Clinical and experimental evidence of Bcl-2 involvement in the response to photodynamic therapy.
OBJECTIVE
The role of apoptosis related proteins in the response of human malignancies to photodynamic therapy (PDT) is under investigation. The aim of the study was to examine the role of p53 and of bcl-2 protein expression in the response to PDT.


METHODS
Paraffin-embedded material from 37 patients with early esophageal cancer treated with PDT (argon dye laser after intravenous injection of hematoporphyrine derivative) was studied immunohistochemically for p53 protein nuclear accumulation and bcl-2 cytoplasmic expression. Patients with residual disease after two rounds of PDT received definitive radiotherapy. In a subsequent in vitro study, W138 human lung fibroblasts and W138-SV-40 virus transformed were assessed for their sensitivity to PDT. The constitutive bcl-2 overexpression of the transformed cells vs. normal cells (assessed with RT-PCR) was 16-fold.


RESULTS
Positive bcl-2 and p53 expression was noted in 10 out of 36 (27%) and 14 out of 36 (39%) patients, respectively. Seven out of 11 tumors (63%) with bcl-2 expression responded completely to PDT vs. 6 out of 26 (23%) of cases with no bcl-2 expression (p = 0.02). No association of p53, T-stage and of histology grade with response to PDT or PDT/RT was noted. The sensitivity to PDT of transformed human fibroblasts compared to normal ones was 4 times more at a fluence of 4.3 J/cm2 (4% vs. 1% cell kill) as well as at a fluence of 5.4 J/cm2 (8% vs. 2% cell kill).


CONCLUSIONS
Bcl-2 protein expression is associated with favorable response to PDT and can be used as a predictor of cancer response to PDT. This finding can be explained by experimental studies showing that PDT induces selective degradation of the bcl-2 protein, leading to apoptosis by decreasing the bcl-2/bax ratio. Studies on PDT combination with agents targeting bcl-2 (i.e. taxanes) are on going to eventually assess a super-additive effect.
Koukourakis
M I
MI
Department of Radiotherapy and Oncology, University of Thessalia, Larisa, Greece. TARG@her.forthnet.gr
Corti
L
L
Skarlatos
J
J
Giatromanolaki
A
A
Krammer
B
B
Blandamura
S
S
Piazza
M
M
Verwanger
T
T
Schnitzhofer
G
G
Kostandelos
J
J
Beroukas
K
K
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001128:Argon; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D002461:Cell Line, Transformed / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004351:Drug Resistance; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D017324:Hematoporphyrin Derivative / Q000627:therapeutic use*; D006801:Humans; D007834:Lasers; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000502:physiology*; D010778:Photochemotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D001128:Argon; D017324:Hematoporphyrin Derivative