Combination toxicity of etoposide (VP-16) and photosensitisation with a water-soluble aluminium phthalocyanine in K562 human leukaemic cells

Abstract

Summary Etoposide (VP-16) is an anti-cancer drug commonly used against several types of tumours and leukaemia, either alone or in combination chemotherapy. Photodynamic therapy (PDT) is another, relatively new modality for treatment of various malignancies. The interactions between VP-16 and PDT, using aluminium tetrasulphophthalocyanine as photosensitiser, in K562 human leukaemic cells were investigated. Cell responses to individual and combined drug treatment under different experimental conditions revealed synergistic drug toxicity. The latter was evident from various events of cell response, including supra-additive accumulation of cells in G2/M cell cycle phase and endonucleolytic DNA fragmentation (apoptosis). The involvement of the cellular antioxidant system in the synergistic interactions of photosensitisation and VP-16 is proposed.Keywords: etoposide; phthalocyanine; photosensitisation; combination therapy; synergy fl-D-glucopyranoside, is an important antineoplastic agent used against several tumour types, either alone (Issel et al., 1984), or in combination therapy (Aisner and Lee, 1991). Etoposide is also commonly used for the treatment of acute myelogenous leukaemia (Champlin and Gale, 1987). The cytotoxicity of VP-1 6 is generally believed to be based on introduction of DNA damage by drug interference with breakage -reunion reaction of DNA -topoisomerase II (formation of DNA -protein cross-links) (Glisson and Ross, 1987;Liu, 1989) and/or induction of direct DNA strand breaks and adducts (van Maanen et al., 1988a, b;Mans et al., 1991). In contrast to the topoisomerase II (topo II) poisoning by VP-16 itself, the direct inactivation of DNA was suggested to be conjugated with oxidation-reduction activation of VP-16 in the cellular environment (Mans et al., 1990(Mans et al., , 1992. In particular, cytochrome P450-dependent mono-oxygenases, peroxidases, prostaglandin synthetase, tyrosinase, etc. may be involved in VP-16 metabolic transformation (van Maanen et al., 1987;Haim et al., 1991;Gantchev et al., 1994a). Evidence has been found that peroxidative metabolic products of VP-16, e.g. the ortho-quinone derivative of etoposide, as well as the short-lived intermediates (phenoxyl and semi-quinone free radicals) are involved in various oxidative reactions and DNA damage (Mans et al., 1990(Mans et al., , 1991Sinha et al., 1990). Recent studies suggest that the interactions of VP-16 free radicals with intracellular reductants (thiols, ascorbic acid, etc.) might play an essential role in the cytotoxic activity of the drug as well (Mans et al., 1992;Kagan et al., 1994; Yokomizo et al., 1995).Light activation of photosensitisers that have been accumulated in tumours is the basis of the photodynamic therapy (PDT) of cancer. Cytotoxic action of photosensitisers may involve oxidative damage to different cell constituents, including depletion of the pool of cell antioxidants (free and protein-bound thiols, ascorbic acid, a-tocopherol, etc.) (Buettner, 1984, Shopova and Gantchev, 1990, Gantchev and van Lier, 1995 L...

Non-monotonic changes in clonogenic cell survival induced by disulphonated aluminum phthalocyanine photodynamic treatment in a human glioma cell line

“…Similar G 2 block has also been reported in human chronic myelogenous leukemia cells after AlPcS photosensitization under a wide range of light dose and pre-incubation times [24]. …”

Combination of Near Infrared Light-Activated Photodynamic Therapy Mediated by Indocyanine Green with Etoposide to Treat Non-Small-Cell Lung Cancer

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Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

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