Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment.
BACKGROUND
Mutations within the tumor suppressor TP53 gene are one of the most common genetic alterations present at high frequency in human tumors and have been shown to be associated with resistance to radio-chemotherapy. The lack of the wild type TP53 gene in cancer cells could be exploited for therapeutic advantage using a sequence of two antagonistic drugs. The aim of this study was to selectively kill p53 deficient cells (FaDu and H1299) by taxol and to protect p53 wild type cells (A549) by the prior administration of nutlin-3 in comparison to certain known anticancer drugs (5-fluorouracil, camptothecin, roscovitine).


METHODS
Cytotoxic and cytostatic properties of 5-fluorouracil, camptothecin, roscovitine and nutlin-3 administrating alone or in combination with taxol were investigated in vitro by flow cytometry.


RESULTS
It was found that nutlin-3 induced growth arrest and protected A549 cells from taxol. FaDu and H1299 cells responded to the same treatments with mitotic arrest and massive apoptosis. Other compounds (5-fluorouracil, camptothecin and roscovitine) revealed weaker selectivity and elevated toxicity in comparison to nutlin-3.


CONCLUSIONS
We propose a therapeutic strategy protecting normal cells from taxol while increasing apoptosis selectively in p53-deficient cells using nutlin-3.
Tokalov
Sergey V
SV
OncoRay - Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74/PO Box 86, 01307 Dresden, Germany. Sergey.Tokalov@oncoray.de
Abolmaali
Nasreddin D
ND
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D002166:Camptothecin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry / Q000379:methods; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D000077546:Roscovitine; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D007093:Imidazoles; D010879:Piperazines; D011687:Purines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077546:Roscovitine; C482205:nutlin 3; D005472:Fluorouracil; D002166:Camptothecin