A p53 growth arrest protects fibroblasts from anticancer agents.
Reversible inhibitors of the cell cycle such as the TGF-betas have been exploited to protect dividing cells from exposure to anticancer drugs and radiation. Here, rat embryo fibroblast (REF) lines expressing different p53 mutations were used to test whether the p53 growth arrest could also chemoprotect cells from high doses of anticancer drugs. Whereas the doubling times of the different REF lines at 37 degrees C were similar, cells bearing temperature-sensitive mutations (mouse 135V or human 143A) were growth arrested at 31 degrees C. Temperature-dependent p53 activity was associated with increased levels of MDM2 and p21/WAF1, and the induction of an integrated p53-responsive luciferase gene. The REF lines exhibited similar sensitivities to common anticancer drugs when grown at 37 degrees C. However, when exposed to the same agents following transient incubation at 31 degrees C, the p53-arrested cells exhibited a marked survival advantage as shown by colony-forming assays. Chemoprotection was not universal, in that colony formation was not enhanced significantly after treatment with cisplatin or 5-fluorouracil, two drugs which can cause cellular damage throughout the cell cycle. Like other negative growth regulators, an activated p53 checkpoint may mediate the survival of cells exposed to drugs that target DNA synthesis or mitosis.
McCormack
E S
ES
OSI Pharmaceuticals Inc., 106 Charles Lindbergh Blvd., Uniondale, NY 11553-3649, USA. Smccormack@OSIP.com
Bruskin
A M
AM
Borzillo
G V
GV
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D018929:Cell Culture Techniques; D002470:Cell Survival; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts; D008938:Mitosis; D051381:Rats / Q000196:embryology; D013234:Stem Cells; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004247:DNA