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.
BACKGROUND
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.


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.
Grem
J L
JL
NCI-Navy Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland 20889-5105, USA. gremj@mail.nih.gov
Yee
L K
LK
Schuler
B
B
Hamilton
J M
JM
Chen
A P
AP
Chabuk
C
C
Grollman
F
F
Grabenc
M
M
Allegra
C J
CJ
Takimoto
C H
CH
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019454:Chronotherapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*
D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil