Contact your health care provider immediately , day or night, if you should experience any of the following symptoms:. Always inform your health care provider if you experience any unusual symptoms. You will be checked regularly by your health care professional while you are taking leucovorin, to monitor side effects and check your response to therapy.
Leucovorin is a compound similar to folic acid, which is a necessary vitamin. It has been around and in use for many decades. Leucovorin is a medication frequently used in combination with the chemotherapy drugs fluoruracil and methotrexate. This is further supported by previous findings demonstrating that treatment with Actinomycin D, an inhibitor of RNA synthesis, blocked the enhancement of CEA transcript in FU-treated cells [ 18 ]. However, the actual biochemical mechanism underlying FU-mediated increase of CEA is entirely unknown.
In any case, the hypothesis that selection of CEA positive FU-resistant cells could play a role, does not appear to be easily acceptable. The role possibly played by drug-induced up-regulation of CEA expression deserves particular attention. Actually, it has been demonstrated that immunogenic peptides, generated by endocellular processing of proteins predominantly located in malignant cells, can be presented in association with HLA molecules to responder host's lymphocytes.
Moreover, animal studies demonstrated synergistic effects between antitumor chemotherapy and immune responses, even when host's responses are particularly weak [ 22 ]. Many CEA-based cancer vaccines approaches are currently being evaluated in clinical trials involving patients with malignant diseases of the digestive tract. The preliminary results have shown that it is possible to induce an effective antigen-specific cellular and humoral response [ 9 , 13 , 14 , 16 ].
However, so far, no correlation has been demonstrated between immunostimulation and clinical outcome. One of the possible explanations is that CEA is heterogeneously expressed in the tumor. Therefore, some of the neoplastic cells may escape recognition by vaccine-induced CEA-specific CTLs because of reduced expression of target antigen. In the light of this hypothesis, pharmacological intervention able to induce changes of the antigenic-immunogenic profile of tumor cells is of potential clinical interest.
We and other authors previously reported that treatment with different compounds e. A similar event has also been observed for the expression of class-I HLA molecules [ 20 ]. Moreover, CEA expression enhancing agents are able to increase the level of this antigen in various clones expressing different basal level of the marker, including clones expressing only marginal amounts of CEA protein [ 24 ]. In conclusion, the rationale to utilize the optimal treatment schedule of the FUL-OXA combination capable of inducing both growth inhibition and CEA up-regulation, appears to be of considerable value, since drug-induced overexpression of the antigen is expected to make tumor cells more susceptible to the cytolytic activity of specific effector lymphocytes.
Curr Med Chem Anticancer Agents. Goldberg RM: Advances in the treatment of metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. J Exp Clin Cancer Res. CAS Google Scholar. Marshall J: The role of bevacizumab as first-line therapy for colon cancer. Semin Oncol. Wong SF: Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. Curr Opin Drug Discov Devel.
J Lab Clin Anal. Clin Cancer Res. J Natl Cancer Inst. Pharmacol Res. Int J Cancer. J Clin Oncol. J Pharmacol Exp Ther. Eur J Cancer. Anticancer Res. Download references. Comparisons between different tested conditions were done with Mann-Whitney unpaired non parametric test for experiments described in Figures 5A,B and 6. Solid and open squares and dashed line: Oxa alone. Solid square and solid line: FUFA alone.
Bars represent Standard Deviations two independent experiments. Time course incorporation of 14 CFU in nucleic acids. The presence of Oxa was found to modify the intracellular metabolic profile of FU.
These effects on cell cycle are quite different from one drug to the other with Oxa inducing a shift towards G 2 accumulation and FUFA leading to a greater proportion of cell in G 1 —S and a lower proportion in G 2 phase. This reduction in TS activity of the control cells may be attributable to progressive cellular confluence in the small well plates.
This rebound was found to be maintained in the presence of Oxa Figure 4B. A Time course of TS activity. Solid square and solid line: Control without drugs.
Open square and dashed line: Oxa alone. Solid diamond and solid line: FUFA alone. The curves Control and Oxa alone do not differ significantly. Non parametric unpaired test. B Time course of TS protein. The two curves control and Oxa alone do not differ significantly. Changes in mitochondrial membrane permeability were observed in the presence of the tested drugs. These effects are detailed in Table 1. Globally, the addition of Oxa does not amplify the action of FUFA upon mitochondrial membrane permeability change.
The intracellular evolution of total reduced folates is shown in Figure 5. The presence of Oxa itself does not modify the intracellular concentration of reduced folates. Noteworthy, it was found that a marked decrease in reduced folate levels occurred in the presence of FUFA.
This time profile of intracellular reduced folates was very similar to that observed when adding Oxa to FUFA Figure 5. Time course of total reduced folates concentration logarithmic scale, s. Solid square and solid line: control without drugs. The two curves: control and Oxa alone are not statistically different.
To that end, the individual cellular targets of the considered drugs were examined. The supra-additive interaction which had previously been shown Fischel et al, was confirmed in the present study on the WiDr human colon cancer cell line using the same conditions drugs, concentration, time of exposure used for the previously published results.
The presence of cytotoxic synergy between Oxa and FU had been previously reported by Raymond et al with both in vitro and in vivo data on human HT 29 colon cancer xenografts. However, this reduction of Pt binding is moderate and one of the possible reasons for this phenomenon, which occurs during cell exposure to FU, may lie in the fact that FU anabolites can be fraudulously incorporated into RNA and DNA Grem, and this incorporation may compromise the binding of Pt to nucleic acids.
Conversely, and probably for the same reasons of reciprocal impairment of nucleic acid drug binding, it was found that, during cell exposure to Oxa-FUFA, there were fewer FU anabolites incorporated into nucleic acids as compared to what is observed with the FUFA sequence alone Figure 3.
In the present study, using flow cytometry analysis, it was shown that the FUFA sequence induces an accumulation of cells in the G 1 early S phase. This observation is in agreement with known comparable data Pizzorno et al, recently confirmed by Backus et al The impact of Oxa on cell cycle with an increased proportion of cells in the G 2 phase also concurs with the cell cycle effects of platinum derivatives Mastbergen et al, This accumulation of cells in S phase is compatible with a slow-down of cell proliferation in agreement with the decrease in TS activity which was observed in the present study.
Indeed, cell proliferation and TS activity are closely related as recently underlined by the data of Grem et al The enzyme dihydropyrimidine dehydrogenase DPD regulates the FU catabolic route in liver and, importantly, at the tumoural cell level Beck et al, The impact of the variability in tumoural DPD activity on FU cytotoxic activity has been previously demonstrated with both in vitro Fischel et al, and in vivo data Etienne et al, DPD activity was previously thought to be inhibited by cisplatin, a clinically-proven FU modulator Leteurtre et al, ; Nishiyama et al, Recent pharmacokinetic studies have suggested that Oxa may inhibit FU catabolism Papamichael et al, , although this finding was not confirmed by other investigators Graham et al, The present investigation included a close examination of the main FU metabolic routes.
At this level, it appears that in the presence of Oxa there was a significant decrease in the intracellular levels of FUH 2. This points to the possibility that Oxa may inhibit DPD activity. The shift towards fewer catabolites and more anabolites of FU in the presence of Oxa was not however translated in the present study by an increase in FU anabolite incorporation into nucleic acids Figure 3.
This direct impact of Oxa on TS activity should be kept in mind and further explored in preclinical investigations or clinical studies with different Oxa-FUFA schedules. In contrast, the present data did not show that the presence of Oxa modified the FU-induced TS protein increase which had been previously described by Chu et al Experimental studies have established that the stabilisation of the ternary complex is enhanced by the presence of high levels of CH 2 FH 4 Moran and Scanlon, On this basis, clinical data have been provided that show better antitumour efficacy when FU is combined with leucovorin folinic acid , a precursor of CH 2 FH 4 Etienne et al, We reported, in cancer patients treated by FU-based chemotherapy, that, at pretreatment stage, the tumoural concentration of reduced folates was a predictor of an objective response to treatment Etienne et al, Cisplatin has been previously shown to upregulate the intracellular concentration of reduced folates Vitols et al, We thus examined the possible impact of Oxa on the intracellular levels of total reduced folates.
It makes 5FU work better. It may also be given with tegafur-uracil which is a similar drug to 5FU. Folinic acid is sometimes given with methotrexate, which is used to treat different types of cancer.
It is mainly used with higher doses of methotrexate to help reduce the side effects. This is sometimes called folinic acid rescue or leucovorin rescue. It is best to read this information with our general information about chemotherapy and the type of cancer you have. You will usually be given folinic acid in the chemotherapy day unit or during a stay in hospital. A chemotherapy nurse will give it to you at the same time as your chemotherapy treatment.
During treatment you will usually see a cancer doctor, a chemotherapy nurse, or a specialist nurse, and a specialist pharmacist.
This is who we mean when we mention doctor, nurse or pharmacist in this information. Before or on the day of treatment, a nurse or person trained to take blood phlebotomist will take a blood sample from you. This is to check that your blood cells are at a safe level to have the chemotherapy part of the treatment. You will see a doctor or nurse before you have treatment. They will ask you how you have been feeling. If your blood results are okay, the pharmacist will prepare your drugs.
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