Photodynamic therapy with hypericin in a mouse P388 tumor model: vascular effects determine the efficacy.
Hypericin, a polycyclic quinone obtained from plants of the Hypericum genus, exhibits strong photodynamic antitumor effects. In the present study, PDT efficacy of hypericin under different conditions was compared in a P388 mouse tumor model. Plasma and tumor drug measurements and assessment of vascular damage by fluorescein dye exclusion were performed to determine the relative contributions of vascular effects and direct tumor cytotoxicity. Furthermore, the influence of modifying tumor oxygenation on PDT effect was also evaluated. Study of PDT efficacy and tissue distribution revealed that PDT efficacy was more dependent on plasma concentration than tumor drug level. Fluorescein dye exclusion indicated the complete microvascular occlusion in the tumor and surrounding skin immediately after effective PDT treatments, while only a limited vascular occulation was observed after non-effective PDT treatment. It was found that neither tumor hypoxia induced by hydralazine nor increasing tumor oxygenation achieved by nicotinamide could significantly affect the effectiveness of various PDT protocols. These results suggest that tumor vasculature damage might be the primary mechanism of hypericin-mediated PDT effect. The existence of this potent secondary vascular effect is likely to account for the inability of tumor oxygenation modifiers to affect tumor response after PDT with hypericin.
Laboratorium voor Farmaceutische Biologie en Fytofarmacologie, Faculteit Farmaceutische Wetenschappen, Katholieke Universiteit Leuven, Van Evenstraat 4, B-3000 Leuven, Belgium.
B
B
Chen
I
I
Zupkó
P A
PA
de Witte
D000818:Animals; D000873:Anthracenes; D001808:Blood Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D019793:Fluorescein / Q000378:metabolism; D006830:Hydralazine / Q000627:therapeutic use; D007275:Injections, Intravenous; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009536:Niacinamide / Q000627:therapeutic use; D010100:Oxygen / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D014665:Vasodilator Agents / Q000627:therapeutic use
D000873:Anthracenes; D017319:Photosensitizing Agents; D014665:Vasodilator Agents; D009536:Niacinamide; D006830:Hydralazine; D010569:Perylene; C004965:hypericin; D010100:Oxygen; D019793:Fluorescein