The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers.
We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.
Hamada
M
M
Department of Surgery, Okayama University Medical School, Japan.
Fujiwara
T
T
Hizuta
A
A
Gochi
A
A
Naomoto
Y
Y
Takakura
N
N
Takahashi
K
K
Roth
J A
JA
Tanaka
N
N
Orita
K
K
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011836:Radiation Tolerance; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53