Lung tumor induction in A/J mice and clastogenic effects in CD-1 mice of the sequence-selective DNA alkylating agents (+)-CC-1065 and (-)-CC-1065.
The in vivo genotoxic effects of the antitumor antibiotic, (+)-CC-1065, and its unnatural enantiomer, (-)-CC-1065, were investigated in two mouse models. These two compounds alkylate AT-rich regions of double stranded DNA with distinct sequence selectivities. (+)-CC-1065 dose-dependently increased the chromosomal aberration frequency in bone marrow cells of CD-1 mice from 1.2 +/- 0.8% in vehicle control animals to 5.0 +/- 1.2%, 11.4 +/- 3.9%, and 20.6 +/- 2.3% 24 hours following single intravenous doses of 2, 4, and 8 micrograms/kg, respectively. (-)-CC-1065 was significantly less potent with a maximal response at 8 micrograms/kg approximately one-third of that observed for (+)-CC-1065. (+)-CC-1065 induced a significant (P < or = 0.05), three-fold increase in the number of lung tumors/mouse in strain A/J mice from 0.27 +/- 0.15 for vehicle control animals to 0.83 +/- 0.15 24 weeks following a single intravenous dose of 8 micrograms/kg. This effect was paralleled by corresponding threefold increases in the percentage of mice with tumors and the percentage of mice with multiple tumors, compared to vehicle controls. (-)-CC-1065 at 8 micrograms/kg induced 0.67 +/- 0.15 tumors/mouse and resulted in slightly smaller increases in the tumor incidence and multiple tumor incidence, compared to (+)-CC-1065. The above results demonstrate that single intravenous doses of (+)- CC-1065 and (-)-CC-1065 which cause chromosomal damage in CD-1 mice also induce an increased incidence of lung tumors in A/J mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Linseman
D A
DA
Department of Investigative Toxicology, Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
Branstetter
D G
DG
Yu
R L
RL
Aaron
C S
CS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000648:ultrastructure; D015197:Carcinogenicity Tests; D002869:Chromosome Aberrations; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000633:toxicity*; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000648:ultrastructure; D051379:Mice; D008805:Mice, Inbred A; D009153:Mutagens / Q000633:toxicity*; D013237:Stereoisomerism
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D009153:Mutagens; C018782:CC 1065