Antitumor activity of the weekly intravenous push schedule of 5-fluoro-2'-deoxyuridine +/- N-phosphonacetyl-L-aspartate in mice bearing advanced colon carcinoma 26.
We have investigated the effects of N-(phosphonacetyl)-L-aspartate (PALA) administered i.v. as a single dose (100 mg/kg) on the antitumor activity of 5-fluoro-2'-deoxyuridine (FdUrd) and 5-fluorouracil (FUra), on the pharmacokinetic parameters of FdUrd and FUra, and on the tumor pyrimidine ribonucleotide triphosphate pools in mice bearing advanced colon carcinoma 26 and leukemia 1210. The antitumor activity was evaluated with PALA administered i.v. 24 h prior to the maximum tolerated dose of FUra and FdUrd administered by: (a) 4 days of continuous infusion (schedule 1, c.i. days 1-4); (b) daily for 4 days by i.v. push (schedule 2, i.v. days 1-4); and (c) weekly for 3 weeks (schedule 3, i.v. weekly for 3 weeks). The maximum tolerated doses of FdUrd were 20, 150, and 400 mg/kg/day and for FUra were 25, 50, and 80 mg/kg/day for schedule 1, 2, and 3, respectively. At the maximum tolerated doses, the antitumor activity in mice bearing advanced colon carcinoma can be summarized as follows: (a) FdUrd is significantly more active than FUra; (b) for both drugs the weekly for 3 weeks i.v. push schedule is superior to the c.i. or i.v. push daily for 4 days schedules; (c) pretreatment with PALA enhances the antitumor activity of FdUrd and FUra and resulted in 95 and 13% complete responses, respectively; (d) long-term survivors with FUra could only be achieved in the presence of PALA; in mice bearing leukemia 1210 cells, FdUrd or FUra with or without PALA exhibited no significant antitumor activity when PALA was administered in a single dose 24 h prior to fluoropyrimidine treatment; and (e) in C-26 and L1210, PALA reduced the pools of CTP and UTP equally, to about 10% of controls with significant difference in their rates of recovery.
van Laar
J A
JA
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
Durrani
F A
FA
Rustum
Y M
YM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D003570:Cytidine Triphosphate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000378:metabolism
D000970:Antineoplastic Agents; D005467:Floxuridine; D001224:Aspartic Acid; D003570:Cytidine Triphosphate; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D014544:Uridine Triphosphate