title: A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.
abstract: N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.
authors.affiliation: Beatson Oncology Centre, Western Infirmary, Glasgow, U.K.
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: W
authors.initials: W
authors.lastname: Oster
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: P A
authors.initials: PA
authors.lastname: Canney
authors.forename: H
authors.initials: H
authors.lastname: Yosef
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil