Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy

Barbara Fingleton, Ramkumar Menon, Kathy J. Carter, P. Dawn Overstreet, David L. Hachey, Lynn M. Matrisian, J. Oliver McIntyre

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

As molecularly targeted agents reach the clinic, there is a need for assays to detect their presence and effectiveness against target molecules in vivo. Proteinase inhibitors are one example of a class of therapeutic agent for which satisfactory methods of identifying successful target modulation in vivo are lacking. This is of particular importance while these drugs are in clinical trials because standard maximum-tolerated dose-finding studies often are not suitable due to lack of toxicity. Saliva represents a readily accessible bodily fluid that can be repeatedly sampled and used for assaying in vivo effects of systemic drugs. Here we show the development of a simple assay that can be used to measure proteinase activity in saliva and proteinase inhibition after systemic treatment with three different proteinase inhibitors. A variety of gelatinolytic activities present in human and murine saliva have been assayed with a fluorescent dye-labeled substrate and assigned to different proteinase categories by inclusion of specific classes of inhibitors. Treatment of mice with either matrix metalloproteinase inhibitors or a urokinase inhibitor for a period as short as 48 hours results in levels of the drugs that can be detected in saliva by mass spectrometry and concomitant decreases in salivary proteinase activity, thus demonstrating that these inhibitors successfully modulate their targets in vivo.

Original languageEnglish (US)
Pages (from-to)7865-7874
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number23
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

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Saliva
Human Activities
Peptide Hydrolases
Biomarkers
Pharmaceutical Preparations
Matrix Metalloproteinase Inhibitors
Maximum Tolerated Dose
Fluorescent Dyes
Mass Spectrometry
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fingleton, B., Menon, R., Carter, K. J., Overstreet, P. D., Hachey, D. L., Matrisian, L. M., & McIntyre, J. O. (2004). Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. Clinical Cancer Research, 10(23), 7865-7874. https://doi.org/10.1158/1078-0432.CCR-04-1252

Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. / Fingleton, Barbara; Menon, Ramkumar; Carter, Kathy J.; Overstreet, P. Dawn; Hachey, David L.; Matrisian, Lynn M.; McIntyre, J. Oliver.

In: Clinical Cancer Research, Vol. 10, No. 23, 01.12.2004, p. 7865-7874.

Research output: Contribution to journalArticle

Fingleton, B, Menon, R, Carter, KJ, Overstreet, PD, Hachey, DL, Matrisian, LM & McIntyre, JO 2004, 'Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy', Clinical Cancer Research, vol. 10, no. 23, pp. 7865-7874. https://doi.org/10.1158/1078-0432.CCR-04-1252
Fingleton, Barbara ; Menon, Ramkumar ; Carter, Kathy J. ; Overstreet, P. Dawn ; Hachey, David L. ; Matrisian, Lynn M. ; McIntyre, J. Oliver. / Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 23. pp. 7865-7874.
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