Topotecan lactone selectively binds to double- and single-stranded DNA in the absence of topoisomerase I.
We report the first experimental observation that a clinically important camptothecin [CPT; topotecan (TPT), a water-soluble CPT] binds directly and noncovalently to double-stranded DNA and single-stranded DNA structures in the absence of topoisomerase I, but only in the lactone form. We observed clear DNA sequence specificity of the TPT lactone binding to duplex DNA, which was comprised of alternating purine-pyrimidine sequences that contained dT. These structural studies of direct TPT lactone-DNA binding support several important considerations involving possible mechanism(s) of anticancer activity of CPT-type drugs containing a 20(S) lactone moiety.
Yao
S
S
BioNumerik Pharmaceuticals Inc., San Antonio, Texas 78229, USA.
Murali
D
D
Seetharamulu
P
P
Haridas
K
K
Petluru
P N
PN
Reddy
D G
DG
Hausheer
F H
FH
D000970:Antineoplastic Agents / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D004277:DNA, Single-Stranded / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007783:Lactones / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D019772:Topotecan / Q000378:metabolism*
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D007783:Lactones; D019772:Topotecan; D004247:DNA; D004264:DNA Topoisomerases, Type I