This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stetson, P. L. Articles by Ensminger, W. D. Search for Related Content PubMed PubMed Citation Articles by Stetson, P. L. Articles by Ensminger, W. D.

Tissue-specific Pharmacodynamics of 5-Bromo-2'-deoxyuridine Incorporation into DNA in VX2 Tumor-bearing Rabbits¹

Upjohn Center for Clinical Pharmacology [P. L. S., N. J. J., D. P., P. S., C. A. K., Z. Y., W. D. E.], Department of Pharmacology [P. L. S., J. M., W. D. E.], Department of Internal Medicine [I. S. W., W. D. E.], Department of Surgery [J. A. K.], Unit for Laboratory Animal Medicine [D. R. A.], University of Michigan School of Medicine, Ann Arbor, Michigan 48109; School of Pharmacy [J. G. W.], University of Michigan, Ann Arbor, Michigan 48109

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation in to DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 µM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: I_max for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C₅₀ for the arterial BrdUrd concentration generating incorporation that is I_max/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

¹ This research supported in part by NIH Grant CA-33825.

² To whom requests for reprints should be addressed.

Received 5/13/88. Revised 8/25/88. Accepted 8/31/88.

This article has been cited by other articles:

				P. Jecker, A. Beuleke, I. Dressendorfer, R. Pabst, and J. Westermann Long-term Oral Application of 5-Bromo-2-Deoxyuridine Does Not Reliably Label Proliferating Immune Cells in the LEW Rat J. Histochem. Cytochem., March 1, 1997; 45(3): 393 - 402. [Abstract] [Full Text] [PDF]