Interaction of CC-1065 and its analogues with mouse DNA and chromatin.
CC-1065 is a potent antitumor antibiotic which is cytotoxic to P388 and L1210 leukemia cells in vitro and in vivo. CC-1065 covalently binds to calf thymus DNA preferentially to adenine-thymine regions at N3 of adenine. Here, we compare CC-1065 interaction with P388-derived chromatin, DNA, and histones as measured by electronic absorption and circular dichroism. Two CC-1065 analogues (U-71,184 and its enantiomer, U-71,185) which show different biological activities from CC-1065 were also studied. The shape and temporal behavior of the induced circular dichroism curves generated by CC-1065 or its analogues bound to chromatin were similar to CC-1065 plus DNA. This suggested that CC-1065 and its analogues bind to the minor groove of chromatin DNA in a manner similar to calf thymus DNA. However, the binding of CC-1065 and its analogues to DNA induced a more intense circular dichroism band than binding to chromatin. The order of interaction for both chromatin and DNA was CC-1065 greater than U-71,184 greater than U-71,185. In contrast to the essentially irreversible binding to DNA after 24-h incubation, binding to chromatin was primarily a reversible interaction, the degree of reversibility being U-71,185 greater than U-71,184 = CC-1065. CC-1065 binds weakly and nonspecifically to histones.
Moy
B C
BC
Department of Cancer and Infectious Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Prairie
M D
MD
Krueger
W C
WC
Bhuyan
B K
BK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D000080890:Duocarmycins; D006657:Histones / Q000378:metabolism; D007211:Indoles; D007933:Leucomycins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D012965:Sodium Chloride / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D000080890:Duocarmycins; D006657:Histones; D007211:Indoles; D007933:Leucomycins; D012965:Sodium Chloride; C018782:CC 1065; D004247:DNA