Researchers at Virginia Commonwealth University’s Massey Cancer Center have created a new platinum-based, anti-cancer agent able to overcome acquired drug resistance by first modifying the way it is absorbed into cancer cells and then attacking the DNA of those cancer cells.
The findings may help researchers design a new generation of anti-cancer drugs that selectively target cancer cells, reduce resistance and side effects and expand the range of tumors that can be treated by platinum.
In the Dec. 26 issue of the journal Inorganic Chemistry researchers reported on the design of a new trinuclear platinum compound and demonstrated that its cellular absorption is significantly greater than that of neutral cisplatin, as well as other multi-nuclear platinum compounds. The enhanced uptake into cancer cells takes advantage of weak molecular interactions on the cells’ surface. These results underscore the importance of the new compound’s “non-covalent” interactions, prior to the attack on DNA. Non-covalent interactions minimize potential side reactions and produce changes in the structure of proteins and DNA, which is different from currently used drugs. This research was selected as the cover article for the print version of the journal, Issue 26.
Researchers compared the cytotoxicity and cellular concentrations of three anti-cancer drugs including the phase II clinical drug, BBR 3464, cisplatin and the new trinuclear platinum compound. In a laboratory model, human ovarian cancer cells were exposed to each drug.
“In platinum antitumor chemistry our objective is to design and develop complexes acting by new mechanisms of action,” said Nicholas Farrell, Ph.D., professor and chair in the Department of Chemistry at VCU, and lead author of the study. “Resistance to current drugs is due to poor cellular absorption and an increased ability of the cell to process or repair the damage caused by the chemotherapeutic agent.”
“Our novel compound was designed to overcome resistance by emphasizing new modes of DNA binding, and in the process we have found that the amount of platinum drug entering cells is increased,” he said. “The effectiveness of a platinum drug in killing cells is directly related to its concentration inside the cell.”
DNA-damaging agents, such as cisplatin, are among the most effective classes of compounds in clinical use for the treatment of cancer. The principal function of cisplatin is to bind to DNA. Platinum drugs are the largest class of anti-cancer drugs in the clinic and the most important in terms of treatment. Cisplatin is a chemotherapy drug that is given for the treatment of metastatic testicular or ovarian cancers, and some advanced bladder cancer, and is a very effective drug in combination with other therapies.
However, according to Farrell, these current agents have limited activity against many common human cancers, and they are susceptible to acquired drug resistance. He added that resistance to cisplatin has become a clinically relevant issue – especially for patients battling ovarian cancer because they develop resistance to cisplatin at a rapid rate.
Farrell said that use of the “non-covalent” approach and emphasizing cell uptake may help minimize the side effects of current platinum drugs. He said that both cell uptake and the ability of the cell to minimize the effect of DNA attack, or DNA repair, play a critical role in cellular resistance to cisplatin by altering its ability to effectively kill tumor cells. By understanding the features of cisplatin that contribute to resistance, Farrell and his team designed the new compound to circumvent these problems.
This work was supported by a grant from the National Institutes of Health. The study can be accessed via http://pubs3.acs.org/acs/journals/toc.page?incoden=inocaj&indecade=0&involume=44&inissue=.
Researchers in the VCU departments of chemistry and biology, and the Department of Pharmacology and Toxicology in the VCU School of Medicine collaborated on this research. Researchers included Amanda L. Harris, Ph.D.; Xiaohong Yang, Ph.D.; Alex Hegmans, Ph.D.; Lawrence Povirk; and John J. Ryan, Ph.D. Lloyd Kelland, Ph.D., from the Institute of Cancer Research in England also contributed to this work.
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