Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: Relationship with DNA binding affinity and cytotoxicity

Journal Article · Tue Jan 16 00:00:00 EST 1990 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00454a033· OSTI ID:6718554

Capranico, G; Kohn, K W; Pommier, Y ^[1]; Zunino, F ^[2]

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1. National Institutes of Health, Bethesda, MD (USA)
2. Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan (Italy)

Topoisomerase II mediated double-strand breaks produced by anthracycline analogues were studied in SV40 DNA. The compounds included doxorubicin, daunorubicin, two doxorubicin stereoisomers (4{prime}-epimer and {beta}-anomer), and five chromophore-modified derivatives, with a wide range of cytotoxic activity and DNA binding affinity. Cleavage of {sup 32}P-end-labeled DNA fragments was visualized by autoradiography of agarose and polyacrylamide gels. Structure-activity relationships indicated that alterations in the chromophore structure greatly affected drug action on topoisomerase II. In particular, removal of substituents on position 4 of the D ring resulted in more active inducers of cleavage with lower DNA binding affinity. The stereochemistry between the sugar and the chromophore was also essential for activity. All the active anthracyclines induced a single region of prominent cleavage in the entire SV40 DNA, which resulted from a cluster of sites between nucleotides 4237 and 4294. DNA cleavage intensity patterns exhibited differences among analogues and were also dependent upon drug concentration. Intensity at a given site dependent on both stimulatory and suppressive effects depending upon drug concentration and DNA sequence. A good correlation was found between cytotoxicity and intensity of topoisomerase II mediated DNA breakage.

• OSTI ID: 6718554
• Journal Information: Biochemistry; (USA), Vol. 29:2; ISSN 0006-2960
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ANTINEOPLASTIC DRUGS
BIOLOGICAL EFFECTS
DNA HELICASES
BIOCHEMICAL REACTION KINETICS
STRAND BREAKS
DNA REPAIR
AUTORADIOGRAPHY
DOXORUBICIN
GENETIC EFFECTS
IN VITRO
PHOSPHORUS 32
SIMIAN VIRUS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
DAYS LIVING RADIOISOTOPES
DRUGS
ENZYMES
ISOTOPES
KINETICS
LIGHT NUCLEI
MICROORGANISMS
NUCLEI
ODD-ODD NUCLEI
PARASITES
PHOSPHORUS ISOTOPES
RADIOISOTOPES
REACTION KINETICS
RECOVERY
REPAIR
VIRUSES
550201* - Biochemistry- Tracer Techniques