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N-(phosphonacetyl)-L-aspartate and calcium leucovorin modulation of fluorouracil administered by constant rate and circadian pattern of infusion over 72 hours in metastatic gastrointestinal adenocarcinoma.

AbstractBACKGROUND:
We have reported that N-(phosphonacetyl)-L-aspartic acid (PALA) 1266 mg/m2 can safely be given 24 hours prior to the start of a 72-hour infusion of fluorouracil (FUra) and leucovorin (LV) at doses of 2000 and 500 mg/m2/day. Since inhibition of aspartate carbamoyltransferase (ACTase) activity was evident 4 hours post PALA, we wished to evaluate PALA given 1 hour prior to FUra. Further, we studied the toxicity and pharmacokinetics with FUra given by either fixed- or variable-rate infusion.
PATIENTS AND METHODS:
Twenty-seven patients with gastrointestinal tract adenocarcinomas were treated with PALA 1266 mg/m2/15 min followed by a 72-hour infusion of FUra and LV (1750 & 500 mg/m2/day) given by fixed- or variable-rate (peak at 4:00 A.M.).
RESULTS:
Clinical toxicity was similar in two consecutive cycles in 17 patients receiving fixed- and variable-rate infusion at the same FUra dose. Overall, grade 3 stomatitis and hand-foot syndrome occurred in 12% and 4% patients receiving fixed- and in 16% and 10.5% of patients receiving variable-rate infusions. Six of 24 evaluable patients (25%) had a partial response. The profile of FUra plasma levels (Cp) over a 24-hour period during fixed- and variable-rate infusions were strikingly different, but the average Cp and area under the concentration-time curves were comparable. ACTase activity was significantly decreased at 4 and 24 hours after PALA (12% and 18% of baseline; P < 0.001), but enzyme activity had recovered to 40% by 72 hours.
CONCLUSIONS:
This regimen was active and well tolerated with similar toxicities with FUra given by either fixed- or variable rate infusion. PALA 1266 mg/m2 significantly inhibited ACTase activity for at least 24 hours.
AuthorsJ L Grem, L K Yee, B Schuler, J M Hamilton, A P Chen, C Chabuk, F Grollman, M Grabenc, C J Allegra, C H Takimoto
JournalAnnals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 12 Issue 11 Pg. 1581-7 (Nov 2001) ISSN: 0923-7534 [Print] England
PMID11822758 (Publication Type: Journal Article)
Chemical References
  • Aspartic Acid
  • sparfosic acid
  • Aspartate Carbamoyltransferase
  • Phosphonoacetic Acid
  • Leucovorin
  • Fluorouracil
Topics
  • Adenocarcinoma (drug therapy, pathology, secondary)
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
  • Aspartate Carbamoyltransferase (antagonists & inhibitors, metabolism)
  • Aspartic Acid (administration & dosage, analogs & derivatives)
  • Chronotherapy
  • Female
  • Fluorouracil (administration & dosage, pharmacokinetics)
  • Gastrointestinal Neoplasms (drug therapy, pathology)
  • Humans
  • Infusions, Intravenous
  • Leucovorin (administration & dosage)
  • Male
  • Middle Aged
  • Phosphonoacetic Acid (administration & dosage, analogs & derivatives)

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