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.

Abstract

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)

• Authors: D A Linseman, D G Branstetter, R L Yu, C S Aaron
• Journal: Natural toxins (Nat Toxins) Vol. 3 Issue 1 Pg. 32-40 ( 1995) ISSN: 1056-9014 [Print] United States
• PMID: 7749581 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Duocarmycins
• Indoles
• Leucomycins
• Mutagens
• CC 1065

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Bone Marrow (drug effects, ultrastructure)
• Carcinogenicity Tests
• Chromosome Aberrations
• Duocarmycins
• Indoles
• Leucomycins (toxicity)
• Lung Neoplasms (chemically induced, genetics, ultrastructure)
• Mice
• Mice, Inbred A
• Mutagens (toxicity)
• Stereoisomerism