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: 2.07). 06/2012; 26(3):629-48, ix. DOI: 10.1016/j.hoc.2012.02.002
Source: PubMed

ABSTRACT 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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    ABSTRACT: To investigate the impact of 5-formyltetrahydrofolate on the activities of pralatrexate, as compared to methotrexate (MTX), in vitro. Cells were exposed to (6S)5-formyltetrahydrofolate (5-formylTHF) for 24 h, before or after a 6-h exposure to antifolates following which the cellular accumulation and activities of the drugs were evaluated in HeLa cells. A 24-h delay between a 6-h exposure to antifolates and a subsequent 24-h exposure to 4 μM 5-formylTHF sustained the full activities of both antifolates. A 72-h interval was required between a single exposure of up to 4 μM 5-formylTHF and subsequent exposure to drugs to sustain activities of the antifolates. When cells were incubated with 4 μM 5-formylTHF for 24 h weekly, for 4 weeks, there was no significant increase in the IC50 for pralatrexate, but the MTX IC50 increased 2.5-fold as compared to cells growing continuously in 25 nM 5-formylTHF. This cyclical exposure to 5-formylTHF increased the cell folate pool by 16 %, had no significant effect on the intracellular pralatrexate level, but decreased intracellular MTX by 15 %. An extracellular concentration of MTX 50-fold higher than that of pralatrexate was required to achieve an intracellular level, and growth inhibition, comparable to that of pralatrexate. Cyclical exposures to 5-formylTHF at levels in excess of what is achieved in most clinical "rescue" regimens do not affect pralatrexate accumulation nor antitumor activity in HeLa cells, in contrast to MTX. An important element in preserving pralatrexate activity is achieving a sufficient interval between exposure to 5-formylTHF and the next dose of antifolate.
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    ABSTRACT: High-dose methotrexate (MTX) can produce acute kidney injury, impairing MTX elimination. Continuous venovenous hemofiltration (CVVH) may enhance elimination in this setting, although its use is largely unstudied. A 79-year-old man received IV MTX for central nervous system lymphoma, and over a 34-h period his serum creatinine increased from 1.09 to 2.24 mg/dL. His serum MTX concentration (sMTX) at the end of this time period was 59.05 µmol/L. After urinary alkalinization and leucovorin and glucarpidase (CPDG2) treatment, sMTX decreased. Fluid overload ensued and CVVH was initiated. The initial MTX extraction ratio and clearance were 0.22 and 47.0 mL/min, respectively. No MTX extraction occurred at an sMTX of 0.15 µmol/L. Continuous venovenous hemodialysis was initiated, and sMTX further declined. CVVH may help eliminate MTX and provide renal replacement at moderate sMTX.
    12/2014; 7(6):590-2. DOI:10.1093/ckj/sfu093
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    ABSTRACT: The liver is one of the most commonly involved extrapulmonary sites in sarcoidosis. Hepatic sarcoidosis has a broad range of presentations from scattered, asymptomatic noncaseating granulomas with normal liver enzymes, which are very common in patients with known pulmonary sarcoidosis, to portal hypertension and cirrhosis, which are relatively uncommon. Diagnosis is based on a combination of clinical, laboratory and histological manifestations. The authors' protocol for management of patients with suspected sarcoidosis of the liver without focal lesions includes a transjugular liver biopsy with portal pressure measurements to confirm the diagnosis, rule out coexisting liver diseases and to identify select patients with fibrosis or portal hypertension for consideration of immunosuppression. Steroids and azathioprine are the preferred agents and methotrexate is not recommended.
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