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Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 1996; Vol. 37 (3), pp. 229-34. - Publication Year :
- 1996
-
Abstract
- 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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents pharmacokinetics
Aspartic Acid pharmacology
Female
Fluorouracil therapeutic use
Humans
Infusions, Intravenous
Male
Middle Aged
Neoplasms metabolism
Phosphonoacetic Acid pharmacology
RNA, Neoplasm
Thioinosine pharmacokinetics
Thioinosine pharmacology
Thionucleotides pharmacokinetics
Antimetabolites, Antineoplastic pharmacology
Antineoplastic Agents pharmacology
Aspartic Acid analogs & derivatives
Fluorouracil pharmacokinetics
Neoplasms drug therapy
Phosphonoacetic Acid analogs & derivatives
Thioinosine analogs & derivatives
Thionucleotides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0344-5704
- Volume :
- 37
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 8529282
- Full Text :
- https://doi.org/10.1007/BF00688321