5-fluorouracil Research Articles

Overview of the human papilloma virus: types and its treatment

The human papillomavirus (HPV) is the most prevalent sexually transmitted disease in the United States and one of the most common causes of sexually transmitted infections (STDs) globally. Warts are cutaneous and occasionally mucous lesions brought on by HPV, with 2-20% of elementary school students getting them. There are three types of warts: non-genital warts, flat warts, and plantar warts. Non-genital warts are hyperkeratotic, exophytic, dome-shaped papules or plaques commonly associated with HPV-1, 2, 4, 27, or 57. Flat warts appear as flesh-coloured, erythematous to brown, or hyperpigmented smooth papules with a flat top and a diameter of 2 to 5 mm. Plantar warts, also known as verrucae plantaris, are cutaneous lesions on the plantar aspect of the foot that result from a human papillomavirus infection of keratinocytes (HPV).Genital warts are transmitted through sexual contact, while autoinoculation and vertical transfer do occasionally happen. After engaging in sexual activity with an infected partner, about 70% of people experience anogenital warts. Treatment for HPV includes imiquimod cream formulations, photodynamic treatment (PDT), green tea, chemical cautery, fluorouracil cream, cryotherapy, and surgical treatment. Common warts are hyperkeratotic, exophytic, dome-shaped papules or plaques commonly found in fingers, dorsal surfaces of hands, knees, or elbows. Flat warts are flesh-coloured, erythematous to brown, or hyperpigmented smooth papules with a flat top and a diameter of 2 to 5 mm. Plantar warts are unique in their location and appearance, primarily affecting high-pressure locations on the palms and soles and are uniquely linked to HPV type 1.

UPLC-MS/MS Method Development and Validation of Tegafur, Gimeracil, and Oteracil in Rat Plasma and its Application for Pharmacokinetic Study

A successful combination of Tegafur, Gimeracil, and Oteracil is used to treat stomach cancer in adults. Once converted to 5-fluoro uracil, the active form of Tegafur inhibits the manufacture and function of DNA and RNA, hence preventing the proliferation of cancer cells. Consequently, a new, sensitive, and cost-effective bioanalytical approach for the detection of these medications performed by liquid chromatography-mass spectrometry on rat plasma is needed. Isocratic mode was employed at room temperature to achieve separation on a C18 column (150x4.6mmx3.5μm). A mobile phase composed of ACN and 0.1% formic acid was used in the 40:60 ratio with a flow rate of 1mL/min. An analysis was conducted on Tegafur, Gimeracil, and Oteracil using a 6-minute retention time and the retention times of them were found to be 2.027, 3.176, and 4.015 respectively. The R2 values were found to be 0.9999 showing the method linear. The method developed was found to be accurate and precise as per ICH guidelines.

Multi-Sensitive Au NCs/5-FU@Carr-LA Composite Hydrogels for Targeted Multimodal Anti-Tumor Therapy.

Multifunctional targeted drug delivery systems have been explored as a novel cancer treatment strategy to overcome limitations of traditional chemotherapy. The combination of photodynamic therapy and chemotherapy has been shown to enhance efficacy, but the phototoxicity of traditional photosensitizers is a challenge. In this study, we prepared a multi-sensitive composite hydrogel containing gold nanoclusters (Au NCs) and the temperature-sensitive antitumor drug 5-fluorourac il (5-FU) using carboxymethyl cellulose (Carr) as a dual-functional template. Au NCs were synthesized using sodium borohydride as a reducing agent and potassium as a promoter. The resulting Au NCs were embedded in the Carr hydrogel, which was then conjugated with lactobionic acid (LA) as a targeting ligand. The resulting Au NCs/5-FU@Carr-LA composite hydrogel was used for synergistic photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy. Au NCs/5-FU@Carr-LA releases the drug faster at pH 5.0 due to the acid sensitivity of the Carr polymer chain. In addition, at 50 °C, the release rate of Au NCs/5-FU@Carr-LA is 78.2%, indicating that the higher temperature generated by the photothermal effect is conducive to the degradation of Carr polymer chains. The Carr hydrogel stabilized the Au NCs and acted as a matrix for drug loading, and the LA ligand facilitated targeted delivery to tumor cells. The composite hydrogel exhibited excellent biocompatibility and synergistic antitumor efficacy, as demonstrated by in vitro and in vivo experiments. In addition, the hydrogel had thermal imaging capabilities, making it a promising multifunctional platform for targeted cancer therapy.

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Application of topical 5-Fluorouracil to reduce the recurrence of odontogenic keratocyst: A prospective study with 2-year follow-up

ObjectivesThe purpose of this prospective study was to evaluate the effect of topical 5-Fluorouracil as an adjunct therapy in reducing the recurrence of odontogenic keratocyst. MethodsForty-eight patients with proven incisional biopsy as odontogenic keratocyst were included in this clinical study. The patients were divided into two equal groups, the test group patients were treated with 5-Fluorouracil cream after cyst enucleation. However, the control group patients were treated with cyst enucleation only. Recurrence (yes/no) was the primary outcome variable evaluated by clinical signs of inflammation, swelling, or pain within a 2-year follow-up. The pain was measured on a visual analogue scale, and swelling was measured pre-surgically using vertical and horizontal references, 1 week, 1 month, 3 months, 6 months, 12 months, and 24 months. Computed tomography was performed pre-surgically and 24 hours post-surgically, at 12-month, and 24-month intervals to evaluate local bone density. The T-test was used to compare between two studied groups. ResultsPost-surgical follow-up showed uneventful wound healing in both groups with no clinical signs of recurrence or swelling, pain results demonstrated that patients have decreased records throughout the observation periods with no significant difference between both groups. Normal sensation was encountered in all patients except for one patient in the control group who showed no sensation (score 2). Post-surgical radiographic findings revealed a considerable shift in bone density in all patients of both groups at the site of excised lesions during the follow-up periods compared with immediate post-surgical radiographs. However, the test group patients demonstrated a significant increase of bone density between different evaluation periods (P = 0.001) than the control group. ConclusionConservative enucleation of odontogenic keratocyst combined with topical application of 5-Fluorouracil is an effective treatment with lower recurrence rates, less morbidity, and normal bone healing.

The Recent Trends of Systemic Treatments and Locoregional Therapies for Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10-20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.

5-Fluoro uracil mediated transformation of surface-active ionic liquid based micellar nanoaggregates into pH-responsive vesicular nanoaggregates as promising drug delivery vehicle

Surface-active ionic liquids (SAILs) are poised as significant contenders in sustained and targeted drug delivery due to their membrane-like structures and their ability to transport drug molecules regardless of their polarity. In order to design a simple system that an encapsulate the anticancer drug and release it in a sustained manner, herein we designed vesicular nano-aggregates through synergistically interacting chemotherapeutic drug 5-Fluoro Uracil (5-FU) with the biocompatible SAILs, Choline Oleate ([Ch][Ol]) and Tetramethyl guanidine Oleate ([TMG][Ol]). The intention for designing the system is to offers less complexity and improved drug loading efficiency and targeted and sustained release. The molecular interactions have been proven by computational approach and the size of the nanoaggregates was determined using techniques such as Dynamic Light Scattering (DLS), Förster Resonance Energy Transfer (FRET) and Small-Angle Neutron Scattering (SANS). SANS fitting data and TEM images confirmed the transition of prolate ellipsoid micelles at [5-FU] = 0 mM to uni-lamellar ([5-FU] = 1 mM) and multi-lamellar vesicles ([5-FU] = 2 mM). These vesicular nano-aggregates are studied for their stability against temperature, pH-response and ionic strength of solution, revealing stability up to 60 °C, robust at physiological pH 7.4 and remain stable to exposure to Na+ and Ca2+ ions at concentrations up to 180 mM and 50 mM, respectively. The vesicular nano-aggregates ([Ch][Ol]/5-FU and [TMG][Ol]/5-FU) when exposed to physiological pH (i.e., 7.4) released 64.8 % and 61.2 % drug release whereas when the same systems were exposed to cancerous pH (5.2 and 6.7) released 95.9 % and 84.5% (pH 5.2 and 6.7) and 94.8 % and 81.2 % (pH 5.2 and 6.7) for the [Ch][Ol]/5-FU and [TMG][Ol]/5-FU systems, respectively. Results for the studied system encompasses them as a promising candidate for drug release at specific sites. The anticipated research might pave the way for the development of a biocompatible and stimuli-responsive drug carrier that would allow for the localized delivery of an anticancer drug.

Safety and adherence to self-administered intravaginal 5-fluorouracil cream following cervical intraepithelial neoplasia (CIN) 2/3 treatment among HIV-positive women in Kenya: A phase 1 clinical trial.

To determine the safety, tolerance, and adherence to self-administered intravaginal 5% fluorouracil (5FU) cream as adjuvant therapy following cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) treatment among women living with HIV (WLWH) in Kenya. A Phase I Pilot trial was performed among 12 WLWH in Kenya, aged 18-49 years between March 2023-February 2024 (ClinicalTrial.gov NCT05362955). Participants self-administered 2g of 5FU intravaginally every other week for eight applications. Safety was assessed using a standardized grading scale, and adherence was evaluated using self-report, inspection of used applicators, and weighing of the study drug. The mean age and CD4 count were 43.9 years and 781 cells/mm3, respectively. Seven (58%) had an 8th-grade education or less. All 12 reported at least one grade I adverse event (AE), 1 (8%) reported a grade 2 AE, no grade 3 or 4 AEs were reported. Increased vaginal discharge (n=9, 75%) and irritation (n=5, 42%), with a mean duration of 3.2 and 2.8 days, respectively, were the most commonly reported AEs. Provider-observed AEs included grade 1 cervical erythema and superficial abrasions. All participants tolerated all eight 5FU doses, and 96% adherence was demonstrated. Self-administered 5FU following CIN2/3 treatment among WLWH in Kisumu, Kenya, was safe, tolerable, and associated with high adherence. Randomized trials are needed to investigate whether adjuvant 5FU can improve treatment outcomes or serve as primary cervical precancer treatment in sub-Saharan Africa. A self-administered therapy may be transformative in increasing access to treatment and, hence, secondary prevention of cervical cancer.

AGITG MONARCC: A randomized phase 2 study of panitumumab monotherapy and panitumumab (pan) plus 5 fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer—A trial by the Australasian Gastro-Intestinal Trials Group (AGITG).

AGITG MONARCC: A randomized phase 2 study of panitumumab monotherapy and panitumumab (pan) plus 5 fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer—A trial by the Australasian Gastro-Intestinal Trials Group (AGITG).

Magnetic stirring hydroxylation for fabrication of a highly modulated Cu-intercalated 3D titanium aluminum carbide MXene network for efficient electrochemical detection of fluorouracil

With the growing incidence of cancer, cytostatic drugs that block the growth of cancer cells are being increasingly consumed, raising concerns regarding pharmaceutical pollutants. Halogen-containing antineoplastic fluorouracil (FLU) residues are continuously released into environmental water and soil surfaces, and upon entering the environment, they cause carcinogenic risks to environmental organisms and are hazardous to human health. Thus, on-site monitoring devices must be designed to prevent such hazardous pollutants from spreading to water, land, and ecosystems. We used erosion hydroxylation to fabricate a Cu-intercalated titanium aluminum carbide (TAC) MXene (Cu-Ti3Al1-xC2-OHx or Cu-TAC-3) for the on-site monitoring of cytotoxic FLU in environmental samples. The three-dimensional Cu-TAC-3 network was prepared using a simple, environmentally friendly magnetic stirring process, wherein Cu groups were intercalated into the hydroxylated TAC active sites to enhance the electrochemical properties. The physicochemical properties of Cu-TAC-3 were characterized spectroscopically. Furthermore, a Cu-TAC-3-modified glassy carbon electrode (GCE) was fabricated that could electrochemically detect FLU under various conditions, achieving a good sensitivity of 0.7033 μA/µM cm−2, linearity between 0.001 to83.76 μM, and a low limit of detection of 0.54 nM (70 ng mL−1). Cu-TAC-3/GCE demonstrated excellent electrochemical activity toward FLU even in real environmental samples, with a recovery of above 97 % from spiked samples. These sensors are therefore practical for the on-site electrochemical monitoring of FLU.

Cavitands based nanocapsule as smart and highly effective vehicle for 5-fluorouracil anti-cancer drug delivery: DFT insights

The nanomaterials have been widely investigated as drug delivery system for a variety of anticancer drugs to limit their adverse effects while transporting to the target site. In the current study, we report the cavitand-based nanocapsules as a drug delivery vehicle for nitrosourea (NU) and fluorouracil (FU) anti-cancer drugs. FU and NU drugs interact with the nanocapsules with the interaction energies in gas phase (solvent) −24.78 kcal/mol (–22.39 kcal/mol) and −21.58 kcal/mol (-20.45 kcal/mol), respectively. The results of Quantum theory of atoms in molecules (QTAIM) and noncovalent index (NCI) analyses indicate that the FU@Capsule and NU@Capsule complexes are mainly stabilized through hydrogen bonding and van der Waals interactions. Electron density difference (EDD) and natural bond order (NBO) analyses reveal that significant amount of charge is transferred from the nanocapsule to drug molecules. Frontier molecular orbital (FMO) analysis also reveals slight reduction in the energy gap. AIMDS analysis shows that cavitand capsules can efficiently carry the anti-cancerous drug to their target site without distorting complexes. The dipole moments and pH effect are studied to understand the drug release mechanism of considered anticancer drugs. The decrease in adsorption energy and increase in interaction distances indicate that anticancer drugs can easily be off-loaded from the carrier (nanocapsule) at the target site due to the low pH of cancerous cells compared to the normal cells. Therefore, cavitand nanocapsule can be employed as an excellent drug delivery carrier in smart targeted drug delivery.

Combination therapy with imiquimod and 5-fluorouracil cream for the treatment of actinic keratoses, a prospective open-label nonrandomized uncontrolled pilot trial

Combination therapy with imiquimod and 5-fluorouracil cream for the treatment of actinic keratoses, a prospective open-label nonrandomized uncontrolled pilot trial

Removal of fluorouracil from aqueous environment using magnetite graphene oxide modified with γ-cyclodextrin.

Fluorouracil (FU) is a widely utilized antineoplastic medication in the pharmaceutical industry for combating gastrointestinal cancers. However, its presence in wastewater originating from pharmaceutical facilities and hospital effluents has a potential effect on DNA, and cannot be efficiently eliminated through conventional treatment methods. Consequently, the adoption of advanced technologies becomes crucial for effectively treating such wastewater. Accordingly, this study investigated the efficiency of magnetite graphene oxide nanocomposite functionalized with γ-cyclodextrin for removing fluorouracil from aqueous solutions. The magnetite graphene oxide nanocomposite functionalized with γ-cyclodextrin was synthesized via the hydrothermal method. Next, the effect of pH, temperature, adsorbent content, and contact time on the fluorouracil removal efficiency was explored. Ultimately, the experimental data were matched against Langmuir, Freundlich, and Temkin isotherms and Kinetic models. Accordingly, the efficiency of the absorbent used was dependent on the pH, contact time, temperature, and initial concentration of the adsorbent. The results indicated that the maximum removal efficiency for fluorouracil was achieved within the contact time of 45 min and adsorbent content of 0.020 g. In addition, the optimal pH for removing the medicine was 7. The conditions of the adsorption process followed Langmuir isotherm with correlation coefficients of 0.992 and a quasi-second kinetic model with a correlation coefficient of 0.999, with the maximum adsorption capacity of the adsorbent synthesized for the evaluated medicine estimated as 190.9 mg/g. The results showed that the magnetite graphene oxide nanocomposite functionalized with γ-cyclodextrin could be used as an effective and available adsorbent for removing fluorouracil from pharmaceutical wastewater.

Metformin's effect on male rats experiencing CMF-induced neurotoxicity.

Numerous cancers are treated with the chemotherapy drugs cyclophosphamide (CP), methotrexate (MT), and fluorouracil (FU). However, it should be noted that neurotoxicity is a possible side effect of chemotherapy. The pharmaceutical agent metformin (MTF) is used to control type 2 diabetes. The administration of MTF has been documented to exhibit a reduction in specific toxic effects associated with chemotherapy. The primary purpose of this research was to examine whether MTF could mitigate the neurotoxicity brought on by cranial magnetic field (CMF). A cohort of forty male rats was divided into four distinct groups, with ten animals in each. We classified them as either saline, MTF, CMF, or CMF+MTF. The rats in the experiment group received two doses of CMF via intraperitoneal injection and were also given MTF in their drinking water at a concentration of 2.5 mg/mL on a daily basis. Brain tissue was obtained for ELISA of Bax, Bcl-2, and caspase-3 expression, as well as to determine NMDA and AMPA receptor mRNA expression by real-time polymerase chain reaction (RT-PCR) analysis. Expression of AMPAR, NMDAR, Bax, Bcl-2, and caspase-3 was not notably different between the saline and MTF groups. In contrast, mRNA expression for AMPAR, NMDAR, Bax, and caspase-3 was notably upregulated in the CMF group, while Bcl-2 was downregulated. The co-administration of MTF and CMF did not mitigate these side effects. neurotoxicity was induced in rats by CMF treatment, but the elevation of the glutamatergic system and the elevation of apoptotic proteins were not prevented by the MTF co-treatment.

Driving sustainability: IoT sensor integration for efficient car AC control

The Car AC Control Using IoT Sensor. The interior temperature of the car rapidly increases mostly during the hot summer months. This paper aims to address the challenge of maintaining a comfortable interior temperature in car, especially during hot summer months. To overcome this problem a mobile application is developed which helps to monitor the temperature in the car by using the Internet of Things (IoT). With this application the AC can be switched ON before getting into the car as the AC controller is linked to the mobile application. To power the system, a lithium-ion battery is used, which is recharged by the conversion of kinetic energy generated by the vehicle's movement, particularly from the wingtips. The intelligent design of air conditioners will ensures the efficient energy consumption with which the battery life can be prolonged. The proposed method will monitor the temperature inside the car.

Biological evaluation, molecular modeling and dynamic simulation of IDQ bulk and IDQNPs: Organo nano-bio interface in the medical field

The study aimed to synthesize 7,7-dimethyl-10-aryl,-7,8-dihydro-5H-indeno-[1,2-b]-quinoline-9,11(6H,10H)‑dione nanoparticles (IDQNPs) and to explore their biological activities i.e. anticancer, antioxidant and antibacterial. For this purpose, we prepared IDQNPs in a single non-solvent i.e. water by simple reprecipitation method. These nanoparticles were highly fluorescent organic nanoparticles (FONPs). The DLS measurements detected that 114 nm size of synthesized IDQNPs. A microphotograph taken using field emission scanning electron microscope (FE-SEM) of air-dried nanoparticle film showed nanoflakes with a feathery shape. Moreover, absorption and emission spectroscopy measurements displayed discrete peak of IDQNPs from their bulk molecule. The highly fluorescent IDQNPs ultimately give higher quantum yield compared to parental IDQ. Fluorescent organic nanoflakes are additionally utilized in vitro for anticancer and antimicrobial activity and antioxidant properties. Cytotoxicity of IDQ and IDQNPs were determined on the basis of measurement of in vitro growth inhibition of breast cancer cell lines in 96 well plates by using 5-fluoro uracil as a standard. The in vitro cytotoxicity of the IDQNPs assayed against MCF-7 cell lines showed higher cytotoxicity with the lower IC50 value i.e. 3.94 than IDQ parent indicating their efficiency in killing the cancer cells even at low concentrations. Furthermore, antioxidant and antibacterial activities were done by DPPH 96 well method and well plate diffusion method respectively. IDQNPs showed significant antioxidant property against DPPH radical. The IDQ parent compound and IDQNPs suspension at concentration 5 mg, 10 mg, and 100 µL, 200 µL respectively does not show activity against E. coli and Stap. Aureus. The molecular docking and dynamic simulation study were as done for IDQ bulk material. The finding of our study recommend that IDQNPs is a suitable candidate for preclinical cancer and antioxidant studies. This report may open a new avenue in the medical field and life science.

A new stability indicating HPLC and LC-APCI-MS methods for the estimation of Flucytosine in pharmaceutical dosage forms

Flucytosine is an anti-fungal agent which acts against mycotic infections. The anti-mycotic activity of Flucytosine is due to its conversion in to 5-fluoro uracil. In the present study the authors have proposed a new stability indicating isocratic RP-HPLC as well as LC-APCI-MS methods for the estimation of Flucytosine and the methods are validated as per ICH guidelines. Thermo scientific - TSQ Quantis with Vanquish HPLC coupled with MS was employed for the study with Simpack C18 (250 mm x 4.6 mm x 5µm) column. A triple quadrupole mass spectrometer with atmospheric pressure chemical ionization (APCI) source, running in the positive mode (as well as negative mode) was used for the detection. A mixture of 0.1% Acetic acid: Methanol was used as mobile phase (50:50, v/v) (UV detection at 235 nm). A wide linearity concentration range 1.0-120 μg/ml was observed and the method is found to be precise and accurate and can be used for the estimation of marketed formulations. Stress degradation studies were performed and the method is found to be selective and specific.

The Heterogeneous Impact of Prediagnostic Folate Intake for Fluorouracil-Containing Induction Chemotherapy for Head and Neck Cancer.

Fluorouracil (FU) exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism. Evidence that folate may play a role in the carcinogenic process via folate-mediated one-carbon metabolism has given rise to the hypothesis that pre-diagnostic folate intake may induce heterogeneous chemosensitivity to FU-containing induction chemotherapy (IC) in head and neck cancer. To assess this hypothesis, we conducted a cohort study to investigate whether the association between prediagnostic dietary folate intake and cancer survival differed between treatment regimens with and without FU-containing IC in 504 cases of locally advanced (stage III/IV) HNSCC, using an epidemiologic database combined with clinical data. In total, 240 patients were treated with FU-containing IC followed by definitive treatment, and 264 patients were treated with definitive treatment alone. Definitive treatment is defined as (1) the surgical excision of a tumor with clear margins, with or without neck lymph node dissection; or (2) radiotherapy with or without chemotherapy. In the overall cohort of the FU-containing IC group, a higher folate intake was significantly associated with better overall survival (adjusted hazard ratios (HRs) for the highest compared to the lowest folate tertiles (HRT3-T1) = 0.42, 95%CI, 0.25-0.76, Ptrend = 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HRT3-T1: 0.83, 95%CI, 0.49-1.42, Ptrend = 0.491)). A consideration of the cumulative dose of FU-containing IC showed that the survival impact of prediagnostic folate intake differed statistically significantly by treatment regimen (Pinteraction = 0.012). In conclusion, an association between prediagnostic folate intake and HNSCC survival significantly differed by FU-containing IC. This finding indicates that in the carcinogenic process, folate status causes HNSCC to be heterogenous in terms of one-carbon metabolism.

Acetyl-terminated PAMAM dendrimers for pH-sensitive delivery of irinotecan and fluorouracil: A molecular dynamics simulation study

Acetyl-terminated poly(amidoamine) dendrimer (G4ACE) was investigated as a pH-responsive nanocarrier for co-delivery of irinotecan (IRI) and fluorouracil (FU) using molecular dynamics simulations. The loading capacity of G4ACE at low pH is lower than that of physiological conditions. Drug molecules prefer to interact with dendrimer through conjugation on the surface monomers. The calculated ΔGbind for G4ACE:xIRI:yFU at neutral pH is about −17.4 and −5.9 kcal.mol−1 for IRI and FU, respectively; while, the corresponding values at acidic environment are −11.8 and −2.1 kcal.mol−1, respectively. Thus, when the complex reaches the acidic environment of cancer cells, it quickly releases the bound FU molecules.

Plumbago zeylanica L. exhibited potent anticancer activity in Ehrlich ascites carcinoma bearing Swiss albino mice

ObjectivesWe investigated the anticancer activity of the PzMH fraction (hexane fraction) extracted from the roots of Plumbago zeylanica L., an ethnomedicinally significant plant widely distributed in India. MethodsThe PzMH fraction was obtained through rigorous extraction and purification processes. In vitro cytotoxicity assays were performed to assess its effects on Ehrlich ascites carcinoma (EAC) cells. Acute toxicity studies were conducted to evaluate its safety profile. An in vivo study was carried out on EAC-bearing Swiss albino mice to assess its anticancer efficacy. Flow cytometric and microscopic analyses were done to examine the induction of cell death by the PzMH fraction. Western blot analysis was used to investigate the molecular mechanisms involved. ResultsThe PzMH fraction exhibited a significant cytotoxic effect in vitro, resulting in 50% cell death in EAC cells at low concentrations. The calculated GI50 value for the PzMH fraction was 42.74 µg/ml, demonstrating a comparable efficacy to the standard drug 5-fluoro uracil (GI50 = 43.38 µg/ml). The safety of therapeutic doses was confirmed through acute toxicity studies, which yielded an LD50 value of 500 mg/kg body weight. In the in vivo study, the PzMH fraction demonstrated a substantial 79.05% inhibition in the growth of EAC cells at the 300 mg/kg body weight dose of PzMH fraction. Flow cytometric and microscopic analyses revealed distinct apoptotic features in EAC cells treated with the PzMH fraction. Cell cycle analysis showed a significant arrest at the G0/G1 stage following treatment. PzMH treatment elicited a response characterized by escalated levels of cleaved caspases-3 and −9, while concurrently leading to a decreased expression of the Bcl2 protein, as evidenced by Western blot analysis. ConclusionsThe current research provides empirical evidence supporting the anticancer activity of the PzMH fraction extracted from P. zeylanica. The observed cytotoxicity, safety, and apoptosis-inducing properties make it a promising candidate for further investigation as a potential cancer therapy. Further exploration of its phytochemical composition, including major compounds such as 4-hydroxybenzaldehyde, trans-cinnamic acid, plumbagin and lawsone, contributes to our understanding of its mechanisms of action.