Liblomycin-mediated DNA cleavage in human head and neck squamous carcinoma cells and purified DNA.
Liblomycin (LBM), a novel bleomycin analogue, and bleomycin A2 (BLM A2) were compared with respect to their relative potential to inhibit growth in a human head and neck squamous carcinoma cell line and to produce DNA damage within cellular DNA and nuclei DNA and against isolated naked DNA. Against the BLM-sensitive cell line 183A, the concentration of LBM that inhibits cell growth by 50% was 1.1 microM for a 30-min drug exposure, while it was 23 microM for BLM A2. Drug-mediated DNA double-strand cleavage within cells was compared with the relative ability of these drugs to produce DNA cleavage in isolated 183A cell nuclei. Though 30-min exposures of cells to equimolar concentrations of both drugs resulted in 4-fold greater cellular DNA damage by LBM than BLM A2, the two drugs were nearly equipotent in producing DNA injury within isolated nuclei. Against Simian virus 40 DNA, however, LBM was 10-fold less effective than BLM A2 in producing Forms II and III DNA from Form I DNA. Radioactivity from either [3H]BLM A2 or 125I-LBM found associated with cells after a 30-min incubation period was also assessed in the 183A cell line. The exposure of cells to radiolabeled drug (1 microM) resulted in a 71-fold greater amount of cell-associated radioactivity for LBM than for BLM A2. The relative abilities of the 183A cell line to partially reseal LBM- or BLM A2-mediated DNA double-strand breaks were also assessed. No preferential repair of overall drug-mediated DNA injury, however, was observed. Finally, drug-mediated specific cleavage sites on pBR322 DNA were determined. At doses that gave the same extent of DNA cleavage, both BLM A2 and LBM gave similar patterns of strand scission, although minor differences were observed. Taken together, these data demonstrate that the greater efficacy of LBM against the BLM-sensitive head and neck squamous cell line is due mainly to LBM's greater association with cells over a defined time period, even though the DNA cleaving ability of LBM is relatively lower than that of BLM A2.
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
K
K
Wassermann
L A
LA
Zwelling
J W
JW
Lown
J A
JA
Hartley
K
K
Nishikawa
J R
JR
Lin
R A
RA
Newman
D001483:Base Sequence; D001761:Bleomycin / Q000494:pharmacology* / Q000031:analogs & derivatives; D002294:Carcinoma, Squamous Cell; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000302:isolation & purification / Q000528:radiation effects; D006258:Head and Neck Neoplasms; D006801:Humans; D008969:Molecular Sequence Data; D010957:Plasmids; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*
D004273:DNA, Neoplasm; D001761:Bleomycin; C054113:liblomycin