Reactions of glutathione with the catechol, the ortho-quinone and the semi-quinone free radical of etoposide Consequences for DNA inactivation

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

“…Similarly, in our previous studies with Namalva Burkitt's lymphoma cells (Gantchev et al, 1994b, photosensitisation of K562 cells results in division block and, depending on the extent of the treatment, is followed either by cell regrowth or by predominant cell death. Unlike photosensitisation with Photofrin, which induces S-phase cell cycle arrest (Gantchev et al, 1994d) (Mans et al, 1991(Mans et al, , 1992Ritov et al, 1995). It is, however, kic toxicity of the noteworthy that the intracellular accumulation of these as calculated for products depends strongly on the presence of cellular Kclusive drugs (Fi, antioxidants (e.g.…”

“…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.)…”

“…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).…”

“…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 in the cellular environment (Mans et al, 1990(Mans et al, , 1992. In particular, cytochrome P450-dependent mono-oxygenases, peroxidases, prostaglandin synthetase, tyrosinase, etc.…”

Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation

“…In analogy, EPR spectra corresponding to larger quinone/GSH ratios are assigned to the free semiquinones EQ ·− and CLQ ·− and those corresponding to smaller quinone/GSH ratios assigned to GSH-conjugated semiquinones (Table I). GSH addition to the quinone ring has been detected in previous works for other orthoquinones [16] and EQ itself [23,33]. In fact, the GSH adduct of EQ has been recently found and characterized in myeloperoxidaseexpressing human myeloid leukaemia HL60 cells when treated with etoposide for 30 min [23].…”