PubMed · 8685611
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S Greifzu. 1996. Chemo quick guide: alkylating agents.. https://pubmed.ncbi.nlm.nih.gov/8685611/
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We examined the effect of p53 inactivation on the response of U87MG glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These studies were motivated by three observations: (a) some human astrocytomas are sensitive to BCNU and some are resistant; (b) chemosensitive astrocytomas are more likely to be found in young adults whose tumors are more likely to harbor a p53 mutation; and (c) mouse astrocytes lacking the p53 gene are more sensitive to BCNU than wild-type cells. Here, we observed that p53 inactivation by transfection with pCMV-E6 sensitized U87MG cells to BCNU. Compared with control U87MG-neo cells with intact p53 function, the clonogenic survival of U87MG-E6 cells exposed to BCNU was reduced significantly. In U87MG-E6 cells, sensitization to BCNU was associated with failure of p21(WAF1) induction, transient cell cycle arrest in S phase, accumulation of polyploid cells, and significant cell death. In contrast, resistance to BCNU in U87MG-neo cells was associated with up-regulation of p53, prolonged induction of p21(WAF1), sustained cell cycle arrest in S phase, and enhancement of DNA repair. U87MG cells with disrupted p53 function were less able to repair BCNU-induced DNA damage and survive this chemotherapeutic insult. The question arises of whether p53 dysfunction might be a chemosensitizing genetic alteration in human astrocytic gliomas.
[reaction in text] A novel photocyclization of tosylstilbenoids is used in the preparation of a cyclopropafuroindolone analogue of the DNA-alkylating unit of the antitumor compound CC-1065.
The antitumor drug adozelesin is a potent cytotoxic DNA-damaging agent. Here we determined how adozelesin affects chromosomal DNA replication at a molecular level in a yeast model system and examined the influence of checkpoint kinase genes, the human homologues of which are mutated in cancer. Analysis of replication intermediates using two-dimensional gel electrophoresis showed that adozelesin inhibited the activity of a replication origin and stalled replication fork progression through chromosomal DNA at the origin. RAD53 and MEC1 protein kinase genes, homologues of human CHK2 and ATM, respectively, regulate an intra-S-phase DNA damage checkpoint and, when mutated, permit unchecked replication of damaged DNA in S-phase. Mutations in these genes did not abrogate adozelesin-induced inhibition of origin activity and fork progression at the replication origin. However, novel replication intermediates indicative of DNA breaks were detected only in the rad53 mutant, suggesting a role for the wild-type gene in maintaining chromosome integrity in the presence of the drug. In contrast to the inhibition of the active replication origin by adozelesin, normally silent origins present in the same chromosome were activated by adozelesin in rad53 and mec1 mutant cells. Thus, an antitumor drug that damages DNA can induce an abnormal replication pattern in a chromosome by activating silent origins, depending upon defects in yeast checkpoint kinase genes, the homologues of which are mutated in cancer. Implications of an abnormal replication pattern for the epigenetic regulation of gene expression are discussed.