10-Propargyl-10-deazaaminopterin C??? ??, ??, ??
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Pralatrexate, an injectable DHFR inhibitor, was launched for the treatment of patients with relapsed or refractory PTCL. PTCL is an
aggressive form of non-Hodgkin’s lymphoma (NHL) characterized by
the proliferation of abnormal T-lymphocytes that circulate in the peripheral bloodstream. The inhibition of the folate enzymes DHFR and thymidylate synthase is a well-validated method of cancer treatment.
In vitro, pralatrexate is
slightly less potent than MTX in inhibiting DHFR derived from murine
leukemia L1210 cells (K
i = 18.2 pM vs. 5.75 pM) and human leukemia
CCRF-CEM cells (K
i = 13.4 pM vs. 5.4 pM). However, it is transported
into both types of cells with 10-fold higher efficiency than MTX,
thereby providing a more potent inhibition of cell growth as compared
with MTX. In vivo, intraperitonally administered pralatrexate at 60 mg/
kg twice weekly for three or four doses caused complete lymphoma
regressions in 89, 56, and 30% of HT, RL, and SKI-DLBCL-1 xenografted
mice, respectively, whereas a similar dosing of MTX at 40 mg/kg twice
weekly did not produce complete regression. The posttreatment tumor
diameter was also smaller in pralatrexate-treated animals.
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An antifolate with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma.
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ChEBI: A pteridine that is the N-4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl derivative of L-glutamic acid. Used for treatment of Peripheral T-Cell Lymphoma, an aggressive form of non-Hodgkins lymphoma.
Clinical Use
Pralatrexate, an injectable dihydrofolate reductase (DHFR)
inhibitor, has a superior potency and toxicity profile compared to
other DHFR inhibitors. In 2009, the compound was launched by
Allos and approved in the U.S. for the treatment of patients with
relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single
agent. It is the first drug approved for this indication.70 In 2010,
orphan drug designation was received in the E.U. for the treatment
of cutaneous T-cell lymphoma (CTCL).
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The most common adverse reactions associated with pralatrexate are mucositis, thrombocytopenia, nausea, and fatigue. Folic acid and vitamin B12 supplements are administered as adjunct therapies to potentially reduce pralatrexate-related hematological toxicity and mucositis.
10-Propargyl-10-deazaaminopterin ?? ?? ? ???
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