The Antifolates

Department of Medicine and the Albert Einstein Cancer Center, The Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Hematology/oncology clinics of North America (Impact Factor: 2.3). 06/2012; 26(3):629-48, ix. DOI: 10.1016/j.hoc.2012.02.002
Source: PubMed


This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate, its cytotoxic determinants, mechanisms of resistance, and transport into and out of cells has led to the development of a new generation of antifolates, a process that continues in the laboratory and in the clinics. New approaches to folate-based cancer chemotherapy are described based on the targeted delivery of drugs to malignant cells.

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    • "A methotrexate (MTX) was chosen as a model anticancer drug. This is one of the oldest antifolate drugs widely used in the treatment of cancer, rheumatoid arthritis, and other diseases (Visentin et al. 2012). There have already been studies of HES as a drug carrier , including conjugates with bioactive compounds such as deferoxamine (Mousa et al. 1992) and HES-based hydrogels for the controlled release of biomacromolecules (Wohl-Bruhn et al. 2012): however, to our knowledge, this is the first application of antifolate covalently conjugated to HES in experimental anticancer treatment. "
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    ABSTRACT: At present, effective anticancer therapy remains one of the most challenging tasks facing the scientific community. A major limitation to most conventional low-molecular weight anticancer chemotherapeutics is their unfavourable uptake by healthy tissue, fast metabolism and lack of tumour cell selectivity. One way to solve this problem is the application of hybrid nanoparticles containing widely known therapeutic substances. This study was performed with the aim of investigating the potential of use hydroxyethyl starch (HES) as a high-molecular weight carrier for anticancer drug (methotrexate, MTX). HES-MTX conjugates were characterized in terms of MTX content, hydrodynamic size, zeta potential, and drug release kinetics. In vitro biological characteristics were determined using different cancer cell lines. The antitumor effect in vivo was tested in NOD/SCID mice subcutaneously inoculated with MV-4-11 human leukaemia cells and CDF1 mice intraperitoneally inoculated with P388 murine leukaemia cells. The in vivo experiments revealed the considerably higher antitumor efficacy of HES-MTX conjugates in comparison to unconjugated drug. The results presented in this article demonstrate that the application of HES as an anticancer drug carrier can improve the treatment efficacy and have significant implications for the future design and implementation of drug-carrier conjugates. The study should help create new opportunities in the design of HES-based innovative drug-carrier conjugates.
    06/2014; 2(3). DOI:10.1002/prp2.47
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    • "Most of the deaths associated with breast cancer are a result of metastasis and its physiologic effects on morbidity and mortality.1 Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of a variety of malignancies, such as breast cancer.2 MTX presents high structural homology to folic acid, being able to bind to folic acid receptor.3 The mechanism of action consists of transportation into cells mostly by the reduced folate carrier (RFC). "
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    ABSTRACT: Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.
    International Journal of Nanomedicine 03/2014; 9(1):1583-91. DOI:10.2147/IJN.S56506 · 4.38 Impact Factor
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    ABSTRACT: Cancers of diverse origins exhibit marked glucose avidity and high rates of aerobic glycolysis. Increased understanding of this dysfunctional metabolism known as the Warburg effect has led to an interest in targeting it for cancer therapy. One promising strategy for such targeting is glycoconjugation, the linking of a drug to glucose or another sugar. This review summarizes the most salient examples of glycoconjugates, in which known cytotoxins or targeted anticancer therapeutics have been linked to glucose (or another glucose transporter substrate sugar) for improved cancer targeting and selectivity. Building on these examples, this review also provides a series of guidelines for the design and mechanistic evaluation of future glycoconjugates.
    Chemical Science 06/2013; 4(6):2319-2333. DOI:10.1039/C3SC22205E · 9.21 Impact Factor
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