5 years ago

Chemoradiation Cancer Therapy: Molecular Mechanisms of Cisplatin Radiosensitization

Chemoradiation Cancer Therapy: Molecular Mechanisms of Cisplatin Radiosensitization
Yi Zheng, Qinfen Tian, Yanfang Dong, Léon Sanche, Limei Zhou
Sensitization of malignant cells to ionizing radiation plays a key role in cancer treatments that combine chemotherapy and radiation therapy. Enhancement by chemotherapeutic agents of DNA base damages and clustered damage, which are among the most detrimental cellular modifications, is expected to contribute significantly to the radiosensitization process; however, with the exception of double-strand breaks (DSBs), no measurements exist on the enhancement of such damages induced by the abundant secondary low-energy electrons (LEEs) created by ionizing radiation. This lack of information restricts our global understanding of the molecular mechanisms involved in chemoradiation therapy. Here we measure the enhancements of LEE-induced damages resulting from the binding of cisplatin to plasmid DNA (pGEM-3Zf(−), 3197 bp). The enhancement factors (EFs) are reported for base damages (BDs) on one strand and clustered damages consisting of BDs and single-strand break (SSBs) with adjacent BDs on the opposite strand. Five-monolayer films of cisplatin–plasmid-DNA complexes in a molar ratio of 5:1 are prepared by lyophilization and irradiated in vacuum with monoenergetic electrons at the resonance energies of 4.6 and 9.6 eV. Cross-links, SSBs, DSBs and the loss of the supercoiled configuration are analyzed by the agarose gel electrophoresis. Irradiated samples are treated with E. coli base excision repair endonuclease (Nth and Fpg) enzymes to reveal by electrophoresis base modifications occurring within two helical turns of the DNA helix. From the dose–response curves, the total DNA damages induced at each energy are 244 ± 42 and 359 ± 44 × 10–15 electron–1 molecule–1, while the percentages of base modifications in these totals are 55 and 54%, respectively. Binding of cisplatin to DNA increases base modifications by EFs of 2.4 and 1.9, respectively; these are the largest finite EFs observed. Enhancement of all lesions can be explained by invoking two general mechanisms of electron transfer coupled to transient anions formation in cisplatin–DNA complexes. The present results provide more complete information on the radiosensitization of LEE-induced damages to DNA by cisplatin.

Publisher URL: http://dx.doi.org/10.1021/acs.jpcc.7b05271

DOI: 10.1021/acs.jpcc.7b05271

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