Abstract
N-(Phosphonacetyl)-L-aspartate (PALA) inhibits aspartate carbamoyltransferase (ACTase), the second step in de novo pyrimidine biosynthesis, resulting in a decrease in uridine and cytidine nucleotide pools and accumulation of phosphoribosylpyrophosphate.1,2 Preclinical studies suggest that the biochemical effects of P ALA may increase the metabolism of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms.2–6 Further, promising clinical activity has been reported with low dose PALA, 250 mg/m2, given 24 hours prior to high-dose infusional 5-FU on a weekly schedule.7,8
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Collins, K.D., and Stark, G, R.: Aspartate transcarbamylase, interaction with the transition state analogue N-(phosphonacety)-L-aspartate. J. Biol Chem., 246: 6599–6605, 1971.
Grem, J.L., King, S.A., O’Dwyer, P.J., and Leyland-Jones, B.: N-(Phosphon-acetyl)-L-Aspartate (PALA): a review of its biochemistry and clinical activity. Cancer Res., 48: 441 (1988).
Ardalan, B., Glazer, R.I., Kensler, T.W., Jayaram, H.N., Pham, T.V., MacDonald, J.S., and Cooney, D.A. Synergistic effect of 5-fluorouracil and N-(phosphonacety)-L-aspartate on cell growth and ribonucleic acid synthesis in human mammary carcinoma. Biochem. Pharmacol., 30: 2045 (1981).
Liang C.M., Donehower, R.C., and Chabner, B.A. Biochemical interactions between N-(phosphonacetyl)-L-aspartate and 5-fluorouracil. Mol. Pharmacol., 21: 224 (1982).
Major, P.P., Egan, E.M., Sargent, L., and Kufe, D.W., Modulation of 5-FU metabolism in human MCF-7 breast carcinoma cells. Cancer Chemother. Pharmacol., 8: 87 (1982).
Martin, D.S., Stolfi, R.L., Sawyer, R.C., Spiegelman, S., Casper, E.S., and Young, C.W. Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: a murine study with clinical relevance. Cancer Res., 43: 2317 (1983).
Ardalan, B., Singh, G. Silberman, H.A.: Randomized Phase I and Phase II study of short-term infusion of high-dose fluorouracil with or withour N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancer. J. Clin. Oncol. 6: 1053 (1988).
O’Dwyer, P.J., Paul, A.R., Walczak, J., Weiner, L.M., Litwin, S., and Comis, R.L.: Phase II study of biochemical modulation of fluorouracil by low-dose PALA in patients with colorectal cancer. J. Clin. Oncol. 8: 1497 ( 1990.
Grem, J.L., Hoth, D., Hamilton, M.J., et al: An overview of the current status and future directions of clinical trials of 5-fluorouracil and folinic acid. Cancer Treat. Rep. 71: 1249 (1987).
The Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J. Clin. Oncol. 10: 896 (1992).
Calabro-Jones, P.M., Byfield, J.E., Ward, J.F., and Sharp, T.R.: Time-dose relationships for 5-fluorouracil cytotoxicity against human epithelial cancer cells in vitro. Cancer Res. 42: 4413 (1982).
Moran, R.G., Scanlon, K.L.: Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res. 51: 4618 (1991).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Grem, J.L., McAtee, N., Drake, J.C., Steinberg, S., Allegra, C.J. (1993). Dose-Dependent Inhibition of Aspartate Carbamoyltransferase in Peripheral Blood Mononuclear Cells in Patients Receiving N-(Phosphonacetyl)-L-Aspartate. In: Rustum, Y.M. (eds) Novel Approaches to Selective Treatments of Human Solid Tumors. Advances in Experimental Medicine and Biology, vol 339. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2488-5_13
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2488-5_13
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6060-5
Online ISBN: 978-1-4615-2488-5
eBook Packages: Springer Book Archive