Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

BACKGROUND: Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria sTo examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (inclu

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides.

The medicinal plant Artabotrys hexapetalus (synonyms: A.uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors.

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.

DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.

Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.

Management of cutaneous T-cell lymphomas: Established and emergent therapies.

Cutaneous T-cell lymphoma is an uncommon group of non-Hodgkin's lymphoma primarily affecting the skin. It is comprised of a variety of entities with different clinical behaviours and prognosis. Mycosis fungoides is the commonest subtype, and Sézary syndrome is a much rarer form of cutaneous T-cell lymphoma. At this stage, control rather than cure is the goal of therapy, with particular emphasis placed on preserving quality of life. Our review of the efficacy, safety profile and accessibility of treatment modalities for mycosis fungoides/Sézary syndrome is a tailored guide for the clinician treating these rare conditions.

Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of PfDHFR inhibitors.

Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is counted as one of the attractive and validated antimalarial drug targets. However, the point mutations in the active site of wild-type PfDHFR have developed resistance against the well-known antifolates. Therefore, there is a dire need for the development of inhibitors that can inhibit both wild-type and mutant-type DHFR enzyme. In the present contribution, we have constructed the common feature pharmacophore models from the available PfDHFR. A representative hypothesis was prioritized and then employed for the screening of natural product library to search for the molecules with complementary features responsible for the inhibition. The screened candidates were processed via drug-likeness filters and molecular docking studies. The docking was carried out on the wild-type PfDHFR (3QGT); double-mutant PfDHFR (3UM5 and 1J3J) and quadruple-mutant PfDHFR (1J3K) enzymes. A total of eight common hits were obtained from the docking calculations that could be the potential inhibitors for both wild and mutant type DHFR enzymes. Eventually, the stability of these candidates with the selected proteins was evaluated via molecular dynamics simulations. Except for SPECS14, all the prioritized candidates were found to be stable throughout the simulation run. Overall, the strategy employed in the present work resulted in the retrieval of seven candidates that may show inhibitory activity against PfDHFR and could be further exploited as a scaffold to develop novel antimalarials. Communicated by Ramaswamy H. Sarma.

Alemtuzumab is an effective third-line treatment versus single-agent gemcitabine or pralatrexate for refractory Sézary syndrome: a systematic review.

The efficacy of alemtuzumab for the treatment of refractory Sézary syndrome (SS) versus other third-line agents such as pralatrexate and gemcitabine is poorly characterized. To elucidate the effectiveness of alemtuzumab versus other third-line options for the treatment of refractory SS, we conducted a meta-analysis of existing data. A systematic review was performed in March 2017 based on a search using Ovid-MEDLINE® and OVID-EMBASE® for articles evaluating single-agent alemtuzumab, gemcitabine, or pralatrexate for the treatment of SS and mycosis fungoides (MF). Twenty-two publications were identified that fulfilled all search criteria (total n = 323 patients), with six publications of lower quality being excluded from our analysis in order to decrease the risk of bias (final: n = 308 patients; 93 with SS and 147 with MF). Across all studies, alemtuzumab was significantly more effective in patients with SS (overall response rate [ORR]: 81%; complete response rate [CRR]: 38%) than patients with MF (ORR: 29%; CRR: 8%). However, gemcitabine was more effective than alemtuzumab or pralatrexate in treating MF. Alemtuzumab-treated patients had more frequent side effects, which were influenced by route of administration and dose. There was a lower incidence of lymphopenia and other serious adverse events in patients treated with subcutaneous (38%) compared to intravenous regimens (68%), and lower-dose (5%) compared to high-dose alemtuzumab regimens (54%). No significant differences were found in the effectiveness of different routes of administration or dosing regimens. Our review supports the use of low-dose subcutaneous alemtuzumab as a third-line treatment for SS.

Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis.

BACKGROUND: Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated. PATIENTS AND METHODS: This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed. RESULTS: Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 109/L vs. 5 × 109/L, P = .0003). CONCLUSION: Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.

Adverse Reactions in Antifolate-Treated Toxoplasmic Retinochoroiditis.

This study seeks to define factors affecting the development of adverse reactions to intensive therapy of toxoplasmic retinochoroiditis with antifolate agents (pyrimethamine/sulfadoxine) and antibiotics followed by secondary antifolate prophylaxis. The study was of retrospective and observational nature. Medical files were reviewed of 551 patients suffering from ocular toxoplasmosis during 1994-2013. All patients were treated with the same protocol: 3-week intensive pyrimethamine/sulfadoxine plus antibiotic/steroid therapy. Three hundred and fourteen out of the 551 patients qualified for the subsequent 6-month long secondary antifolate prophylaxis. The type and occurrence rate of adverse reactions were taken into account. The probability of an adverse reaction during the intensive therapy phase was 33.4%. Hypertransaminasemia was the most common event observed in 24.6% of the patients, but it assumed a severe character in just 0.9%, with male gender and age over 25 years being the predisposing factors. Less common adverse effects included thrombocytopenia (8.3%), hypersensitivity skin reactions (3.0%), and abdominal pain (1.4%). The adverse effects of secondary antifolate prophylaxis, most commonly hypersensitivity skin reactions and hypertransaminasemia, followed by thrombocytopenia and abdominal pain, were observed in 4.9% of the patients. Ten of them (2.7%) had to discontinue the treatment while eight others continued with pyrimethamine alone without further adverse effects, which suggests that discontinuation of the sulfonamide decreased the propensity for adverse reactions. The treatment strategy in these patients differed from previous reports in that it used lower doses of pyrimethamine/sulfonamide, with no folinic acid supplementation. Nonetheless, the rate and severity of adverse events were no greater than those noticed with traditional regimens, with higher antifolate doses and folinic acid supplementation. We conclude that the dose and drug-mitigated treatment strategy we employed deserves consideration as a promising alternative to traditional treatments for ocular toxoplasmosis.

Histidine catabolism is a major determinant of methotrexate sensitivity.

The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR-Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme-formimidoyltransferase cyclodeaminase-that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.

Simultaneous determination of plasma methotrexate and 7-hydroxy methotrexate by UHPLC-MS/MS in patients receiving high-dose methotrexate therapy.

The plasma concentrations of methotrexate (MTX) and its major metabolite 7-hydroxy methotrexate (7-OH-MTX) are highly correlated with the toxicities in patients with high-dose MTX therapy. Routine monitoring of MTX and 7-OH-MTX plasma levels is useful for dose adjustment of rescue drugs and toxicity prevention. A UHPLC-MS/MS method for simultaneous determination of plasma MTX and 7-OH-MTX was developed, validated, and applied in 181 plasma samples. The ion transition was m/z 455.2 → 308.2 for MTX and m/z 471.2 → 324.1 for 7-OH-MTX. The flow rate was 0.4 mL/min with a run time of 2.6 min. The calibration range was 0.002-2 µM for MTX, and 0.01-10 µM for 7-OH-MTX. The intra-day and inter-day inaccuracy and imprecision were -5.50% to 10.93% and less than 9.20% for both analytes. The internal standard (MTX-D3) normalized recovery and matrix factor were consistent at four quality control levels. 14 h, 38 h, and 62 h after dosing, MTX and 7-OH-MTX plasma levels were significantly higher in patients with impaired renal function compared to those with normal renal function. 7-OH-MTX plasma levels were significantly higher in patients with impaired liver function compared to those with normal liver function.

Advances in ovarian cancer therapy.

Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment.

Treatment of prurigo with methotrexate: a multicentre retrospective study of 39 cases.

BACKGROUND: Prurigo is a common primary pruritic condition. Treatment is challenging. Methotrexate (MTX) is effective for the treatment of pruriginous dermatoses, but its use in prurigo has been little studied. OBJECTIVES: To investigate the efficacy and safety of MTX in the treatment of difficult-to-treat prurigo. METHODS: Patients from six university dermatology departments treated with MTX between 2006 and 2016 for difficult-to-treat prurigo (i.e. with failure to conventional therapies) were included in this retrospective multicentre study. Patients with other pruritic dermatoses were excluded. Clinical efficacy was recorded after 3, 6 and 12 months of treatment: (i) subjective efficacy, that is, evaluation of the pruritus by the patient and (ii) objective efficacy, that is, assessment of cutaneous lesions by the physician: complete or almost complete remission (CR) (healing of lesions), partial remission (PR) (incomplete improvement of lesions) or failure (no improvement or worsening). The overall response rate (ORR) included CR and PR. RESULTS: Thirty-nine patients with previous failure of topical steroids, H1-antihistamine drugs or phototherapy were included. The median weekly dose of MTX was 15 mg (range 5-25 mg). The median follow-up was 16 months (2-108). The mean time between onset of MTX and objective efficacy was 2.4 ± 1.2 months and the mean duration of response was 19 ± 15 months. The ORR was 91% at 3 months [n = 36, CI 95% (81.2-100.8%), CR 44%], 94% at 6 months [n = 32, CI 95% (85.7-102.2%), CR 56%] and 89% at 12 months [n = 28, CI 95% (77.4-100.6%), CR 57%]. Seven patients stopped MTX because of failure, and five because of the discovery of hepatocarcinoma (n = 1), elevated transaminases (n = 1), infectious pneumonitis (n = 1) or gastrointestinal symptoms (n = 2). CONCLUSION: Methotrexate is a therapeutic option in difficult-to-treat prurigo.

Dermatitis herpetiformis and bone mineral density: analysis of a French cohort of 53 patients.

The characteristics of patients with dermatitis herpetiformis (DH) in France is poorly documented. Furthermore, the risk of fractures and bone mineral density (BMD) in DH remain under-described, and recommendations for systematic screening for osteoporosis in DH are lacking. To describe the characteristics of DH in a large French cohort and evaluate the association between BMD and features of osteoporosis. Patients were recruited from the French Association of Gluten Intolerants (AFDIAG) and a single university dermatology department. A telephone questionnaire was used to record features of DH, history of fractures, calcium intake, treatment, and the gluten-free diet (GFD). Serum calcium and 25(OH) vitamin D3+D2 levels, as well as BMD, were measured. We included 53 patients (27 men) with a median age of 49 years (range: 23-86). Median disease duration before inclusion was 14 years (range: 2-55); 51 patients (96%) were adherent to a GFD and had no digestive symptoms. Overall, 18 (34%) had a history of fractures; 16 high-velocity (traumatic) and two low-velocity (non-traumatic). Mean BMD, measured in 48 patients, was normal (femoral neck: 0.956 ± 0.210 g/cm2; lumbar spine: 1.091 ± 1.199 g/cm2). In all, 18 patients (38%) had osteopenia and one (2%) osteoporosis. T-score for bone density did not differ with and without fractures. Calcium intake and serum calcium level were normal in all patients. Screening for osteoporosis does not appear to be mandatory for DH patients with good adherence to a GFD and without digestive symptoms or additional risk factors of osteoporosis.

Safety and benefits of interventions to increase folate status in malaria-endemic areas.

For decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine-pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria-endemic countries. We conclude that formal cost-benefit analyses are required.

Reduced folate and serum vitamin metabolites in patients with rectal carcinoma: an open-label feasibility study of pemetrexed with folic acid and vitamin B12 supplementation.

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study.

Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: Novel strategies to overcome cancer chemoresistance.

Our current understanding of the mechanisms of action of antitumor agents and the precise mechanisms underlying drug resistance is that these two processes are directly linked. Moreover, it is often possible to delineate chemoresistance mechanisms based on the specific mechanism of action of a given anticancer drug. A more holistic approach to the chemoresistance problem suggests that entire metabolic pathways, rather than single enzyme targets may better explain and educate us about the complexity of the cellular responses upon cytotoxic drug administration. Drugs, which target thymidylate synthase and folate-dependent enzymes, represent an important therapeutic arm in the treatment of various human malignancies. However, prolonged patient treatment often provokes drug resistance phenomena that render the chemotherapeutic treatment highly ineffective. Hence, strategies to overcome drug resistance are primarily designed to achieve either enhanced intracellular drug accumulation, to avoid the upregulation of folate-dependent enzymes, and to circumvent the impairment of DNA repair enzymes which are also responsible for cross-resistance to various anticancer drugs. The current clinical practice based on drug combination therapeutic regimens represents the most effective approach to counteract drug resistance. In the current paper, we review the molecular aspects of the activity of TS-targeting drugs and describe how such mechanisms are related to the emergence of clinical drug resistance. We also discuss the current possibilities to overcome drug resistance by using a molecular mechanistic approach based on medicinal chemistry methods focusing on rational structural modifications of novel antitumor agents. This paper also focuses on the importance of the modulation of metabolic pathways upon drug administration, their analysis and the assessment of their putative roles in the networks involved using a meta-analysis approach. The present review describes the main pathways that are modulated by TS-targeting anticancer drugs starting from the description of the normal functioning of the folate metabolic pathway, through the protein modulation occurring upon drug delivery to cultured tumor cells as well as cancer patients, finally describing how the pathways are modulated by drug resistance development. The data collected are then analyzed using network/netwire connecting methods in order to provide a wider view of the pathways involved and of the importance of such information in identifying additional proteins that could serve as novel druggable targets for efficacious cancer therapy.

A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.

Pemetrexed ameliorates experimental arthritis in rats.

Pemetrexed (PMTX) is an anti-folate drug as methotrexate. The purpose of this study was to assess the efficacy of PMTX on collagen-induced arthritis (CIA). Forty Wistar albino rats were randomized into four groups. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant. Animals were sacrificed at the 15th day after the onset of arthritis. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and malondialdehyde (MDA) levels were increased, and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were decreased in the arthritis group. In the PMTX-treated (0.2 and 1 mg/kg/week i.p.) groups, the levels of TNF-α, IL-17, and MDA were decreased; the activities of SOD, CAT, and GPx and the expressions of Nrf2 and HO-1 were restored, and perisynovial inflammation and cartilage-bone destruction were decreased. PMTX has anti-arthritic potential in the CIA model and may be a therapeutic agent for rheumatoid arthritis.

How folate metabolism affects colorectal cancer development and treatment; a story of heterogeneity and pleiotropy.

Folate was identified as an essential micronutrient early in the twentieth century and anti-folate chemotherapy such as 5-fluorouracil (5-FU) has been central to the medical management of solid tumours including colorectal cancer for more than five decades. In the intervening years, evidence has been gathered which shows that folate deficiency leads to many human diseases throughout the life-course. However, we still do not know all of the mechanisms behind functional folate deficiency, or indeed its rescue through supplementation with natural and particularly synthetic folates. There is growing evidence that one adverse effect of folic acid fortification programmes is an increased risk of colorectal cancer within populations. The complexity of folate-dependent, one-carbon metabolism and the heterogeneity that exists between individuals with respect to the enzymes involved in the anabolic pathways, and the catabolism of 5-FU, are explored in this review. The enzyme products of some genes such as MTHFR exert multiple and perhaps unrelated effects on many phenotypes, including cancer development. We describe this pleiotropy and the common genetic variants that affect folate metabolism; and discuss some of the studies that have investigated their potential as predictive biomarkers.