New folate analogs of the 10-deaza-aminopterin series Basis for structural design and biochemical and pharmacologic properties

Sirotnak, Francis M.; DeGraw, Joseph I.; Moccio, D. M.; Samuels, Lawrence L.; Goutas, L. J.

doi:10.1007/bf00255903

Cited by 92 publications

(68 citation statements)

References 7 publications

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“…This is in accordance with a study by Sirotnak et al [57] with L1210-RFC cells in another mouse strain. Our data show that dietary folate depletion could further enhance the anti-leukaemic eVect of both drugs, most likely due to less competition for cellular uptake and polyglutamylation by circulating plasma folates [27].…”

Section: Discussionsupporting

confidence: 94%

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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Section: Discussionsupporting

confidence: 94%

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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“…[4][5][6][7][8] Similarly, the V max /K m for the FPGS suggest that pralatrexate is 10 times more efficiently polyglutamylated compared with MTX. [4][5][6][7][8] This biochemistry suggests that pralatrexate should be more potent than MTX and could overcome…”

Section: Introductionmentioning

confidence: 99%

Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

O’Connor

Horwitz²,

Hamlin³

et al. 2009

JCO

159

113

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A B S T R A C T PurposeTo determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and MethodsPralatrexate, initially given at a dose of 135 mg/m 2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m 2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/L, and a platelet count greater than 50,000/L for the first dose of any cycle. ResultsThe every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m 2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B-and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. ConclusionPralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

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“…4 Subgroup analyses have shown that the activity of pralatrexate was equivalent irrespective of the amount of prior therapy, age, prior autologous stem cell transplant, or subtype of PTCL. Pralatrexate belongs to the class of folate analogues known as 10-deazaaminopterins, which have shown markedly superior antitumor effects compared with methotrexate in severe combined immunodeficient (SCID)-beige xenograft models of lymphoma (11,12). Pralatrexate was designed to have greater affinity than methotrexate for the natural folate and antifolate principal transporters reduced folate carrier-1 (RFC-1; an oncofetal protein) and folyl-polyglutamyl synthase, leading to enhanced intracellular accumulation and polyglutamylation in tumor cells.…”

mentioning

confidence: 99%

Pralatrexate Is Synergistic with the Proteasome Inhibitor Bortezomib inIn vitroandIn vivoModels of T-Cell Lymphoid Malignancies

Marchi

Paoluzzi

Scotto

et al. 2010

Clinical Cancer Research

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Purpose: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma.Experimental Design: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies.Results: In vitro, pralatrexate and bortezomib exhibited concentration-and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.Conclusion: Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies. Clin Cancer Res; 16(14); 3648-58. ©2010 AACR.

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New folate analogs of the 10-deaza-aminopterin series Basis for structural design and biochemical and pharmacologic properties

Cited by 92 publications

References 7 publications

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

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

Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

Pralatrexate Is Synergistic with the Proteasome Inhibitor Bortezomib inIn vitroandIn vivoModels of T-Cell Lymphoid Malignancies

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