The best time of day to give the chemotherapy drug cisplatin to people with cancer could be when their healthy tissue is busy mending damaged DNA, according to new research on biological clocks and DNA repair.
The study, now published in PNAS, is the first to map DNA repair in the entirety of a mammal’s genome in the 24 hours following treatment with cisplatin.
The researchers behind the study mapped DNA repair in a mouse genome, identifying specific genes and timings.
“We found,” explains senior study author Aziz Sancar, who is a professor of biochemistry and biophysics at the University of North Carolina in Chapel Hill, “[that] there are close to 2,000 genes, different parts of which are repaired at different times of day, depending on the gene.”
For a mouse, it appears that the busiest time for DNA repair in healthy tissue is before dawn and before dusk.
Prof. Sancar — who won the 2015 Nobel Prize in Chemistry for his work on the “mechanistic studies of DNA repair” — thinks that we can improve cancer treatments by better understanding how DNA repair and biological clocks work together “throughout the genome and in various organs.”
All organisms have biological clocks in the form of specific proteins inside each cell of nearly every organ and tissue.
The genes that code for and control biological clock proteins are similar across a wide range of species — from fungi to fruit flies and mice to humans.
They regulate all the biological processes that follow a roughly 24-hour daily pattern, or circadian rhythm, and they are crucial for healthy functioning of organs and tissue.
However, at present, we know little about the interplay between biological clock genes and other molecular processes, such as DNA repair, which is going on all the time in the body as it defends itself against DNA damage — such as that caused by ultraviolet light.
Cisplatin is a chemotherapy drug widely used in the treatment of many cancers, including ovarian cancer, lung cancer, bladder cancer, testicular cancer, and head and neck cancer. It kills cancer cells by damaging DNA, disrupting DNA repair, and causing the cells to commit suicide.
Unfortunately, the drug’s usefulness is limited by severe side effects — in particular, it is toxic to the liver, the kidneys, the brain, and the rest of the nervous system.
Researchers are keen to find ways to reduce side effects of cisplatin treatment. A relatively new field that is pursuing this goal is chronotherapy, an approach wherein drugs are given at a time to suit the biological clock.
Chronotherapy for anti-cancer drugs has been the subject of several studies already. These have sought to establish the best time of day at which the drug has maximum anti-cancer effects and minimum side effects.
So far, the results of such “chronochemotherapy” studies have been disappointing. But Prof. Sancar believes that the fault could lie in the fact that these studies have taken an “empirical” approach, with doctors giving the drugs at different times of day and then noting which produced the best results.
An approach that takes into account the timings of DNA repair — a key biological process in cancer and normal cells — might have more success. This is the angle that Prof. Sancar and colleagues decided to explore.
In their new study, they discovered that “genome repair is controlled by two circadian programs.” One program concerns the transcription of genes, and the other does not.
Transcription is the mechanism through which the code held in the genome is delivered to the cell by transcribing it from the DNA double helix into a single strand of RNA. The code contains instructions either for making a protein or for regulating a cell process.
The scientists discovered that DNA repair of the transcribed parts of genes was most active just before dawn or just before dusk, whereas DNA repair of non-transcribed parts was usually most active just before dusk.
Prof. Sancar says that they still have a lot to learn about how biological clocks interact with “basic mechanisms of DNA repair.”
However, he and his team believe that more knowledge of this interaction could be important for slowing down cancer by optimizing chemotherapy while reducing its side effects.
“Our work suggests it could be best to give cisplatin to patients when their normal cell DNA repair is at its zenith.”
Prof. Aziz Sancar