Genotoxicity of inhibitors of DNA topoisomerases I (camptothecin) and II (m-AMSA) in vivo and in vitro.
The present study was designed to determine and compare the clastogenicity of m-AMSA and camptothecin (CAMP) in vivo in mouse bone marrow and peripheral blood lymphocytes (PBLs), and in vitro in mouse lymphoma L5178Y cells. m-AMSA interferes with topoisomerase II to induce double-strand DNA breaks. CAMP interferes with topoisomerase I to induce single-strand DNA breaks. Thus, we expected the two drugs to induce different types of chromosomal aberrations (CAs). However, both drugs produced quantitatively and qualitatively similar numbers and types of aberrations under similar experimental conditions. In mouse bone marrow exposed over and 18-h period, both drugs (3 mg/kg) induced approximately 30 damaged cells, with an average of 0.4 chromatid breaks per cell (in 100 cells analyzed/mouse). In addition, both drugs induced only chromatid-type aberrations in mouse bone marrow in vivo when exposure occurred during G2. Cell cycle specificity was indicated by the absence of CAs when exposure to the drugs occurred in vivo in mouse PBLs during G0. In L5178Y cells, m-AMSA was considerably more potent for the induction of mutations and somewhat more potent for the induction of CAs than CAMP was. In contrast to the in vivo bone marrow results, the drugs induced high levels of both chromatid- and chromosome-type aberrations in vitro. The ultimate types of chromosomal damage induced by m-AMSA and CAMP result from a complex interaction of (i) cell cycle specific variations in topoisomerase enzyme levels, (ii) the abilities of these drugs to interfere with the orderly DNA breakage/reunion associated with topoisomerase activity, and (iii) the processing of the damage resulting from these interactions.
Backer
L C
LC
Environmental Health Research and Testing, Research Triangle Park, NC 27709.
Allen
J W
JW
Harrington-Brock
K
K
Campbell
J A
JA
DeMarini
D M
DM
Doerr
C L
CL
Howard
D R
DR
Kligerman
A D
AD
Moore
M M
MM
D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D002842:Chromatids / Q000187:drug effects; D002869:Chromosome Aberrations; D004305:Dose-Response Relationship, Drug; D015321:Gene Rearrangement; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008223:Lymphoma; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D009153:Mutagens; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D002166:Camptothecin