This study was performed to assess the feasibility of administering 1843U89, a potent, noncompetitive inhibitor of thymidylate synthase that does not require polyglutamation for activity, as a 2-min i.v. infusion daily for 5 days every 3 weeks, to determine whether @entity1501 supplementation ameliorates the toxic effects of 1843U89 and permits further dose escalation, and to recommend doses of 1843U89 administered without and with @entity1501 for further clinical evaluations. The study also sought to characterize the pharmacokinetic behavior of 1843U89 and to seek preliminary evidence of anticancer activity. @entity1 with advanced solid @entity5 were treated with escalating doses of 1843U89 as a 2-min i.v. infusion daily for 5 days every 3 weeks. Initially, @entity1 were treated in the absence of high-dose @entity1501 until dose-limiting @entity137 was consistently noted. Next, @entity1 were treated with escalating doses of 1843U89 preceded by 1000 mg of @entity1501 administered p.o. 30 min before each of the 5 daily doses of 1843U89. @entity1 (32) received 101 total courses of 1843U89 at doses ranging from 1 to 6 mg/m(2)/day with and without @entity1501 . At the 2 mg/m(2)/day dose level without @entity1501 , 2 of 7 new @entity1 experienced dose-limiting @entity137 , principally @entity1398 , @entity33 , and malaise in 3 of 11 courses. 1843U89 doses were further increased with @entity1501 to 6 mg/m(2)/day, but repetitive treatment was not feasible at this dose level because of an unacceptable high incidence of severe @entity1398 and @entity33 . Other @entity137 included @entity882 , @entity1910 , and fever. In contrast, repetitive treatment at the 5 mg/m(2)/day dose level was feasible. The pharmacokinetics of 1843U89 were neither dose dependent nor affected by @entity1501 . On day 1, clearance, terminal half-life, and steady-state volume of distribution values averaged 47.1 +/- 21.7 ml/min/m(2), 7.72 +/- 4.09 h, and 16.7 +/- 8.8 liter/m(2)/h, respectively. The results of the study indicate that the administration of 1843U89 as a 2-min infusion daily for 5 days every 3 weeks without and with @entity1501 is feasible at 1843U89 doses as high as 2 and 5 mg/m(2)/day, respectively. Because @entity1501 pretreatment results in no diminution of the antitumor activity of 1843U89 in preclinical studies and ameliorates the toxic effects of 1843U89 in both preclinical models and @entity5 @entity1 , the therapeutic index of 1843U89 may be enhanced by @entity1501 pretreatment and, therefore, the development of 1843U89 with @entity1501 is warranted. However, the question of whether to administer 1843U89 at a dose of 2 mg/m(2)/day with @entity1501 , which is associated with negligible @entity137 , or at its highest feasible dose with @entity1501 , 5 mg/m(2)/day, should be addressed in appropriately designed trials.

A phase I and pharmacokinetic study of 1843U89, a noncompetitive inhibitor of thymidylate synthase, in XXXX with advanced solid @entity5 .

@entity1501 :: ('MESH:D005492', 'Chemical') :: ['folic acid'] @entity1 :: ('9606', 'Species') :: ['Patients', 'patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity', 'toxicities'] @entity882 :: ('MESH:D013921', 'Disease') :: ['thrombocytopenia'] @entity1910 :: ('MESH:D005076', 'Disease') :: ['rash'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer', 'malignancies'] @entity33 :: ('MESH:D052016', 'Disease') :: ['mucositis'] @entity1398 :: ('MESH:D009503', 'Disease') :: ['neutropenia']
@entity1 :: (9606,Species) :: ['patients']
