Sequential administration of thymidine, 5-fluorouracil, and PALA. A phase I-II study.
Twenty-seven patients with colorectal adenocarcinoma, (12) non-small cell bronchogenic carcinoma, (11) gastric adenocarcinoma (3), and adenocarcinoma of unknown primary lesion (1) were treated with the combination of thymidine (TdR), 5-fluorouracil (FU), and N-phosphonacetyl-L-aspartic acid (PALA). PALA 1 g/m2 was given over 1 hour on day 1, followed on day 2 by 30 g of TdR given over 3 hours. FU, 150-300 mg/m2, was administered sequentially over 1 hour immediately following TdR infusion. There were no responses seen using this dose schedule. Gastrointestinal and central nervous system toxicities were dose-limiting. Myelosuppression was seen at all dose levels and was not dose related. Fever and infection occurred in 16% and 3% of the courses. The maximum tolerated dosages on this schedule were PALA, 1 g/m2; TdR, 30 g; and FU, 250 mg/m2. Pharmacologic studies done revealed the following half-lives: TdR, 1.6 hours; thymine, 5.0 hours; FU, 6.8 hours; and FUDR, 3.7 hours. The significant prolongation of the half-life of FU with this drug combination implies that the tumor tissues may be exposed longer to the anticancer action of FU.
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002283:Carcinoma, Bronchogenic / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007263:Infusions, Parenteral; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013936:Thymidine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
D009943:Organophosphorus Compounds; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D005472:Fluorouracil; D013936:Thymidine