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  2. The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy
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  4. The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy - Semantic Scholar
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Nowadays, much effort is being spent on the design of advanced preclinical models that could provide a robust solution to bridge the gap between good preclinical results and success in clinical practice.


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Standard two-dimensional 2D cell cultures for effect testing of anticancer agents are simple and convenient, but present significant limitations in reproducing the complexity and pathophysiology of in vivo tumor tissue Galateanu et al. To accelerate translation research, increasing interest has been focused on using three-dimensional 3D spheroids for modeling cancer and tissue biology. Development of higher throughput assays to quantify phenotypic changes in spheroids is an active research area Galateanu et al.

Furthermore, microarray technology has the potential both to identify novel genes that have key roles in mediating resistance to 5-FU-based chemotherapy and also reveal the gene expression signature of CRC cells as response to 5-FU-based chemotherapy. All the studies were performed using a scaffold free 3D culture system. In this view, multi cellular tumor spheroids MCTSs were obtained as previously described Galateanu et al.

For the described experiments the treatments concentrations were previously optimized on this particular 3D culture model Galateanu et al. The fluorescence of the resulting dichlorofluoroscein DCF was quantified using a fluorimeter Jasco FP , with excitation and emission wavelengths of and nm, respectively. The samples were hybridized using Agilent Gene Expression Hybridization Kit Agilent Technologies , following the manufacturer's instruction. The quantification of the scanned microarray images was done with Feature Extraction Software The obtained data were further exported in GeneSpring GX The raw signals were log transformed and normalized using Quantile normalization method, with a threshold set at 1.

For each probe, the median of the log summarized value from the control samples was calculated and subtracted from each of the samples to get transformed baseline. Probes that present compromised and non-detected flags were filtered out using the Filter Probesets by flags options available in GeneSpring GX The obtained results were further filtered on confidence using Moderated t -test with a p -value cut-off set at 0. The results obtained were further used to generate the list of statistically significant differentially regulated genes between treated MCTS and control MCTS, using a fold change higher than two-fold.

The graphical representation of the distribution of the fold changes and their associated p -values as a volcano plot, was also generated using GeneSpring GX To further characterize the biological pathways that are significant enriched based on the list of statistically significant differentially expressed genes, Single Experiment Analysis in GeneSpring GX The fluorimetric data obtained were statistically analyzed using GraphPad Prism 3.

Figure 1. C MCTSs. The ROS generated could be responsible for damaging effects on proteins and lipids, and could also alter the cell membrane integrity of HT cells, inducing a decrease in cell viability. Figure 2. The captured images revealed the overall morphology of the MCTSs during 7 days of treatment as well as the distribution of the living and the dead cells inside the 3D structures. Consequently, a compact spheroid consisting in bright green living cells was found in the untreated sample.

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After 24 h of treatment some dead cells were identified in the core of the MCTSs. Moreover, after 1 week of treatment we found that the spheroids were disintegrated and the ratio between the living and dead cells was significantly in the favor of the dead cells Figure 2. After performing moderated t -test analysis with Bonferroni correction, the screening process led to the identification of The distribution of the fold changes and their associated p -values in these genes was graphically represented using the volcano plot shown in Figure 3.

Figure 3. Table 2. The top five pathways are represented in Table 3 , along with their respective p -values and ratio of the number of genes in the differential expression gene list under given experimental conditions over the total number of genes found in the respective canonical pathway.

The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy

Table 3. TK1 gene expression was found in our experimental conditions highly downregulated Figure 4. Figure 4. A patient with partial or complete DPD deficiency will accumulate active metabolites and could suffer serious toxicity or even rare fatality, when exposed to fluoropyrimidines. Furthermore, subsequent analysis on large cohorts of patients suffering from 5-FU toxicity and control individuals demonstrated that DPYD has been previously reported as highly polymorphic van Kuilenburg, In vitro studies revealed that DPD overexpression in cancer cell lines is correlated with 5-FU resistance Takebe et al.

Additionally, DPD, TS, and Thymidine phosphorylase TP might be considered independent predictive markers of 5-FU response and that the measurement of all these three markers markedly enhanced the possibility to predict tumor response to 5-FU-based chemotherapy Salonga et al. This reaction provides the only de novo source of thymidylate, which is necessary for DNA replication and repair.

Preclinical studies have demonstrated that TS expression is a key determinant of 5-FU sensitivity. Significant correlations between 5-FU miss-incorporation into RNA and loss of clonogenic potential have been shown in human colon and breast cancer cell lines Kufe and Major, ; Glazer and Lloyd, Consequently, 5-FU miss-incorporation can potentially disrupt many aspects of RNA processing, leading to profound effects on cellular metabolism and viability.

At this level, our results show a significant decrease of ERCC2 and SMUG1 genes expression, with high impact on cell viability and proliferation status. Despite initial sensitivity to OXP, most cancer cells will eventually develop resistance. Some recent studies Oka et al. Additionally, according to Gherman et al.

This lead to a significant decrease of the viable cells number and also in the microtumor's diameter reduction. The underlying mechanisms of the treatment effects mainly involve the suppression of the proliferative status and the induction of the apoptosis. CN and OG designed the study and partially edited the manuscript. BG assessed the antiproliferative status of the cells and contributed to the microarray experiment.

She also had a substantial contribution in the manuscript drafting. AH performed the microarray experiment and data analysis. SV assessed the ROS production in tumor cells. AT was responsible for the coordination of the study and assured a good collaboration between the authors. 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. The authors thank to Mrs.


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  • Agilrom Scientific S. Agilent Technologies dealer in Romania , who kindly provided all the support in microarray sample preparation and data extraction. Chaney, S. American journal of clinical oncology 10 3 , , Articoli 1—20 Mostra altri. Guida Privacy Termini. Indice H.

    Medicine 81 2 , , Journal of clinical oncology 28 5 , , Leukemia 7, , Local neurotoxicity after intra-arterial cisplatin in head and neck cancer. The Veterinary Journal 2 , , Anticancer research 34 5 , , European urology 29, , Cancer investigation 6 1 , , Campen and Schwartzberg, other core patients for whom uridine triacetate should be considered are those with very early onset 5-FU toxicity and individuals with a history of severe 5-FU toxicity.

    Early onset toxicity should also be a red flag for nurses. Vogel emphasized the need to educate nurses, particularly those handling the triage phone calls, that the mouth sores shortly after receiving 5-FU are not the same as the mouth sores that occur a week after treatment with combination cyclophosphamide and doxorubicin. Finally, uridine triacetate could be considered for their future courses of 5-FU, as noted by Dr. Uridine triacetate has demonstrated effectiveness for patients with emergency 5-FU overdose, as well as for those with known or suspected overexposure to 5-FU that occurs because of dihydropyrimidine dehydrogenase deficiency.

    In addition, there was an anecdotal report of a patient with colon cancer experiencing 5-FU overdose that was successfully treated with a 5-day course of oral uridine triacetate. Patients also experienced reduced or absent GI, hematologic, and other toxicities of overexposure to 5-FU.

    Adverse events related to uridine triacetate are reported as mild and infrequent. Oral capecitabine use has increased over the years, noted Dr. It is a prodrug that is enzymatically converted to 5-FU preferentially in tumor cells, which improves its therapeutic ratio, Dr. Schwartzberg added. However, in the setting of severe dihydropyrimidine dehydrogenase deficiency, it is possible to experience life-threatening toxicity from capecitabine.

    If a patient develops capecitabine overdose, uridine triacetate is an appropriate option through the expanded access program to prevent severe morbidity or even death, Dr. Campen said. He noted that unlike 5-FU infusions, which are given over 48 hours, capecitabine is given orally, twice daily, for 14 days of a day cycle. Thus, by day 14, toxicities are already present.

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    Therefore, if a patient had grade 4 toxicity during the capecitabine cycle, uridine triacetate is not an option. The panel recommended steps to be taken by the health-care team while awaiting the arrival of uridine triacetate. First, the patient should definitely be admitted to the hospital, Dr. Schwartzberg continued. For instance, diarrhea should be treated by institutional protocols, and good mouth and skin care is needed.

    If the patient has become neutropenic, pan-cultures should be done, and in some cases, prophylactic antibiotics should be started, added Dr. Finally, the panel stressed the importance of developing and implementing triage plans and protocols for monitoring patients on high-dose methotrexate Table 5 and 5-FU. All members of the panel considered protocols essential for making prompt decisions regarding pharmacologic management, such as treatment with glucarpidase and uridine triacetate.

    These agents are rarely used, so clear instructions should be posted on both inpatient and outpatient areas of clinical oncology sites. In these cases, preparedness is critical, as every minute counts when obtaining these two drugs and securing informed consent, said Dr. Protocols for glucarpidase use may vary, but most generally follow approved use from the package insert 35 and note specific inclusion criteria, said Dr.

    Protocols should be in place to guide the acquisition of uridine triacetate, which would include contact information of the local investigational review board and the pharmaceutical company. Use of the expanded access program has increased dramatically in recent years. In , 1, patients received treatment via the expanded access program.

    The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy - Semantic Scholar

    The basic requirements for a pharmaceutical agent to be accepted into the expanded access program follow:. Clinicians must be careful not to provide a sense of false hope that a particular patient may be able to receive further treatment via the expanded access program. Clinicians also need to make patients aware that drug companies are not required to make their drug available through the expanded access program or to make more of a drug for that purpose.

    There are risks and concerns regarding expanded access programs. In addition, early access to investigational therapies could make phase II and III clinical trials more difficult to perform. Also, from the standpoint of the drug manufacturer, the manufacturing capacity is often limited in early phases, and thus the supply of the drug for expanded access could limit the supply needed for clinical trials.

    From the patient perspective, health insurers may not reimburse substantial costs associated with the drugs. From the physician perspective, the costs to provide access may not be fully compensated; in addition, physicians may face liability issues, and their participation requires commitment i.

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    Health-care professionals should be cognizant of the difference between an investigational new drug IND and a drug in the expanded access program. The main distinction is that expanded access users patients and physicians are not required to provide information about the safety or effectiveness of the drug. In addition, to authorize the expanded access use, the FDA must determine that the patient has a serious or life-threatening disease or condition and that no other comparable or satisfactory therapeutic options are available.

    Moreover, the FDA cannot compel a drug manufacturer or marketer to provide expanded access to its drug, which is voluntary on the part of a company. There are steps if a clinician wants to obtain a drug via the expanded access program.