PREFERENTIAL RADIOSENSITIZATION OF G1 CHECKPOINT - DEFICIENT CELLS BYMETHYLXANTHINES

Purpose: To develop a checkpoint-based strategy for preferential radio sensitization of human tumors with deficient and/or mutant p53. Method s and Materials: A549 human lung adenocarcinoma cell lines differing i n their expression of the p53 tumor suppressor gene were produced by t ransduction with the E6 oncogene from human papilloma virus type 16. T he cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a five fold greater clonogenic survival following 10 Gy radiation. Results: P ostirradiation incubation with millimolar concentrations of the methyl xanthine pentoxifylline (PTX) results in preferential radiosensitizati on of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold se nsitization of the E6+ cells, which results in equal clonogenic surviv al of the two lines. Flow cytometry reveals PTX abrogation of the radi ation induced G2 arrest for both cell lines. PTX also prolongs G1 tran sit for both cell lines. Preliminary results are presented using a nov el methylxanthine, lisofylline (LSF), which has similar cell cycle eff ects on G1 and G2 and achieves differential radiosensitization at micr omolar concentrations that are sustainable in humans. Conclusion: This checkpoint-based strategy is a promising approach for achieving prefe rential radiosensitization of p53- tumors relative to p53+ normal tiss ues. Copyright (C) 1996 Elsevier Science Inc.