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Title: Dynamics of cell cycle perturbations and cell death by topoisomerase inhibitors in human B-lymphoma cell lines
Author: Chin, S.-F.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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This study investigates the relationship between cell cycle perturbations and apoptosis, principally in two human B-lymphoma cell lines with different genotypes after exposure to four topoisomerase inhibitors, CPT, DOX, VP-16 and ICRF-193. Both cell lines (DoHH2 and SU-DHL-4) overexpress bcl-2 due to the t(14;18)(q32,q21) translocation, but DoHH2 alone express active wild-type p53. Using both flow cytometric and molecular biological assays, it was shown that wild-type p53 is required for the expression of apoptosis at low drug concentrations only. The higher level of bcl-2 and mutant p53 in SU-DHL-4 appears to account for its resistance to apoptosis. Kinetic studies on apoptosis in DoHH2 showed that S phase cells were most sensitive to death signals. G2 cells, originating from S phase during drug treatments, were more sensitive to death stimuli than cells that were late S phase or G2. The persistent non-apoptotic G2 cells could be eliminated when allowed to reverse the arrest with caffeine. The ability of SU-DHL-4 cells to arrest without commitment to apoptosis suggests that post-G1 arrest is not a consequence of DNA fragmentation per se. Interestingly, great similarities in cell cycle perturbations, commitment to apoptosis, induction of p53 and p21WAF-1/CIP-1 expression were observed between ICRF-193, a non-DNA-damaging agent, and VP-16, a DNA-damaging agent. Unexpectedly, apoptosis was detected in early S phase cells after ICRF-193 treatment suggesting a requirement for topoisomerase II, possibly for decatenation or chromatin re-organisation during DNA replication. Dysfunction of this topoisomerase II-dependent function could have triggered the p53-p21WAF-1/CIP-1 mediated apoptosis in competent cells (DoHH2) but did not prevent completion of DNA replication in SU-DHL-4.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available