title: Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice.
abstract: Inactivation of p53 function, which frequently occurs in tumors, can significantly modulate tumor cell sensitivity to radiation and chemotherapeutic drugs. However, in addition to acting on malignant cells, anticancer agents act on the cells of tumor stroma, causing activation of a p53 response. The effect of this response on treatment outcome has been the subject of the present study. Tumors with p53-deficient stroma were generated using mouse tumorigenic packaging cells that produce a p53 inhibitory retrovirus, encoding a dominant-negative p53 mutant. Tumors maintaining wild-type p53 in their stroma were formed by cells of similar origin but deficient in retroviral production due to the deletion of the packaging signal in the retroviral vector. Comparison of these tumor models, differing only in p53 status of their stromas, showed that tumors with p53-deficient stroma were significantly more sensitive to experimental chemotherapy and radiotherapy. A similar effect was achieved when anticancer treatment was combined with pharmacologic suppression of p53 by the cyclic form of pifithrin alpha, a small-molecule inhibitor of p53. Potentiation of the anticancer effect of chemotherapy and radiotherapy by p53 suppression in the tumor stroma is likely to be due to the increased sensitivity of p53-deficient endothelium to genotoxic stress as shown both in cell culture and in experimental tumors. Thus, reversible pharmacologic suppression of p53 may be a viable approach to improving anticancer treatment via an enhanced antiangiogenic effect of chemotherapy and radiotherapy.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
authors.forename: Elena A
authors.initials: EA
authors.lastname: Komarova
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hill
authors.forename: Timothy
authors.initials: T
authors.lastname: Browder
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Tararova
authors.forename: Lori
authors.initials: L
authors.lastname: Mavrakis
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D002461:Cell Line, Transformed; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000528:radiation effects; D005347:Fibroblasts; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017154:Stromal Cells / Q000187:drug effects / Q000528:radiation effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D052160:Benzothiazoles; D007093:Imidazoles; C442830:QB 102; D011838:Radiation-Sensitizing Agents; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D003520:Cyclophosphamide; C121565:pifithrin