Formation of different reaction products with single- and double-stranded DNA by the ortho-quinone and the semi-quinone free radical of etoposide (VP-16-213)

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

“…In particueffects, such as cell synchronisation, were avoided and cannot inhibition develaccount for the observed synergy. Moreover, the median J a lower level of effect plot of combined toxicity (Figure 7) Maanen et al, 1988b;Mans et al, 1990Mans et al, , 1991Sinha et ty (Figure 2) and al., 1990) can instantly induce damage to DNA. Therefore, se (Figure 3b and based on the assumption that metabolic oxidoreductive ity) in cell cycle transformations of VP-16 are important for its cytotoxic I cells arrested by action, we suggest that photosensitisation-induced depletion ralue of approxiof intracellular reductants facilitates VP-16 metabolism, trresponds to the probably on the level of VP-16 phenoxyl free radical -owing K562 cells transformations.…”

“…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.…”

“…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.)…”

“…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.…”

The Activation of c-Jun NH2-terminal Kinase (JNK) by DNA-damaging Agents Serves to Promote Drug Resistance via Activating Transcription Factor 2 (ATF2)-dependent Enhanced DNA Repair

“…4, B-D). Etoposide complexes with topoisomerase II and DNA and blocks ligation leading to an accumulation of double-stranded and single-stranded breaks (54). Actinomycin D blocks replication by intercalation (55).…”