Photodynamic therapy of human breast cancer xenografts lacking caspase-3.
The human breast cancer cell line MCF-7 is deficient in procaspase-3 and in caspase-3-dependent steps in apoptosis due to deletion of the CASP-3 gene. We previously found that the cells transfected with empty vector (MCF-7v cells) were considerably less sensitive to photodynamic treatment in vitro with the phthalocyanine photosensitizer Pc 4 than were the cells stably transfected with human procaspase-3 cDNA (MCF-7c3 cells); however, overall cell killing, as determined by a clonogenic assay, was not affected by the presence of procaspase-3. The present study was undertaken to determine whether photodynamic therapy (PDT) in vivo was dependent on the ability of the cells to carry out the late steps in apoptosis that are catalyzed by this caspase. Xenografts of MCF-7 cells and the isogenic-derived MCF-7v and MCF-7c3 cells were generated in female athymic nude mice implanted with an estrogen pellet. MCF-7c3 xenografts, but not those of the other two lines, continued to express procaspase-3, as revealed by Western blots of proteins from the cells and the xenografts. When the xenografts reached 50-120 mm(3), some were treated with PDT (1mg/kg Pc 4 i.v. followed 48 h later by 150 J/cm(2) light at 672 nm and 150 mW/cm(2)), while others served as controls (no treatment, light alone, or Pc 4 alone). All Pc 4-PDT-treated tumors and none of the controls exhibited either complete or strong partial responses, and complete responses were durable for the entire observation period of 16 days. The responses were not dependent upon the presence of procaspase-3 in the xenografts. The results indicate that the rapid response of Pc 4-PDT-treated tumors in vivo is not due to their ability to carry out the major caspase-3-mediated late steps in apoptosis.
Whitacre
Cecilia M
CM
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Satoh
Taroh H
TH
Xue
Liang yan
Ly
Gordon
Nahida H
NH
Oleinick
Nancy L
NL
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D005260:Female; D006801:Humans; D015994:Incidence; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000378:metabolism
D007211:Indoles; D017319:Photosensitizing Agents; C107448:phthalocyanine Pc 4; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases