Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.
Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
A
A
Hageboutros
G R
GR
Hudes
J
J
Brennan
F
F
Green
J
J
Hoffman
F P
FP
LaCreta
J
J
Colofiore
D S
DS
Martin
R F
RF
Ozols
P J
PJ
O'Dwyer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012334:RNA, Neoplasm; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013873:Thionucleotides / Q000493:pharmacokinetics / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D013873:Thionucleotides; D001224:Aspartic Acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D005472:Fluorouracil