Relationship between DNA cross-links, cell cycle, and apoptosis in Burkitt's lymphoma cell lines differing in sensitivity to nitrogen mustard.
We surveyed 11 Burkitt's lymphoma cell lines for chemosensitivity to nitrogen mustard (HN2) in order to determine whether any simple correlates to cytotoxic response might be revealed. The lines tested varied over a 5-fold range in concentration of HN2 required to inhibit tumor cell growth by 50%. Drug sensitivity correlated neither with continental origin of tumor, growth fraction, presence of Epstein-Barr virus, nor with the precise locations of (8;14) translocation breakpoints. Furthermore, contrary to experience with other cell lines, no simple correlation was found between the HN2 sensitivity of the four most divergent lines (low sensitivity, CA46 and MC116 cells; high sensitivity, Namalwa and JLP119 cells) and exposure to DNA cross-links (area under the DNA cross-linking-versus-time curve). In addition, we found similar extents of gene-specific HN2-induced damage in the native and translocated c-myc alleles of CA46 and JLP119 cells. At equimolar HN2 treatment, CA46 cells exhibited a profound arrest in G2M phase, while JLP119 cells exhibited prolonged S-phase delay. This suggested that despite similar DNA cross-link exposure, JLP119 cells were less able to complete DNA replication while repair was in progress. As cell cycle distribution returned to near normal, JLP119 cells exhibited DNA degradation characterized by oligonucleosome-sized DNA fragments prior to cell membrane disintegration. Our findings indicate that HN2-sensitive Burkitt's lymphoma cells may be more susceptible to delay in S phase for a given frequency of DNA cross-links and that prolongation of S phase correlated with apoptotic cell death.
O'Connor
P M
PM
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Wassermann
K
K
Sarang
M
M
Magrath
I
I
Bohr
V A
VA
Kohn
K W
KW
D000478:Alkylation; D002051:Burkitt Lymphoma / Q000473:pathology* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D016259:Genes, myc; D006801:Humans; D066298:In Vitro Techniques; D008466:Mechlorethamine / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D008466:Mechlorethamine; D004247:DNA