PubMed · 10543142
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T Maeda, S Hasegawa, S Sumi. 1999. [Fluorouracil].. https://pubmed.ncbi.nlm.nih.gov/10543142/
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Leukemic cells have been shown to generate several classes of DNA fragments after treatment with cytotoxic cancer chemotherapy agents. However, it is unclear which of these fragmentation events are a direct effect of DNA-damaging chemotherapy agents, and which fragmentation events are caused by downstream processes, such as apoptosis. We have performed a detailed analysis of DNA fragmentation events which occur following cytotoxic chemotherapy in four representative leukemic cell lines (HL-60, Jurkat, K562, and Molt-4). We used a DNA topoisomerase II inhibitor (etoposide), an alkylating agent (melphalan), a nucleoside analog (cytosine arabinoside), and a non-genotoxic agent (N-methylformamide) to induce cell death. We studied high molecular weight and low molecular weight DNA fragmentation events, as well as the specific cleavage of the MLL breakpoint cluster region (bcr). The DNA fragments produced at late time points were largely independent of the agents used, while those generated at earlier time points showed clear differences in terms of fragment size and relative abundance, depending on the agent used. In addition, there were clear differences between cell lines in terms of size, relative abundance, and rate at which DNA fragments were produced by treatment with the same agents. We think that this survey documents the importance of studying several different cell lines, time points, and assays before reaching conclusions about the types of DNA fragments produced during treatment with cytotoxic agents, and provides a useful framework for studying a wide range of DNA fragments produced by cytotoxic agents.
We investigated the amplification of bleomycin-induced DNA cleavage by synthetic triamides containing N-methylpyrrole (Py) and/or N-methylimidazole (Im), PyPyPy, PyPyIm, PyImPy, and PyImIm, using 32P-labeled DNA fragments obtained from the human c-Ha-ras-1 and p53 genes. Peplomycin, a bleomycin analog, plus Fe(II) caused DNA cleavage at the 5'-GC-3' and 5'-GT-3' sequences (damaged bases are underlined). The addition of PyPyPy dramatically enhanced the cleavage, particularly at cytosine residues 3' to consecutive guanines. Alteration in the site specificity was not observed with other triamides (PyPyIm, PyImPy, and PyImIm). DNase I footprinting revealed that PyPyPy bound to the sites adjacent to the sites where DNA cleavage was enhanced by PyPyPy, and that PyPyPy enhanced DNase I-induced cleavage in GC-rich regions. These findings suggest that binding of PyPyPy to the DNA minor groove changes the DNA conformation to allow peplomycin to cleave DNA more efficiently at GC-rich sequences, resulting in intensive site-specific DNA cleavage particularly at cytosines at the 3'-side of polyguanines. The present study on amplifiers of antitumor drugs would appear to offer a novel approach to the establishment of more effective chemotherapy.
The crystal and molecular structure of methotrexate has been determined by X-ray diffraction from a highly hydrated triclinic crystal form in which the asymmetric unit contains two independent methotrexate molecules with their glutamate carboxyl groups coordinated to two strontium ions. The two methotrexates exhibit differing conformations: They are almost related to one another by a pseudocenter of symmetry. This places the C(9)-N(10) bond vectors on opposite sides of the planes of the pteridine rings. The 2,4-diaminopteridines form 2-fold symmetry-related hydrogen-bonded dimers as well as hydrogen bonds to benzoyl carbonyl oxygens and lattice water molecules. This structure provides experimental proof of the existence of pteridine conformers through rotation about the C(6)-C(9) bond. Comparison of these conformers with other free and enzyme-bound methotrexate conformations shows them all to be different and illustrates the ability of the molecule to adapt to its chemical environment. The results from this crystal structure determination are experimental proof that methotrexate has not one preferred molecular conformation but may freely rotate about several bonds. They also suggest that the dihydrofolate reductase-bound methotrexate conformation is greatly influenced by the specific binding site environment of the enzyme.