From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

Walling, Jackie

doi:10.1007/s10637-005-4541-1

Cited by 153 publications

(155 citation statements)

References 296 publications

(285 reference statements)

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“…On one hand, serine hydroxymethyltransferase, and glycine dehydrogenase both provide 5,10-methylene-THF, which is an important cofactorprecursor for nucleotide biosynthesis and DNA methylation; and both processes are increased in many tumors [2,48]. Moreover, the first chemotherapeutic agents (which are chemical derivatives are still used today) were anti-folates and inhibit enzymes in the folate pathway, such as dihydrofolate reductase [49]. Dihydrofolate reductase provides THF, which is a precursor to 5,10-methylene-THF.…”

Section: Triple-negative Breast Cancermentioning

confidence: 99%

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Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Section: Triple-negative Breast Cancermentioning

confidence: 99%

“…The concept of depletion has a long-standing history in cancer treatment with anti-folates, nucleoside analogues, and asparaginase [49,194,195] as examples. The underlying principle for the use of anti-folates and nucleoside analogues is the dependency of fast proliferating cells on de novo DNA synthesis.…”

Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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“…Nowadays, second and third generations of folate antagonists are available based on the rationale design of compounds that harbour speciWc membrane transport, polyglutamylation and/or enzyme targeting properties [63]. Since inhibition of TS is the resultant of one or more of these parameters, we used the in situ TS inhibition assay as a tool to obtain insight how for new generation of antifolates this is translated into potential therapeutic activity [32,48].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to inXux into cells, the cytotoxic action of MTX and other antifolates is dependent on binding to the intracellular targets dihydrofolate reductase (DHFR) [35] and thymidylate synthase (TS) [40], polyglutamylation [33,34], and the rate of drug eZux via members of the multidrug resistance protein family [3,18,63]. TS is a key enzyme in the de novo synthesis of thymidylate necessary for DNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

Mauritz

Peters

Kathmann

et al. 2008

Cancer Chemother Pharmacol

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Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/ MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing aYnities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = ¡0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding aYnity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deWcient chow. Dietary folate depletion signiWcantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor eVects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deWcient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic eVects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding aYnity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic eVect of antifolates may be further improved.

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“…The vitamin D receptor (VDR) was reported to target hSULT2A1 promoter through interaction with CAAT/Enhancer Binding Protein-alpha (C/EBPα) (Song et al, 2006). Methotrexate (MTX) is a widely used drug against cancer and other diseases (Walling, 2006,Green et al, 2006. The efficiency of this drug is through tightly binding to dihydrofolate reductase (DHFR), a key enzyme for DNA and several amino acids synthesis.…”

Section: Introductionmentioning

confidence: 99%

Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)☆

et al. 2007

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Sulfotransferases (SULTs) catalyzed sulfation is important in the regulation of biological activities of hormones and neurotransmitters, the metabolism of drugs, and the detoxification of xenobiotic toxicants. Sulfation also leads to the bioactivation of procarcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) is a major SULT catalyzing the sulfation of hydroxysteroids and xenobiotic alcohols. Our previous studies had shown that the anti-folate drug methotrexate (MTX) can up-regulate several major isoforms of human SULTs. To determine the mechanisms controlling the regulation of hSULT2A1, the 5′-flanking region of hSULT2A1 was constructed into the pGL3-Basic luciferase reporter vector. The transcriptional regulation mechanism of hSULT2A1 promoter was studied using Caco-2 cell line based on the reporter gene assay. Nuclear receptor co-transfection results indicated that human constitutive androstane receptor (hCAR) and human retinoid X receptor α (hRXRα) were involved in the transcriptional regulation of hSULT2A1. RNA interference experiments further proved the role of hCAR in hSULT2A1 regulation. Progressive promoter deletion, DNA sequence alignment, and site directed promoter mutation results suggested that an imperfect inverted repeat DNA motif, IR2 (-186AGCTCAGATGACCC-173), within the hSULT2A1 promoter region mediated the hSULT2A1 induction by MTX. Furthermore, electrophoretic mobility shift assay and super shift assay were employed to characterize the interactions of hCAR and hRXRα with the IR2 element. In summary, we identified an IR2 DNA cis-element located at -186/-173 of hSULT2A1 promoter region; the IR2 element mediates the MTX induction of hSULT2A1 through interacting with hCAR and hRXRα.

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From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

Cited by 153 publications

References 296 publications

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)☆

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