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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Raltitrexed (TomudexTM) is administered intravenously for the palliation of advanced colorectal cancer in cases where 5-FU and folinic acid cannot be used (Figure 3.8). It is one of the most potent antimetabolites in clinical use, with an IC50 value of 9 nM in L1210 cells in in vitro. Raltitrexed was first synthesized in the late 1980s, evaluated in the clinic in the 1990s, and approved in 1998. The thymidylate synthase (TS) inhibitors raltitrexed (TomudexTM), plevitrexed, pemetrexed (AlimtaTM), and nolatrexed (ThymitaqTM).
Colorectal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Raltitrexed is a more potent TS inhibitor and can be given at 3-weekly intervals due to its pharmacokinetics. One trial was terminated early due to an unexpectedly high treatment-related death rate.142 Because of this, there are reservations about the use of this drug, as there are reasonable alternatives in the form of 5-FU and FA and capecitabine. However, it remains available as an alternative to 5-FU or capecitabine in patients who develop angina (coronary vasospasm) on fluoropyrimidines, which is a serious, potentially fatal, and under-recognized serious side effect (in up to 3% of patients).
Gastrointestinal cancer
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Justin S Waters, David Cunningham
Direct inhibition of thymidylate synthase is produced by the folate analogue raltitrexed. This is administered intravenously, and is transported into the cell by the reduced folate carrier. Within the cell, raltitrexed undergoes polyglutamation by the enzyme folyl polyglutamate synthetase. Polyglutamated forms have increased potency for thymidylate synthase, and are retained within the cell, prolonging the inhibitory activity. Plasma levels of raltitrexed after i.v. injection decline rapidly in an initial phase, with a β half-life of 90–120 min, followed by a slow elimination phase, with a terminal half-life of about 8 days. Approximately 40–50% of the drug is excreted in the urine.
Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer
Published in Acta Oncologica, 2020
Anne Dyhl-Polk, Merete Vaage-Nilsen, Morten Schou, Kirsten Kjeldgaard Vistisen, Cecilia Margareta Lund, Thomas Kümler, Jon Michael Appel, Dorte Lisbet Nielsen
Alternative treatment options in patients with colorectal cancer include UFT, S-1 or raltitrexed. In UFT and S-1, the 5-FU prodrug, tegafur, are combined with a dihydropyrimidine dehydrogenase (DPD) inhibitor that reduces the degradation of 5-FU to fluorobetaalanine [39]. Since fluorobetaalanine may be involved in the cardiotoxic effects from fluoropyrimidines [40], DPD inhibition should result in lower incidences of cardiotoxicity. For UFT, lower incidences of cardiotoxicity (1%) have been reported [41], but there are few published data regarding the cardiotoxicity from S-1. Yet, a case series of seven patients whom were successfully treated with S-1 after cardiotoxicity induced by capecitabine has been published [42]. The thymidylate synthase inhibitor, raltitrexed, is an alternative in patients with advanced colorectal cancer. In 42 patients with cardiotoxicity induced by 5-FU or capecitabine, no further cardiac events were reported during treatment with raltitrexed [43]. However, raltitrexed has been associated with a high mortality rate (2–6%) [44].
Can carcinoembryonic antigen replace computed tomography in response evaluation of metastatic colorectal cancer?
Published in Acta Oncologica, 2018
Kethe Hermunen, Eila Lantto, Tuija Poussa, Caj Haglund, Pia Österlund
A phase I–II clinical trial included 81 consecutive, eligible and consenting patients at Helsinki University Central Hospital between March 30, 1998, and February 21, 2001. Each received raltitrexed (1.5-) 3.0 mg/m2 on cycle day one as an intravenous infusion and carmofur 300 (−400) mg/m2 orally divided into three daily doses on cycle days 2–14, followed by a week of rest. The doses in parenthesis were those for the six patients in the phase I portion of the study, but all other patients received the stated raltitrexed treatment [24,25]. Of these 81 patients, 66 had at least two CEA values and CT scans available at baseline and at 2 months and were included in the study. Of these 66 patients, 47 (71%) received treatment as first line and 19 (29%) as second line. Table 1 shows patient characteristics. Median age was 61 years. A good balance existed between gender and site of primary tumor. Of these 66 patients, 39% had metachronous and 61% synchronous metastases, with liver and lung as the most common metastatic sites. Median number of metastatic sites was 2 (range 1–5). Eastern Cooperative Oncology Group (ECOG) performance status was 0–2 with two thirds being 1.
Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Kavita Bhagat, Nitish Kumar, Harmandeep Kaur Gulati, Aanchal Sharma, Amandeep Kaur, Jatinder Vir Singh, Harbinder Singh, Preet Mohinder Singh Bedi
For the last few years, a series of molecules was introduced that showed higher efficacy as well as selectivity against DHFR as shown in Figure 2. After introducing MTX, Raltitrexed was second DHFR inhibitor used for the treatment of malignant colorectal cancer, but it is also used in that patient that is intolerant to 5-fluorouracil. The next drug is Premetrexed introduced in 2001, used for the treatment of non-squamous cell lung cancer and pleural mesothelioma with a combination of cisplatin. Pralatrexate was the last DHFR inhibitor, which was approved by Food and Drug Administration in 2009, experienced a higher affinity toward DHFR and also used in the relapsed peripheral T-cell lymphoma disease [30].