Interrelationship between affinity for DNA, cytotoxicity and induction of DNA-breaks in cultured L1210 cells for two series of tricyclic intercalators

Pierson, V.; Cointet, P. De; Nguyen, Chi Hung; Bisagni, Émile; Gros, Pierre

doi:10.1016/0006-2952(89)90178-0

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…Perhaps the best insight comes from studies where association constants were determined for pairs of drugs in the same study. Consistent with the relative ranking of MMR inhibitors, daunomycin binds ϳ1.5-4-fold less strongly than AD (43)(44)(45), whereas ethidium bromide binds DNA roughly 7-fold less tightly than AD (48), which has a dissociation constant of roughly 300 nM. These binding data quantitatively recapitulate the drug ranking as MMR inhibitors, with the effective concentration for MMR inhibition in crude nuclear extracts roughly 10-fold above the measured dissociation constant for binding to calf thymus DNA.…”

Section: Discussionsupporting

confidence: 64%

“…The reduced ability of ethidium bromide to inhibit MMR, in comparison with AD, also parallels its reduced binding affinity for DNA. When compared directly, ethidium bromide bound 7-fold less well to pBR322 DNA than AD (48). Although association constants for ethidium bromide binding to DNA are variable, the measured binding affinities are consistent with a roughly 10-fold reduced affinity for DNA when compared with AD (49, 50).…”

Section: Figsupporting

confidence: 54%

“…The observation that a DNA intercalating drug is without effect on MMR is less surprising in light of the fact that m-amsacrine has a relatively weak association constant for DNA (K A ϭ 4 ϫ 10 4 M Ϫ1 ) compared with AD (K A ϭ 3.6 ϫ 10 6 M Ϫ1 , taken from Ref. 48). These data indicate that the characterized inhibition of type II topoisomerase activity by AD is likely to be distinct from its ability to inhibit MMR, because other topo II inhibitors do not inhibit MMR.…”

Section: Figmentioning

confidence: 99%

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Human Mismatch Repair and G·T Mismatch Binding by hMutSαin Vitro Is Inhibited by Adriamycin, Actinomycin D, and Nogalamycin

Larson

Drummond

2001

Journal of Biological Chemistry

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Loss of the human DNA mismatch repair pathway confers cross-resistance to structurally unrelated anticancer drugs. Examples include cisplatin, doxorubicin (adriamycin), and specific alkylating agents. We focused on defining the molecular events that link adriamycin to mismatch repair-dependent drug resistance because adriamycin, unlike drugs that covalently modify DNA, can interact reversibly with DNA. We found that adriamycin, nogalamycin, and actinomycin D comprise a class of drugs that reversibly inhibits human mismatch repair in vitro at low micromolar concentrations. The substrate DNA was not covalently modified by adriamycin treatment in a way that prevents repair, and the inhibition was independent of the number of intercalation sites separating the mismatch and the DNA nick used to direct repair, from 10 to 808 base pairs. Over the broad concentration range tested, there was no evidence for recognition of intercalated adriamycin by MutS␣ as if it were an insertion mismatch. Inhibition apparently results from the ability of the intercalated drug to prevent mismatch binding, shown using a defined mobility shift assay, which occurs at drug concentrations that inhibit repair. These data suggest that adriamycin interacts with the mismatch repair pathway through a mechanism distinct from the manner by which covalent DNA lesions are processed.

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Section: Discussionsupporting

confidence: 64%

Section: Figsupporting

confidence: 54%

Section: Figmentioning

confidence: 99%

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Human Mismatch Repair and G·T Mismatch Binding by hMutSαin Vitro Is Inhibited by Adriamycin, Actinomycin D, and Nogalamycin

Larson

Drummond

2001

Journal of Biological Chemistry

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“…The ACMA IC 50 value for the 24 h exposure time agrees well with the results recently obtained for some tricyclic and dialkyldiurea derivatives, otherwise different cell lines have been used. 39,40 The IC 50 value reported here is in the same range as that of palladium (II)-proflavine complexes for 36 h incubation in some cancer cell lines. 41 The Ames tests performed reveal that the intercalation of ACMA into DNA has genotoxic properties, since ACMA displays mutagenic ability in TA 98 and TA 102 for doses from 0.003 to 0.10 mmol ACMA per plate.…”

Section: Discussionsupporting

confidence: 63%

ACMA (9-amino-6-chloro-2-methoxy acridine) forms three complexes in the presence of DNA

Busto

Garcı́a

Leal

et al. 2011

Phys. Chem. Chem. Phys.

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The interaction of ACMA (9-amino-6-chloro-2-methoxy acridine) (D) with DNA (P) has been studied by absorbance, fluorescence, circular dichroism, spectrophotometry, viscometry and unwinding electrophoresis. A T-jump kinetic study has also been undertaken. The experimental data show that, totally unlike other drugs, ACMA is able to form with DNA three complexes (PD(I), PD(II), PD(III)) that differ from each other by the characteristics and extent of the binding process. The main features of PD(I) fulfil the classical intercalation pattern and the formation/dissociation kinetics have been elucidated by T-jump techniques. PD(II) and PD(III) are also intercalated species but, in addition to the dye units lodged between base pairs, they also bear dye molecules externally bound, more in PD(III) relative to PD(II). A reaction mechanism is put forward here. Comparison between absorbance, fluorescence and kinetic experiments has enabled us to determine the binding constants of the three complexes, namely (6.5 ± 1.1) × 10(4) M(-1) (PD(I)), (5.5 ± 1.5) × 10(4) M(-1) (PD(II)) and (5.7 ± 0.03) × 10(4) M(-1) (PD(III)). The Comet assay reveals that the ACMA binding to DNA brings about genotoxic properties. The mutagenic potential studied by the Ames test reveals that ACMA can produce frameshift and transversion/transition mutations. ACMA also is able to produce base-pair substitution in the presence of S9 mix. Moreover, the MTT assays have revealed cytotoxicity. The biological effects observed have been rationalized in light of these features.

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“…In this way, mitoxantrone and BIDA most resemble merbarone (Drake et ah, 1989b), another topoisomerase II reactive agent that has its major actions on DNA strand passage and can inhibit the DNA cleaving actions of w-AMSA. Other topoisomerase II reactive drugs have been reported to produce biphasic dose-response curves of their own DNA cleaving and cross-linking activities in cells (Potmesil et al, 1983;Capranico et al 1986;Pierson et al, 1988Pierson et al, , 1989, in isolated nuclei (Pommier et al, 1985a), and in isolated biochemical systems (Tewey et al, 1984b;Pommier et al, 1985b;Vilarem et al, 1986;Multon et al, 1989;Fosse et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions

Zwelling¹,

Mayes

Hinds

et al. 1991

Biochemistry

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HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. We now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. This appears to be due to the ability of these concentrations of mitoxantrone and amonafide to inhibit topoisomerase II mediated DNA strand passage at a point in the topoisomerization cycle prior to the acquisition of the enzyme-DNA configuration that yields DNA cleavage and topoisomerase II-DNA cross-links. In addition, amonafide can inhibit the cytotoxic actions of m-AMSA and etoposide. Taken together, these results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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Interrelationship between affinity for DNA, cytotoxicity and induction of DNA-breaks in cultured L1210 cells for two series of tricyclic intercalators

Cited by 14 publications

References 26 publications

Human Mismatch Repair and G·T Mismatch Binding by hMutSαin Vitro Is Inhibited by Adriamycin, Actinomycin D, and Nogalamycin

Human Mismatch Repair and G·T Mismatch Binding by hMutSαin Vitro Is Inhibited by Adriamycin, Actinomycin D, and Nogalamycin

ACMA (9-amino-6-chloro-2-methoxy acridine) forms three complexes in the presence of DNA

Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions

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