THERAPEUTIC UTILITY OF UTILIZING LOW-DOSES OF N-(PHOSPHONACETYL)-L-ASPARTIC ACID IN COMBINATION WITH 5-FLUOROURACIL - A MURINE STUDY WITH CLINICAL RELEVANCE
- 1 January 1983
- journal article
- research article
- Vol. 43 (5) , 2317-2321
Abstract
Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c .times. DBA/8 F1) produced significant depression in UTP pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra), it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA and no increase in bone marrow FUra-containing RNA. These biochemical results correlated with the therapeutic findings of significantly increased antitumor activity without an increase in host toxicity. A review of currently reported PALA plus FUra clinical protocols reveals that the experimental parameters which have produced successful therapuetic results in the laboratory (a low-PALA:high-FUra dosage ratio) have not yet been translated into clinical trial. Final judgment on the clinical efficacy of PALA:FUra combinations must await the results of proposed low-PALA:high-FUra clinical trials.This publication has 28 references indexed in Scilit:
- SELECTIVE-INHIBITION OF PYRIMIDINE SYNTHESIS AND DEPLETION OF NUCLEOTIDE POOLS BY N-(PHOSPHONACETYL)-L-ASPARTATE1979
- PHASE-I TRIAL OF N-(PHOSPHONACETYL)-L-ASPARTATE1979
- PHASE-I STUDY OF N-(PHOSPHONACETYL)-L-ASPARTIC ACID (PALA)1979
- MECHANISMS OF SENSITIVITY OR RESISTANCE OF MURINE TUMORS TO N-(PHOSPHONACETYL)-L-ASPARTATE (PALA)1979
- EFFECTS OF N-(PHOSPHONACETYL)-L-ASPARTATE ON MURINE TUMORS AND NORMAL TISSUES INVIVO AND INVITRO AND RELATIONSHIP OF SENSITIVITY TO RATE OF PROLIFERATION AND LEVEL OF ASPARTATE-TRANSCARBAMYLASE1978
- SELECTIVE-INHIBITION OF PYRIMIDINE BIOSYNTHESIS AND EFFECT ON PROLIFERATIVE GROWTH OF COLONIC CANCER-CELLS1977
- PHARMACOLOGICAL AND BIOCHEMICAL EFFECTS OF PYRAZOFURIN IN HUMANS1977
- A phase III study comparing the clinical utility of four regimens of 5-Fluorouracil.A preliminary reportCancer, 1977
- Stable mutants of mammalian cells that overproduce the first three enzymes of pyrimidine nucleotide biosynthesisCell, 1976
- ANTITUMOR ACTIVITY OF N-(PHOSPHONACETYL)-L-ASPARTIC ACID, A TRANSITION-STATE INHIBITOR OF ASPARTATE-TRANSCARBAMYLASE1976