title: Effect of radiation and paclitaxel on p53 expression in murine tumors sensitive or resistant to apoptosis induction.
abstract: OBJECTIVE
  Tumors are thought to differ in their response to cytotoxic agents for a variety of reasons including cell cycle kinetics, degree of hypoxia, differential repair, and ability to survive when stressed. Our previous studies showed that murine mammary carcinoma MCA-4 tumors are relatively sensitive to both radiation and paclitaxel and exhibit a significant apoptotic response following treatment in vivo. In contrast, murine squamous cell carcinoma SCC-VII tumors are relatively resistant to radiation and paclitaxel and exhibit relatively little apoptosis following treatment. Since dysfunctional p53 has been shown to be associated with tumor resistance, perhaps through a dysregulated cell loss mechanism, we examined the role of p53 expression in the differential apoptotic response of these two tumors following cytotoxic treatment in vivo.
  
  
  METHODS
  Mice bearing 8-mm tumors were treated with 40 mg/kg paclitaxel i.v. or 15 Gy local tumor irradiation, and tumors were harvested at several time points up to 2 days following treatment. Histological sections of the tumors were then assessed micromorphometrically for mitotic arrest and apoptosis and immunohistochemically for p53 and p21 expression.
  
  
  RESULTS
  In the apoptosis-sensitive MCA-4 tumors, p53 expression increased rapidly following radiation from 13% at baseline to a peak of 45% within 3 h, and expression remained elevated for more than 24 h. Radiation also upregulated p21 suggesting that radiation-induced apoptosis in MCA-4 tumor is p53 dependent. Paclitaxel also induced an increase in both p53 and p21 expression in MCA-4 cells; however, the increase was delayed compared to that after irradiation. This upregulation occurred after the onset of apoptosis which would suggest that paclitaxel-induced apoptosis is p53 independent. Both radiation and paclitaxel caused p53 upregulation in the apoptosis-resistant SCC-VII tumors. The untreated SCC-VII tumor has 25% cells p53 positive and has a very high level of p21 (87% cells positive) which suggests a downstream defect in p53 response.
  
  
  CONCLUSIONS
  These results show that tumor responsiveness to paclitaxel and radiation, measured by tumor growth delay, was associated with apoptotic response. However, although both agents upregulated p53 expression in these tumors, the association between this upregulation and induction of apoptosis was not clear. Additional studies using these and other tumors are warranted to elucidate the role of p53 and its downstream effectors in the in vivo responsiveness of tumors to paclitaxel and radiation.
authors.affiliation: Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Maebashi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: C G
authors.initials: CG
authors.lastname: Milross
authors.forename: W N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Jibu
authors.forename: L J
authors.initials: LJ
authors.lastname: Peters
authors.forename: L
authors.initials: L
authors.lastname: Milas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects*; D016158:Genes, p53 / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D017239:Paclitaxel / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel