Received 30 Apr Accepted 23 Jul Published 25 Aug Abstract Purpose. Introduction Oxaliplatin is a highly neurotoxic chemotherapy drug routinely used to treat colorectal cancer in the adjuvant and metastatic disease settings [ 1 ]. Methods 2. Study Design This was a descriptive, cross-sectional study using self-reported data from colorectal cancer survivors previously treated with oxaliplatin-based chemotherapy.
Sample and Setting Men and women with a history of stage III-IV colorectal cancer treated with oxaliplatin at the Moffitt Cancer Center between 1 and 8 years before enrollment were included in this study.
Measures Demographic data were obtained via a standard self-report questionnaire. Data Analysis Qualitative descriptive methodology, with the written narrative responses as the method of inquiry, was used to explore the medications and home-based strategies used by colorectal cancer survivors in the self-management of oxaliplatin-related peripheral neuropathy.
Results A total of survivors agreed to participate. All joints ache and take Advil liquid once in a great while. Have numbness tingling ant discomfort in hands and feet. Tried XS Tylenol. Vitamin B6 not helpful Gabapentin I often wonder that it really helps??
Nerve heals it self?? Does not improve numbness. If I forget a dose I get stabbing pains in my fingers. When Istopped Vitamin B1 symptoms seemed to get worse. I've tried Lyrica and amitriptyline in treating upward doses which both messed with my head so I quit. What relieves the pressure, tingling, pain the best is a combination of gabapentin and Oxycontin, which last up to 5 hours. But some days the pressure becomes too great.
I wish this would go away, been to long. I talked wit my chemo oncologist about relieving the pain from the neuropathy. He said the neuropathy symptoms are likely to disappear within a year of completing my treatment.
Always try to keep my hands and feet warm and rub them with lotion. To help the circulation. Wear socks more often especially when I sleep. Sleep on heating pad to keep warm and relieve joint aches. Drinking warm drinks is comforting. Wear gloves on cold days to keep hands warm.
Since chemo when my feet get cold they cramp badly. Foot massages give relief while being massaged but comfort goes away when massaging ends. I have numbness in my fingertips only when they get cold. I have muscle weakness in my fingers doing things like opening lids, containers, writing etc.
At normal temperatures. I have no symptoms. To relieve the numbness and weakness I just try to get them warm by covering them or running them in hot water. At work if my hands are cold, I have trouble writing, opening supplies, and so forth. Cold hurts my fingers and toes so I wear socks and gloves a lot Keep moving I walk bike and do deep water aerobics to help I think it helps!!
Maintained pre-chemotherapy activities: swimming and golf weather permitting. For balance practice standing on 1 leg and alternating legs. I continue my yoga and triathlon training-swim, bike, run, and weights. After taking the supplements and a lot of exercise it slowly went away mostly. It comes back when I get cold.
Muscle weakness, exercise seems to help Walking, water aerobics and free weights were most effective to rebuild strength Foot massage, not very helpful. Exercise more helpful than massage. Massage or rub the affected area Back rubs, especially with electric massages can be quite efficacious, especially from base of spine and down upper leg.
Have attempted massage of feet where discomfort is most severe. Gives Temporary relief Foot massages give relief while being massaged but comfort goes away when massaging ends. If I forget a dose of Neurontin I get stabbing pains in my fingers. Hand massages help somewhat. I have numbness to feet and achy legs and only feel the pain when I'm sitting or when I go to bed—some days I feel it more than others to relieve the pain I usually rub my feet and if it is persistent I take a pain pill that usually helps me get to sleep.
I have not taken any measures to alleviate tis problem, because I haven no idea how to proceed. I have spoken to my oncologist, but he offered no solution. Table 1. Treatments patients have tried to relieve symptoms of neuropathy. View at: Google Scholar A. View at: Google Scholar J. Choi, K. Kong, T.
Mozaffar, and R. Argyriou, P. Polychronopoulos, G. Iconomou, E. Chroni, and H. Alejandro, C. Behrendt, K. Chen, H. Openshaw, and S. Visovsky, M. Collins, L. Abbott, J. Aschenbrenner, and C. View at: Google Scholar E. Smith, S. Beck, and J. Smith, J. Cohen, M. Pett, and S. Within the nervous system, oxaliplatin preferentially accumulates in those cells that express specific membrane transporters such as the multidrug and toxin extrusion proteins MATEs , the organic anion-transporting polypeptides OATPs , and the organic cation transporter OCT Huang et al.
These data were corroborated by other results demonstrating the oxaliplatin-dependent detrimental effect on DRG neurons causing a reduced volume of the neuronal soma and an increase in the number of multinucleated neuronal nuclei Di Cesare Mannelli et al.
The OCT transporter is also expressed on the luminal surface of the blood-brain barrier BBB micro-vessel endothelial cells, the OCT role in transporting oxaliplatin inside the cells has been demonstrated Lin et al. In this regard, recently it has been reported that in a rat brain endothelial cell line expressing OCT protein Friedrich et al. The increased permeability of the BBB allows the chemotherapy agent to enter the brain parenchyma, affecting both the neuronal Park et al.
As for the effects of oxaliplatin on neurons, an increase in oxidative stress is the most remarkable event. In vitro experiments have demonstrated that oxaliplatin is able to increase the reactive oxygen species ROS and the superoxide anion levels as well as protein carbonylation Di Cesare Mannelli et al. In vivo analysis carried out on plasma, sciatic nerves, and lumbar portion of the spinal cord obtained from oxaliplatin-treated rats strengthened the role of oxidative stress in the onset of neuropathic pain Di Cesare Mannelli et al.
Analysis of the signaling pathway that triggers neuropathy highlighted the involvement of activating transcription factor 3 ATF3 protein. This protein is a member of the cAMP-responsive element binding protein family Li et al. Also, its expression has been found significatively increased in oxaliplatin-treated nerves and DRGs Di Cesare Mannelli et al. Moreover, an oxaliplatin-dependent alteration of the cell viability and of the expression of the growth associated protein 43 GAP , a well-known marker of axon development Morucci et al.
With respect to the glial compartment, neuropathic pain has been linked to changes in the gene expression and secretory profile of microglia that elicits a signaling cascade resulting in neuroinflammation Ji et al. As demonstrated by in vitro analysis both in human and murine cells, oxaliplatin induced an increase in pro-inflammatory marker expression such as clusters of differentiation 86 CD86 , and morphological changes shifting from resting to activating shape Branca et al.
The onset of microglia-dependent neuroinflammation also induces the recruitment of astrocytes. Indeed, it has been demonstrated that oxaliplatin treatment causes an increase in the expression levels of glial fibrillary acidic protein GFAP and a modification of astrocytic shape, both in the spinal cord and in some brain areas Di Cesare Mannelli et al. Microglia and astrocyte activation is strictly related to pain sensitivity since the selective inhibition of one or the other cellular type prevented pain development Di Cesare Mannelli et al.
On the other hand, an indiscriminate glial cell silencing impaired the neurorestorative mechanisms promoted by these cell types Di Cesare Mannelli et al. Another important target of oxaliplatin-dependent toxicity is the mitochondrion whose dysfunction leads to the generation of reactive oxygen species ROS.
Although the research on the mechanisms underlying mitochondrial toxicity and ROS generation are only beginning to be analyzed, some studies have fully demonstrated that the antioxidant properties of different molecules are able to mitigate the oxaliplatin-dependent neuropathy Di Cesare Mannelli et al.
These results suggest that ROS generation and mitochondrial impairment are early events in the oxaliplatin-triggered signaling pathway that results in the onset of neuropathy. Over the last 10 years research has highlighted a very important role of epigenetics in determining variations that induce lasting or permanent changes in neuronal function Borrelli et al.
Also, it is now evident that drug exposure leads to epigenomic changes that are the basis of the different individual responses to chemotherapy. Indeed, the focus is now centered on improving the chemotherapeutic efficacy of anticancer molecules through pharmacogenetic and pharmacoepigenetic approaches Mohelnikova-Duchonova, Pharmacogenetics, recently changed to the term pharmacogenomics, is the field of research that encompasses all genes in the genome that may determine drug response Pirmohamed, Indeed, especially for what may concern drug resistance and chemotherapy, the study of genetic polymorphisms is essential to choose the optimal personalized therapeutic treatment, minimizing the side effects produced by chemotherapy Lesko, In view of these fascinating scenarios, it has been recently hypothesized that the pivotal role of single nucleotide polymorphisms SNPs affects the gene coding for oxaliplatin transporters.
The alteration of the expression levels and the functioning of these transporters, in particular, the SNPs occurring in ATP-binding cassette ABCs transporters such as rs, rs, rs, and rs , causes an increase in the oxaliplatin concentration inside the cells in particular, the DRG neurons that may account for an higher risk to develop an oxaliplatin-dependent neuropathy as previously reported Nichetti et al.
It has been reported that a prolonged and high oxaliplatin intracellular accumulation, induced ROS overproduction mediated by mitochondrial impairment Massicot et al. Thus, even if specific transporter polymorphisms are not beneficial for patients that unfortunately do not correctly excrete oxaliplatin leading to its accumulation, the simultaneous use of antioxidant molecules during a chemotherapy regimen could help to retrieve and ameliorate the oxaliplatin-induced neuropathic pain De Monaco et al.
However, there are many other elements that influence chemotherapeutic drug sensitivity, such as the glutathione S transferase P1 GSTP1 , involved in the inactivation of platinum-DNA adducts Kweekel et al. For example, the Val allele variant at exon 5 of the GSTP1 gene confers a significantly decreased risk of developing severe oxaliplatin-related neuropathy Lecomte et al. Moreover, genetic polymorphisms play a key role also in adjuvant therapies where opioid drugs are used in order to ameliorate oxaliplatin-induced neuropathic pain Wang, Despite a clear correlation between oxaliplatin-based neuropathy and individual genetic polymorphisms, pharmacotherapy based on genetic profile is not yet routinely introduced, perhaps because different polymorphisms can correlate and a wide range of genomic analysis in a larger population is needed Peng et al.
In the attempt to find the molecular basis for neuropathy induction and maintenance, attention has recently been turned to epigenetic mechanisms. Epigenetic-dependent alterations of gene expression are independent of DNA sequence alterations, but they are heritable and reversible. Recently, environmental stimuli have been observed to induce long-term epigenetic modifications of the gene expression profile that characterizes neuropathic pain extensively reviewed by Penas and Navarro, If SNPs represent a risk of developing neuropathy, epigenetic regulation of the ABC transporters expression levels may lead to a decreased risk.
Indeed, these transporters regulate the oxaliplatin efflux from cells Sparreboom et al. A similar fascinating result in this field was obtained by the epigenetic modification of the OCT2 transporter both in vitro and in xenografts.
Some authors have promoted the epigenetic expression of this oxaliplatin transporter in renal cancer cells in order to increase the oxaliplatin sensitization of these cells Liu et al. It could be argued that the OCT2 epigenetic modification could induce an oxaliplatin accumulation also into other cell compartments, including the brain, thus leading to the induction of neuropathy.
Epigenetic modifications of glial cells have also been shown to play a role in neuropathic pain. Astrocytic DNA methylation and histone modifications, two of the major epigenetic modifications, induce the production of pro-inflammatory cytokines triggering a microglia neuroinflammatory activation that, in turn, contributes to the development of neuropathy McMahon et al.
It has also been demonstrated that oxaliplatin treatment significantly increased the histone H4 acetylation in the CX3CL1 promoter region in spinal cord neurons Huang et al. In vivo studies have demonstrated involvement in the induction of central sensitization and acute pain behavior after oxaliplatin administration Huang et al.
More recently, it has been evidenced that oxaliplatin treatment is able to increase the expression of 10—11 translocation methylcytosine dioxygenase 1 TET1 , a well-known enzyme involved in DNA demethylation. The researchers found that TET1 up-regulation indirectly acts on Homeobox A6 protein HOX-A6 expression in neurons, thus becoming a pivotal target in ameliorating oxaliplatin-induced neuropathy Deng et al. The oxaliplatin-induced neuropathic pain is a deleterious side effect for patient healthcare that could lead to therapy interruption.
In recent years many efforts have been made in order to both increase the oxaliplatin anti-cancer effects and ameliorate neuropathy. Hopefully, genetic and epigenetic information can help physicians toward a personalized therapeutic strategy. However, many other analyses of pharmacogenetics and epigenetics should be performed in order to corroborate and obtain useful data to seriously improve the benefit from chemotherapeutic treatment.
All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Borrelli, E. Decoding the epigenetic language of neuronal plasticity.
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