Comparison of effects of doxorubicin and radiation on p53-dependent apoptosis in vivo.
The effects of doxorubicin and radiation on apoptosis, p53 expression, and tumor growth in human tumor xenografts were investigated. Human ependymoblastoma (NNE), primitive neuroectodermal tumor (YKP), glioblastoma (KYG) and small cell lung carcinoma (GLS) that are all transplantable to nude mice were treated with doxorubicin (8 mg/kg) or radiation (1 Gy). The histological study was performed by using TUNEL and p53 staining. Cytotoxic effects of doxorubicin and radiation were compared with no-treatment group by the growth curves and apoptotic index of tumor to each treatment. In NNE with wild-type p53, doxorubicin induced growth delay of tumors (tumor volume doubling time; 13.7+/-3.3 days in control group vs 30.4+/-1.5 days in doxorubicin group), but no growth delay of tumors in KYG and GLS with mutant type p53. While radiation-induced apoptosis appeared most frequently at 6 h after irradiation, doxorubicin-induced apoptosis had a tendency to appear later. Furthermore, although the frequency of doxorubicin-induced apoptosis was lower than that of apoptosis by 1 Gy irradiation, apoptotic cells appeared for many hours after the treatment. Doxorubicin-induced apoptosis may be correlated with p53 phenotype because apoptosis was induced only in tumor with wild-type p53, but it appeared less frequently and later than radiation-induced apoptosis.
Hayakawa
K
K
Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan.
Hasegawa
M
M
Kawashima
M
M
Nakamura
Y
Y
Matsuura
M
M
Toda
H
H
Hayakawa
K
K
Mitsuhashi
N
N
Niibe
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin