Toxic effects of chemotherapy are caused by cell-free chromatin fragments that emerge from the dying cells

A large body of work by researchers at the Tata Memorial Centre (TMC), Mumbai has found conclusive evidence in cell lines, animal studies and two phase-2 clinical trials that cell-free chromatin fragments that are released from dying cells have the ability to readily enter healthy cells in the body and integrate into their genomes and trigger DNA damage by breaking the DNA double-strand, cause apoptosis (programmed cell death) and inflammation. Based on these studies, a team led by Dr. Indraneel Mittra, Professor Emeritus, Department of Surgical Oncology at TMC had proposed that “repeated and lifelong assault on healthy cells by cell-free chromatin fragments may be the underlying cause of ageing and multiple age-related disorders including cancer”. They also found that using a combination of two nutraceuticals — resveratrol and copper — minimises the damaging effects of cell-free chromatin fragments.

The researchers have collected sufficient evidence to prove that the toxic effects of chemotherapy are primarily caused by the cell-free chromatin fragments that emerge from dying cells and continue the vicious cycle of killing healthy cells and causing inflammation. This finding challenges the dogma that toxicity caused by chemotherapy is due to the direct damaging effect of drugs on healthy cells.

Based on preclinical studies that showed promising results when the resveratrol-copper combination was used, Dr. Mittra and other researchers at TMC tested it on 25 patients undergoing autologous bone marrow transplantation for multiple myeloma and 30 patients with advanced gastric cancer. In both studies, the toxicity of chemotherapy was far less among patients who received the resveratrol-copper combination.

Evidence from pre-clinical studies also suggests that resveratrol-copper nutraceuticals may prevent the metastatic spread of cancer. The researchers had earlier reported that cell-free chromatin particles released from dying cancer cells are potentially oncogenic. Studies in mice undertaken by the team showed that oncogenes contained in the cell-free chromatin fragments were carried by blood and had accumulated in the brain cells in mice. Though the oncogenes in the brain can potentially lead to metastasis, the study did not investigate whether the dissemination of oncogenes to brain cells indeed led to the development of metastases.

TMC statement

A statement issued on March 1 by TMC categorically stated that the effectiveness of resveratrol-copper for reducing chemotherapy toxicity or increasing cures in cancer patients “remains to be established and is currently under investigation”. The statement was released after Dr. Rajendra Badwe, a senior researcher at TMC told NDTV that the nutraceutical to reduce the toxicity of chemotherapy will be available by June this year after approval by the FSSAI. Several media reports wrongly reported that the nutraceutical to be approved by FSSAI is for preventing cancer metastasis.

Based on extensive pre-clinical studies and two phase-2 clinical trials, there is sufficient evidence to believe that resveratrol-copper would reduce chemotoxicity in patients with cancer, Dr. Mittra tells The Hindu in an email. “Evidence from pre-clinical studies suggests that resveratrol-copper combination may prevent metastatic spread. Randomised trials are now needed to establish the quantum of benefit [in reducing chemotoxicity]. The results of at least one randomised trial should hopefully be available in about a year’s time. In the meantime, and once resveratrol-copper is certified as a nutraceutical, it would be up to any individual to take it for [any of] the above indications if he/she so desires,” Dr. Mittra says.

Despite the absence of clinical trials supporting the use of a resveratrol-copper combination to prevent metastasis, Dr. Mittra does not see any problem in patients using the nutraceutical to prevent cancer metastasis as soon as it becomes available. “Once resveratrol-copper is approved as a nutraceutical anyone should be free to take it. Although at this point, we only have pre-clinical evidence that it prevents metastasis if someone decides to take resveratrol-copper for this indication, being a non-toxic combination, it is unlikely to cause any harm,” he says.

“Resveratrol-copper is probably a nutraceutical product with the most scientific evidence to back it for various conditions. For example, our pre-clinical studies have shown that it retards ageing parameters, such as getting rid of amyloid plaques which are responsible for Alzheimer’s disease. Resveratrol-copper also prevents telomere shortening, inflammation, DNA damage, and chromosomal abnormalities and reduces blood levels of cholesterol and glucose. So resveratrol-copper may have multiple other health benefits to the person who decides to take it,” Dr. Mittra adds. “I have personally been taking resveratrol-copper tablets for the past three years without any side effects. The mother of an oncologist at TMC who is suffering from Alzheimer’s disease has been taking resveratrol-copper tablets for several months now with remarkable improvement in her cognitive score and general mental state.”

On why the researchers are trying to get the combination approved by FSSAI as a nutraceutical and not as a drug by the drug regulator CDSCO, Dr. Mittra says TMC did not take the nutraceutical route willingly. “We had tied up with an industry partner who was sourcing resveratrol and copper from two different vendors for making the resveratrol-copper tablets in a specific formulation. The industry partner was unable to get their resveratrol-copper formulation approved by DCGI since the latter insisted that the respective vendors from whom resveratrol and copper were being sourced register their products with DCGI from their own GMP facilities. This the vendors were unwilling to do. As a result, the industry partner handed over the project to their subsidiary who are involved in the nutraceutical industry.”

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