title: Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717.
abstract: The thymidylate synthase (TS) inhibitor CB 3717 was administered intravenously to 24 adult patients as a single bolus repeated every 3-4 weeks. The doses were escalated from 50 to 400 mg/m2. At the highest level, hydration and urinary alkalinization were routinely performed. A greater than 20% decrease of the creatinine clearance value occurred in 35% of the cycles performed at 400 mg/m2, a dose which could be recommended for phase II studies. Hepatic toxicity, represented by an increase of the glutamic pyruvic transaminase (GPT) plasma levels, occurred in 70% of the patients after the first cycle. GPT peak levels were neither related to the dose nor to the peak drug plasma concentrations or AUC values in the dose range from 225 to 400 mg/m2. Malaise, reported after 46% of the cycles, was the most disturbing side-effect and its occurrence was statistically correlated with the degree of elevation of GPT. A suggestion of antitumor activity was reported for dosages of 300 and 400 mg/m2 in three patients with ovarian cancer refractory to cisplatin. Further clinical evaluations of TS inhibitors rely on the development of more water soluble and less hepato- and nephrotoxic agents.
authors: Department of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland.
authors: C
authors: C
authors: Sessa
authors: M
authors: M
authors: Zucchetti
authors: M
authors: M
authors: Ginier
authors: Y
authors: Y
authors: Willems
authors: M
authors: M
authors: D'Incalci
authors: F
authors: F
authors: Cavalli
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D003404:Creatinine / Q000652:urine; D004341:Drug Evaluation; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005492:Folic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011799:Quinazolines; C031662:CB 3717; D005492:Folic Acid; D003404:Creatinine; D013940:Thymidylate Synthase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase