The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors.
The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile as compared to the classical i.v. bolus administration, prolonged infusions can be inconvenient for the patients and catheter-related problems are common complications. An oral 5-FU formulation would allow for sustained 5-FU plasma concentrations, mimicking the pharmacokinetics (PK) of a continuous infusion with the addition of convenience of administration. The oral administration of 5-FU itself is not feasible due to the high activity of dihydropyrimidine dehydrogenase in the gut wall, which causes rapid metabolism of the drug, and results in decreased and erratic absorption of 5-FU and non-linear PK. To bypass this problem, oral fluoropyrimidine derivatives were developed either in the form of 5-FU prodrugs (i.e. tegafur, doxifluridine or capecitabine), or as enzyme inhibitors (i.e. eniluracil) administered with 5-FU, or as both prodrugs and enzyme inhibitors (i.e. S-1, UFT or BOF-A2). This review will focus on the oral fluoropyrimidine S-1, which consists of the 5-FU prodrug tegafur (ftorafur, FT) and two enzyme inhibitors, i.e. CDHP (5-chloro-2,4-dihydroxypyridine) and OXO (potassium oxonate), in a molar ratio of 1(FT):0.4 (CDHP):1(OXO). Phase II trials have demonstrated that S-1, as a single agent, is active for the treatment of gastric, colorectal, head and neck, breast, non-small cell lung, and pancreatic cancers. Phase III trials are currently underway in gastric cancer and these results are awaited to confirm the phase II findings. Furthermore, the combination of S-1 with cisplatin (CDDP), irinotecan or docetaxel for the treatment of gastric cancer and with CDDP for non-small cell and pancreatic cancer is feasible and active. The activity observed with S-1 in the phase II studies is at least equivalent, if not better, than continuous i.v. and bolus 5-FU and the other oral fluoropyrimidines. Thus, we may finally be seeing the realization of oral treatments for the management of various solid tumors and could be on the brink of a new approach to treatment strategies.
Schöffski
Patrick
P
Department of Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. schoeffski.patrick@web.de
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods; D004304:Dosage Forms; D004334:Drug Administration Schedule; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005641:Tegafur / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
D004304:Dosage Forms; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011355:Prodrugs; D011725:Pyridines; D011743:Pyrimidines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C029269:5-fluoropyrimidine; C104201:gimeracil