Preferential radiosensitization of G1 checkpoint-deficient cells by methylxanthines.
OBJECTIVE
To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53.


METHODS
A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation.


RESULTS
Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans.


CONCLUSIONS
This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.
Russell
K J
KJ
Department of Radiation Oncology, University of Washington Medical Center, Seattle 98195-6043, USA.
Wiens
L W
LW
Demers
G W
GW
Galloway
D A
DA
Le
T
T
Rice
G C
GC
Bianco
J A
JA
Singer
J W
JW
Groudine
M
M
D002470:Cell Survival / Q000528:radiation effects; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C025189:lisofylline; D010431:Pentoxifylline