Phytomedicine 12 (2005) 680–683 www.elsevier.de/phymed
Photoinduced antitumour effect of hypericin can be enhanced by fractionated dosing
ˇ ´ ˇ I. Cavargaa, P. Brezanib, P. Fedorockoc, P. Misˇ kovskyc,d,Ã, N. Bobrovb, ´ b b b ˇ tubnab ´ ´ ˇ F. Longauer , S. Rybarova , L. Mirossay , J. S
ˇice, Slovakia Medical SchoolHospital of L.Pasteur, Kos ˇ ´rik University, Kos ˇice, Slovakia Faculty of Medicine, P. J. Safa c ˇ ´rik University Kos ˇice, Slovakia Faculty of Sciences, P. J. Safa d International Laser Center, Bratislava, Slovakia
Received 26 January 2004; accepted 20 February 2004
The in vivo antitumour activity of the natural photosensitizer hypericin was evaluated. C3H/DiSn mice wereinoculated with ﬁbrosarcoma G5:1:13 cells. When the tumour reached a volume of 40–80 mm3 the mice were intraperitoneally injected with hypericin, either in a single dose (5 mg/kg; 1 or 6 h before laser irradiation) or two fractionated doses (2.5 mg/kg; 6 and 1 h before irradiation with laser light; 532 nm, 70 mW/cm2, 168 J/cm2). All tumours in control groups treated with hypericin alone as well as thoseirradiated with laser light alone had similar growth rates and none of these tumours regressed spontaneously. Complete remission of tumour in photodynamic therapy (PDT)-treated groups was similar (14–17% single dose vs. 33% fractionated dose), but the fractionated schedule of hypericin dosing was found to be more efﬁcient than the single dose, measured by survival assay (po0:05). Our experimentalmodel showed that fractionated administration of hypericin can produce a better therapeutic response than single administration. r 2005 Elsevier GmbH. All rights reserved.
Keywords: Hypericin; Cancerotherapy; Photodynamic therapy; Tumour
Photodynamic therapy (PDT) is an established mode of treatment for various diseases involving cell hyperproliferation, including cancer. Thetreatment typically involves systemic administration of a tumour-localizing photosensitizer and its subsequent activation by light of an appropriate wavelength to create a photoÃCorresponding author. Faculty of Sciences, P. J. Safarik University ˇ ´ Kosˇ ice, Slovakia. Tel.: +55 6222986; fax: +55 6222124. E-mail address: firstname.lastname@example.org (P. Misˇ kovsky). ´
chemical reaction causing photodamageto the tumour (Dougherty et al., 1998). Hypericin is a plant pigment isolated from Hypericum perforatum L. which displays several photodynamic actions (Diwu, 1995). The photodynamic properties of hypericin have been tested in vitro and in vivo by several experimental studies (VanderWerf, 1996; Vandenbogaerde, 1998; Cavarga et al., 2001; Solar et al., 2002). Three mechanisms of PDT-mediated tumourdestruction in vivo have been investigated most intensively. The ﬁrst mechanism is direct tumour cell killing, the second involves damaging the tumour-associated vasculature
0944-7113/$ - see front matter r 2005 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2004.02.011
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with subsequent ischemicnecrosis, and the third mechanism is post-treatment immune response against cancer cells (Dougherty et al., 1998; Dolmans et al., 2002). In recent years the importance of direct photodynamic damage to the tumour vasculature has been stressed as an effective strategy in therapy against solid tumours. Targeting the tumour vasculature by applying a short interval between drug administration andphotoirradiation (short drug-light interval) in PDT with hypericin is more effective than a longer drug-light interval allowing the tumoural concentration of hypericin to peak (Chen et al., 2001; Chen et al., 2002). However, most current clinical PDT protocols use a drug-light interval with the maximal concentration ratio between the tumour and its surrounding healthy tissue (Dougherty et al., 1998). Dolmans...