1843u89 and Neoplasms

Thymidylate synthase (TS) is a folate-dependent enzyme that catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate to 2'-deoxythymidine-5'-monophosphate. This pathway provides the sole intracellular de novo source of 2'-deoxythymidine-5'-triphosphate; therefore, TS represents a critical target in cancer chemotherapy. 5-Fluorouracil (5-FU) was synthesized in 1957 and represents the first class of antineoplastic agents to be developed as inhibitors of TS. While 5-FU has been widely used to treat various human malignancies, its overall clinical efficacy is limited. Therefore, significant efforts have focused on the design of novel, more potent inhibitor compounds of TS. These agents fall into two main categories: folate analogs and nucleotide analogs. Five antifolate analogs are currently being evaluated in the clinic: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L. Our laboratory has identified a novel mechanism of resistance that develops to TS inhibitor compounds, namely drug-mediated acute induction of new TS synthesis; this mechanism is directly controlled at the translational level. The ability of cancer cells to acutely induce the expression of TS may represent a novel mechanism for the development of cellular drug resistance. The future success of TS inhibitor compounds in the clinic may depend on novel strategies to selectively inhibit TS and on novel combination therapies to overcome cellular drug resistance.

Topics: Antineoplastic Agents; Enzyme Inhibitors; Humans; Indoles; Isoindoles; Neoplasms; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes; Thymidylate Synthase

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 folic acid supplementation ameliorates the toxic effects of 1843U89 and permits further dose escalation, and to recommend doses of 1843U89 administered without and with folic acid for further clinical evaluations. The study also sought to characterize the pharmacokinetic behavior of 1843U89 and to seek preliminary evidence of anticancer activity. Patients with advanced solid malignancies were treated with escalating doses of 1843U89 as a 2-min i.v. infusion daily for 5 days every 3 weeks. Initially, patients were treated in the absence of high-dose folic acid until dose-limiting toxicity was consistently noted. Next, patients were treated with escalating doses of 1843U89 preceded by 1000 mg of folic acid administered p.o. 30 min before each of the 5 daily doses of 1843U89. Patients (32) received 101 total courses of 1843U89 at doses ranging from 1 to 6 mg/m(2)/day with and without folic acid. At the 2 mg/m(2)/day dose level without folic acid, 2 of 7 new patients experienced dose-limiting toxicity, principally neutropenia, mucositis, and malaise in 3 of 11 courses. 1843U89 doses were further increased with folic acid to 6 mg/m(2)/day, but repetitive treatment was not feasible at this dose level because of an unacceptable high incidence of severe neutropenia and mucositis. Other toxicities included thrombocytopenia, rash, 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 folic acid. 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 folic acid is feasible at 1843U89 doses as high as 2 and 5 mg/m(2)/day, respectively. Because folic acid 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 cancer patients, the therapeutic index of 1843U89 may be enhanced by folic acid pretreatment and, therefore,

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exanthema; Female; Folic Acid; Humans; Indoles; Infusions, Intravenous; Isoindoles; Male; Middle Aged; Mouth Mucosa; Neoplasms; Neutropenia; Quinazolines; Stomatitis; Thymidylate Synthase