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 progression of lung cancer. However, its importance to proliferation and response to chemoradiotherapy remains unclear. Thus, to assess its influence 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. Furthermore, treatment with cisplatin and radiation did not reduce the size of mt-p53 tumors, while wt-p53 tumors regressed by approximately 60%. Terminal-deoxytransferase-mediated dUTP-biotin nick-end labeling assay revealed apoptosis to be the mechanism responsible for the regression. Interestingly, apoptosis occurred in mt-p53 tumors although only at high doses of cisplatin and not at the magnitude detected in wt-p53 tumors. Cell labeling by staining with bromodeoxiuridine indicated that p53 is an important factor in modulating growth in NSCLC tumors. Our results are consistent with the notion that correction of a single genetic lesion enhances the therapeutic effect of chemotherapy.
Perdomo
J A
JA
First Department of Surgery, Okayama University Medical School, Japan.
Naomoto
Y
Y
Haisa
M
M
Fujiwara
T
T
Hamada
M
M
Yasuoka
Y
Y
Tanaka
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D002455:Cell Division / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin