Pralatrexate
Pralatrexate, sold under the brand name Folotyn, is a medication used for the treatment of relapsed or refractory peripheral T-cell lymphoma.
Pralatrexate was approved for medical use in the United States in September 2009, as the first treatment for Peripheral T-cell Lymphoma, an often aggressive type of non-Hodgkins lymphoma.
Medical uses
Pralatrexate is indicated for the treatment of people with relapsed or refractory peripheral T-cell lymphoma.Available forms
It is administered intravenously weekly for 6 weeks in 7-week cycles, with mandatory folic acid and vitamin B12 supplementation to mitigate toxicities like mucositis.Side effects
Pralatrexate is associated with several notable side effects, most prominently mucositis, which is considered the most frequently observed adverse event during treatment for relapsed or refractory peripheral T-cell lymphoma. Mucositis risk can be reduced through supplementation with leucovorin, cyanocobalamin, and folic acid. Other adverse effects described include myelosuppression, anemia, thrombocytopenia, neutropenia, and gastrointestinal symptoms, which require monitoring and supportive care to mitigate toxicity.Mechanism of action
Pralatrexate is a folate analog metabolic inhibitor designed to selectively enter cancer cells that overexpress the reduced folate carrier. Once inside the cell, pralatrexate competitively inhibits dihydrofolate reductase, disrupting folate-dependent processes crucial for DNA synthesis, RNA production, and cell division, ultimately leading to apoptosis. Its enhanced cellular uptake and polyglutamylation contribute to prolonged intracellular retention and potent cytotoxicity, distinguishing it from other antifolate agents.Discovery
Research on this class of drugs began in the 1950s at SRI International, where scientists were focused on developing new chemotherapies and antifolates that would be effective against tumor cells.In the late 1970s, researchers at Memorial Sloan Kettering Cancer Center discovered, that cancerous cells take in natural folate through a protein identified as plasma membrane transporter. Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to ensure they get enough folate.
A subsequent scientific collaboration was ultimately formed among SRI International, Memorial Sloan Kettering Cancer Center, and the Southern Research Institute with the intention of developing an antifolate with greater therapeutic selectivity – an agent that could be more effectively internalized into tumors and would be more toxic to cancer cells than normal cells.
This collaboration, supported by the National Cancer Institute, led to the identification of pralatrexate in the mid-1990s. Pralatrexate was later licensed to Allos Therapeutics in 2002 for further development. Allos Therapeutics, Inc. was acquired by Spectrum Pharmaceuticals, Inc. on September 5, 2012. Allos is a wholly owned subsidiary of Spectrum.