Photodynamic therapy combined with a cysteine proteinase inhibitor synergistically decrease VEGF production and promote tumour necrosis in a rat mammary carcinoma.
OBJECTIVE
Photodynamic therapy (PDT) and inhibition of cathepsin B proteases by cystatin (cysteine proteinase inhibitor, CPI) are potential new tumour treatment modalities. We have investigated the efficacy of PDT and CPI alone and in combination on a solid mammary carcinoma transplanted into Wistar rats.


METHODS
Intraperitoneally injected single doses of chlorine e6 or HpD as photosensitizers were excited at 630 nm (90 J/cm(2)). CPI (500 micro g per animal) was injected around the tumour daily during the 8-day treatment. Inoculation of tumour was either on day 1 of the protocol, or 8 days before. On day 8, tumour size was measured, tumour necrosis and vascularization were determined based on haematoxylin and eosin (H&E)-stained sections and serum vascular endothelial growth factor (VEGF) levels measured using an enzyme-linked immunosorbent assay kit.


RESULTS
No differences (two-way anova) were found for treatments started with various time lags. At doses where CPI or PDT alone had no or negligible effect, their combination caused a marked (P < 0.001) decrease in serum VEGF, paralleled by a significant decrease in tumour size and number of capillary vessels, and a significant increase in necrosis (up to 80% of the tumour tissue).


CONCLUSIONS
The combination of PDT and CPI could be a useful approach in tumour therapy as the two agents appear to be synergistic and probably decrease VEGF production by the tumour tissue.
Zsebik
B
B
University of Debrecen, Medical and Health Science Center, Faculty of Medicine, Department of Biophysics and Cell Biology, 98 Nagyerdei krt, 4012 Debrecen, Hungary.
Symonowicz
K
K
Saleh
Y
Y
Ziolkowski
P
P
Bronowicz
A
A
Vereb
G
G
D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D015891:Cystatins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009336:Necrosis; D009368:Neoplasm Transplantation; D010778:Photochemotherapy / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A