Chromatin comprises a complex mixture of DNA and proteins that forms the structural basis of chromosomes in the cellular nuclei. When cells die, they release cell-free chromatin particles or "cfChPs" into the circulatory system. In 1996, evidence for tumour-derived DNA circulating in the blood of cancer patients was first reported. This evidence caught the interest Dr. Indraneel Mittra, who is now Professor Emeritus and the Dr. Ernest Borges Chair in Translational Research at Tata Memorial Centre in Mumbai, India. His tryst with research on genetic material in cancer metastases began, and after 15 years of research he has presented various papers, developing a body of evidence that indicates the critical role of cfChPs in orchestrating development of not only cancer, but various other diseases. Emerging evidence indicates that cfChPs play an essential role in ageing, sepsis, cancer development, and chemotherapy-related toxicity.
With respect to the latter, Prof. Mittra explains, "Chemo-toxicity is not primarily caused by chemotherapeutic drugs, but rather by cfChPs that are released from the first cells that die after chemotherapy. The released cfChPs set in motion a cascading effect, increasingly damaging the DNA of healthy host cells, and triggering inflammatory processes in a vicious cycle that perpetuates and prolongs the toxicity of chemotherapy." Recently, a team from Tata Memorial Centre have demonstrated the therapeutic benefits of a pro-oxidant mixture of resveratrol and copper, R-Cu, in patients undergoing chemotherapy for advanced gastric cancer. Combining R with Cu (R-Cu) leads to the generation of free oxygen radicals which can inactivate the offending cfChPs.
In this context, the research team launched a single-arm phase II clinical trial to study the synergistic effects of R-Cu administration on cfChPs inactivation in patients with advanced gastric cancer. The primary objective was to determine whether R-Cu, via cfChPs' inactivation, was successful in reducing the grade ≥ 3 toxicity seen with docetaxel-based chemotherapies. To this end, the researchers monitored the likely changes in the toxicities of chemotherapeutic treatments using a grading system that provides a framework for the assessment of unwanted physiological effects.
The results were promising—although R-Cu did not reduce haematological toxicities, it significantly reduced the incidence of non-haematological toxicities comprising hand-foot syndrome, diarrhoea, and vomiting. Moreover, R-Cu reduced docetaxel exposure compared to the control arm without affecting efficacy in terms of overall survival.
Prior to this, two studies from Prof. Mittra's group used mouse models to demonstrate the benefits of R-Cu administration in the prevention of ageing and sepsis. The first of these indicated that the cfChPs that are released from the billions of cells that die in the body every day and damage healthy cells is the underlying cause of ageing, and prolonged oral administration of R-Cu leads to the downregulation of multiple biological parameters of ageing including neurodegeneration, which is associated with Alzheimer's disease. The other study showed how cfChPs trigger sepsis after bacterial infection in mice; administering R-Cu prevented this pathological process, including the prevention of fatality.
The research group has also conducted human studies. One of their previous works suggested that cfChPs released from dying cancer cells enter surrounding surviving cancer cells and trigger DNA damage and inflammation and further contribute to their aggressive behaviour—effects that could be mitigated by R-Cu administration. Another study reports reduced grade 3/4 mucositis and reduced levels of inflammatory proteins (or "cytokines") in the serum and saliva of R-Cu-treated patients receiving bone marrow transplants with high-dose melphalan—a chemotherapeutic used to treat plasma cell cancers.
Dr. Mittra, who is the corresponding author of these articles, concludes, "Our evidence suggests that R-Cu can be a novel, cost-effective, and non-toxic agent which can be used for multiple disease conditions including cancer and metastasis prevention."
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Reference
Title of main paper: A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study)
Journal: Medical Oncology
DOI: https://doi.org/10.1007/s12032-022-01862-1
Authors: Vikas Ostwal1, Anant Ramaswamy1, Prabhat Bhargava1, Sujay Srinivas1, Sarika Mandavkar1, Deepali Chaugule1, Zoya Peelay1, Akshay Baheti2, Harshali Tandel3, Vishal Kumar Jadhav3, Sushma Shinde3, Shraddha Jadhav4, Vikram Gota4, and Indraneel Mittra5
Affiliations:
1Department of Medical Oncology, Tata Memorial Centre, India
2 Department of Radiodiagnosis, Tata Memorial Centre, India
3 Translational Research Lab, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), India
4 Department of Clinical Pharmacology, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), India
5 Professor Emeritus, Department of Surgical Oncology, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), India
About Professor Indraneel (Neel) Mittra from Tata Memorial Centre, India
Professor Mittra is Dr. Ernest Borges Chair in Translational Research and Professor Emeritus, Department of Surgical Oncology at TMC/ACTREC, India. A fellow of the Royal College of Surgeons of England, Prof. Mittra obtained his Ph.D. from University of London and undertook postdoctoral work with Nobel Laureate Prof. Renato Dulbecco. Prof. Mittra has been instrumental in setting up the first dedicated breast unit in India and has published his basic, clinical, and public health research in several reputed journals including Nature, Lancet, and Cell.
Funding information
The study was supported by Department of Atomic Energy, Government of India, through its grant CTCTMC to Tata Memorial Centre, awarded to Prof. Mittra.
