No abstract available

A randomized early phase II study using l-leucovorin (l-LV) and 5-fluorouracil (5-FU) in gastric cancer was conducted. The administration schedules: Arm A was 250 mg/m2 of l-LV and 600 mg/m2 of 5-FU weekly, arm B was 100 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days, and arm C was 10 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days. PR was obtained in 10/28 (35.7%) of arm A, 7/28 (25.0%) of arm B and 0/17 (0%) of arm C, in complete cases. In eligible cases, 30.3%, 21.9% and 0%, respectively. Because there was no responder in arm C, the entry to arm C was stopped by controller at the point where 17 patients were treated with arm C. Median survival time was 9.6 months in arm A, 8.0 months in arm B and 5.9 months in arm C. Major toxicities were stomatitis, diarrhea and neutropenia. Stomatitis was seen more in arm B and C than in arm A. These data suggest that the high dose of l-LV and 5-FU seems to be a very promising combination, but there was no responder using low-dose l-LV schedule against gastric cancer. We thus selected arm A for the next late phase II study against gastric cancer.

135 patients with locally advanced or metastatic colorectal cancer were entered into a phase III trial evaluating the efficacy of chemoimmunotherapy [recombinant interleukin 2 (rIL2)/5-fluorouracil (5-FU) and leucovorin (LV)] versus chemotherapy alone (5-FU/LV). A cycle of chemoimmunotherapy comprised a constant intravenous infusion of rIL2 at a dose of 18 x 10(6) U/m2/24 h for 120 h, followed by three bolus injections of 5-FU (600 mg/m2) and LV (25 mg/m2) at weekly intervals. Patients receiving chemotherapy alone received 5-FU/LV at the same dose at weekly intervals for 6 weeks followed by a rest period of 2 weeks, constituting one cycle of therapy. A maximum of 6 months therapy was given in both arms of the study. The response rates (complete and partial responses) were 17% in patients receiving rIL2/5-FU/LV versus 16% in those in the 5-FU/LV arm of the study. Median survival and progression-free survival were comparable for the two groups of patients, although there was a trend for a prolongation of survival in patients receiving chemoimmunotherapy compared with chemotherapy alone, beyond 12 months. Retrospective subgroup analyses revealed a significantly increased survival in poor prognosis patients (ECOG 1) treated with rIL2/5-FU/LV when compared to those receiving chemotherapy alone. Therefore, further studies evaluating the dose and duration of chemoimmunotherapy in patients with metastatic colorectal cancer seem warranted.

Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.

Folinic acid (FA) is generally administered to patients with CNS tumors in order to treat severe neurological disorders caused by methotrexate (MTX); therefore, we herein examined the effects of the co-administration of FA on MTX concentrations in the rat brain and cerebrospinal fluid (CSF) as well as the pharmacokinetics of MTX. MTX was intravenously or intrathecally administered to rats with or without FA. MTX concentrations were assessed by HPLC. No significant differences were observed in pharmacokinetic parameters, including kel, Vd, AUC, Cltot and t1/2, between the FA-treated and non-treated groups. MTX concentrations were not significantly different in the brain or CSF 6 hr after the intrathecal administration of MTX. However, compare to intravenous administration of MTX, intravenous administration of both FA and MTX significantly decreased MTX concentrations in the brains and CSF. These results suggest that FA inhibits the influx of MTX into the brain and CSF, possibly by competing with folate carriers, but has no effect on its efflux from these regions. Therefore, FA may be administered to CNS tumor patients receiving intrathecal MTX therapy in order to treat the adverse effects of MTX without affecting its concentrations in the brain and CSF.

Methotrexate (MTX) is a widely used therapeutic agent for the treatment of cancer and autoimmune diseases. However, its efficacy is often limited by adverse effects, such as intestinal toxicity. Although treatment with leucovorin (LV) is the most common method to reduce the toxic effects of MTX, it may also compromise the therapeutic effects of MTX. The gut microbiome has been reported to be associated with the intestinal toxicity of MTX. In this study, the intestinal damage of MTX was ameliorated by treatment with LV. Moreover, the population, diversity, and principal components of the gut microbiota in MTX-treated mice were restored by treatment with LV. The only element of the gut microbiota that was significantly changed after treatment with LV was Bifidobacterium, and supplementation with Bifidobacterium longum ameliorated MTX-induced intestinal damage. In conclusion, our results suggest that the balance and the composition of gut microbiota have an important role in the LV-mediated protection against MTX-induced intestinal toxicity. This work provides foundation of data in support of a new potential mechanism for the prevention of MTX-induced intestinal toxicity.

5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a p-value of <0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.

Fewer treatment options are available for refractory metastatic colorectal cancer (mCRC). In early trials, S-1 monotherapy was effective for mCRC patients after chemotherapy failure and its combination with oral leucovorin therapy offers promising results in untreated mCRC. Hence, we conduct a Phase II trial to assess the efficacy of S-1 plus oral leucovorin (SL) in refractory mCRC that progressed after multiple prior standard therapies.

Targeted drug delivery to colon cancer cells can significantly improve the efficiency of treatment. We firstly synthesized carboxyl-modified mesoporous silica nanoparticles (MSN⁻COOH) via two-step synthesis, and then developed calcium leucovorin (LV)-loaded carboxyl-modified mesoporous silica nanoparticles based on galactosylated chitosan (GC), which are galectin receptor-mediated materials for colon-specific drug delivery systems. Both unmodified and functionalized nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), nitrogen sorption, and dynamic light scattering (DLS). Drug release properties and drug loading capacity were determined by ultraviolet spectrophotometry (UV). LV@MSN⁻COOH/GC had a high LV loading and a drug loading of 18.07%. In vitro, its release, mainly by diffusion, was sustained release. Cell experiments showed that in SW620 cells with the galectin receptor, the LV@MSN⁻COOH/GC metabolized into methyl tetrahydrofolic acid (MTHF) and 5-fluorouracil (5-FU)@MSN⁻NH₂/GC metabolized into FdUMP in vivo. MTHF and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) had combined inhibition and significantly downregulated the expression of thymidylate synthase (TS). Fluorescence microscopy and flow cytometry experiments show that MSN⁻COOH/GC has tumor cell targeting, which specifically recognizes and binds to the galectin receptor in tumor cells. The results show that the nano-dosing system based on GC can increase the concentrations of LV and 5-FU tumor cells and enhance their combined effect against colon cancer.

Calcium folinate (leucovorin), which is converted in vivo into biologically active folate, enhances the potency of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer. A common dosage of leucovorin in adjuvant and palliative settings is 60 mg/m(2). The aim was to determine the levels of tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (methyleneTHF), and 5-methyltetrahydrofolate (methylTHF) in tumour and mucosa of colorectal cancer patients who received different dosages of leucovorin intravenously at time of surgery.

Blood-based epigenome-wide association studies that aim at comparing CpG methylation between colorectal cancer (CRC) patients and controls can lead to the discovery of diagnostic or prognostic biomarkers. Numerous confounders can lead to spurious associations. We aimed to see if 5-fluorouracil (5-FU)/leucovorin chemotherapy administered to cases prior to the collection of their blood has an effect on methylation. 304 patients who received treatment and 273 who did not were profiled on the HumanMethylation450 array. Association tests were adjusted for confounders, including proxies for leukocyte cell counts. There were substantial methylation differences between these two groups that vanished once the leukocyte heterogeneity was accounted for. We observed a significant decrease of T cells in the treatment group (CD4+: p=10(-6); CD8+: p=0.036) and significant increase of NK cells (p=0.05) and monocytes (p=0.0006). 5-FU/leucovorin has no effect on global and local blood-based methylation profiles, other than through differences in the leukocyte compositions that the treatment induced.

Methotrexate, a folate antagonist, is a mainstay treatment for childhood acute lymphoblastic leukemia. It is also widely used in a low dose formulation to treat patients with rheumatoid arthritis. In rats, methotrexate is known to induce micronuclei formation, leading to genetic damage, while vitamin A is known to protect against such methotrexate-induced genetic damage. Leucovorin (folinic acid) is generally administered with methotrexate to decrease methotrexate-induced toxicity.

Adjuvant chemotherapy of leucovorin-modulated 5-fluorouracil (5-FU/LV), capecitabine, and adding oxaliplatin to 5-FU/LV or capecitabine (FLOX/OX) have been standard regimens for high-risk stage II or III colon cancer (CC). We aimed to evaluate their patterns of use, association with survival, and rate of emergency room visit (ER) or hospitalization during the treatment period. High-risk stage II or III patients aged >65 years diagnosed between 2007 and 2015, underwent colectomy, and received any of these three regimens were selected from SEER and Texas Cancer Registry (TC) linked with Medicare data. Chi-square test, Kaplan-Meier survival curves, Cox regression, and logistic regression were used in data analysis. A total of 5621 (1080 stage II and 4541 stage III) patients with median age of 72 years were included in this study. For stage II, 24.4% used 5-FU/LV, 31.2% used capecitabine, and 44.4% used FLOX/OX; the respective numbers for stage III were 13.8%, 17.9%, and 68.3%. Patients aged <70 years, not in the West region, not in Medicare state-buy-in program, and with no comorbidity were more likely to use FLOX/OX. FLOX/OX was associated with improved overall survival (OS) in stage II and III patients and improved cancer-specific survival in stage III patients compared with 5-FU/LV. The survival benefit of FLOX/OX was sustained in stage III patients aged ≥70 years. Capecitabine had the lowest ER/hospitalization rate with 19.2% in stage II and 28.9% in III. The use of FLOX/OX was associated with improved survival compared with 5-FU/LV among CC patients. Capecitabine was associated with the lowest ER/hospitalization rate.

The 3-year disease-free survival rate of the twice-daily regimen was not inferior to that of the conventional three-times-daily regimen, and the twice-daily regimen did not lead to an increase in adverse events. The effectiveness of the twice-daily regimen highlights an increased number of treatment options for patients. This will facilitate personalized medicine, particularly for elderly or frail patients who may experience more severe side effects from the combination therapy.

The trend in neoadjuvant therapy for locally advanced gastric cancer (LAGC) is to use more drugs or therapies in combination. This study aimed to assess the safety and effectiveness of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) plus apatinib in the treatment of LAGC.

Seven genes involved in folate metabolism are located on chromosome 21. Previous studies have shown that folate deficiency may contribute to mental retardation in Down's syndrome (DS).

Environmental contaminants can deleteriously affect aquatic animals. One such contaminant is 5-fluorouracil (5-FU), a long-prescribed chemotherapeutic drug. Leucovorin (LV) is co-administered with 5-FU, potentiating its effects. Zebrafish (Danio rerio) larvae were reared in ng/L treatments of either 5-FU, LV, or a combined 5-FU/LV mixture for 8 dy. Survival was measured daily and swimming behavior assessed every other day. After 8 dy, larval length was measured, and densitometry of p53-labeled cryostat sections determined the extent of apoptosis. No significant differences in survival or apoptosis were found; larvae in the highest concentrations were largest. Changes in behavior of 5-FU-treated larvae were based on exposure duration; changes in LV-treated larvae were affected by drug concentration and duration. Larvae co-exposed to 5-FU/LV had responses like 5-FU-treated larvae. Overall, early developmental exposure of zebrafish larvae to environmentally-relevant concentrations of 5-FU and LV did not adversely affect survival, growth, and behavior suggesting realistic concentrations are sublethal and non-toxic.

The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 Mpro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 Mpro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the Mpro cavity and thus having conformational stability. Glutamic acid (Glu166) of Mpro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 Mpro.

Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40-50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity.

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.