Cycle drug effects
Cell Survival drug effects
Cell Survival radiation effects
Cells, Cultured
Dose-Response Relationship, Radiation
Embryo, Mammalian
Fibroblasts drug effects
Fibroblasts radiation effects
G2 Phase drug effects
Mice
Mice, Knockout
Mitosis drug effects
Mitosis radiation effects
X-Rays
Caffeine pharmacology
Cell Cycle radiation effects
G2 Phase radiation effects
Genes, p53
Radiation-Sensitizing Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 55
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 7712468