IN-VIVO INFLUENCE OF P53 STATUS ON PROLIFERATION AND CHEMORADIOSENSITIVITY IN NON-SMALL-CELL LUNG-CANCER

Alteration of the p53 gene product is a frequent event in the progress ion of lung cancer. However, its importance to proliferation and respo nse to chemoradiotherapy remains unclear. Thus, to assess its influenc e directly in vivo, we implanted into nude mice two kinds of human non -small-cell lung cancer (NSCLC) cells: H226br having a homozygous gene mutation in p53 (mt-p53) and H226b with intact p53 (wt-p53). We found that mt-p53 tumors grew substantially faster than wt-p53 tumors. Furt hermore, treatment with cisplatin and radiation did not reduce the siz e of mt-p53 tumors, while wt-p53 tumors regressed by approximately 60% . Terminal-deoxytransferase-mediated dUTP-biotin nick-end labeling ass ay revealed apoptosis to be the mechanism responsible for the regressi on. Interestingly, apoptosis occurred in mt-p53 tumors although only a t high doses of cisplatin and not at the magnitude detected in wt-p53 tumors. Cell labeling by staining with bromodeoxiuridine indicated tha t p53 is an important factor in modulating growth in NSCLC tumors. Our results are consistent with the notion that correction of a single ge netic lesion enhances the therapeutic effect of chemotherapy.