Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair.
Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-l-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-l-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells.
Fischer
Joshua L
JL
Indiana University Cancer Center, Indiana University School of Medicine, Room 155, 1044 West Walnut Street, Indianapolis, IN 46202, USA.
Mihelc
Elaine M
EM
Pollok
Karen E
KE
Smith
Martin L
ML
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004260:DNA Repair; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D016678:Genome / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051379:Mice; D009928:Organ Specificity; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000378:metabolism; D012645:Selenomethionine / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D014466:Ultraviolet Rays
D009944:Organoplatinum Compounds; D016566:Organoselenium Compounds; D016159:Tumor Suppressor Protein p53; D004247:DNA; D012645:Selenomethionine; C008493:methylselenic acid