Kinetic heterogeneity of an experimental tumour revealed by BrdUrd incorporation and mathematical modelling

Bull Math Biol. 2002 Mar;64(2):355-84. doi: 10.1006/bulm.2001.0280.

Abstract

In the present paper we propose a method of analysis of the cell kinetic characteristics of in vivo experimental tumours, that uses DNA-BrdUrd flow cytometry data at various times after the bromodeoxyuridine (BrdUrd) injection and mathematical modelling. The model of the cell population takes into account the cell-cell heterogeneity of the progression rate across cell cycle phases within the tumour, and assumes a strict correlation between the durations of S and G2M phases. The model also allows for a nonconstant DNA synthesis rate across S phase. In addition, the measurement process is modelled, considering the possibility of nonimpulsive labelling and providing a representation of the time course of the bivariate DNA-BrdUrd fluorescence distribution. Sequential DNA-BrdUrd distributions were obtained in vivo from a human ovarian carcinoma transplanted in mice and, for comparison, in vitro from a cell line of the same origin. From these data, that included the fractional density and the mean BrdUrd-fluorescence of BrdUrd-positive cells as a function of the DNA-fluorescence, kinetic parameters such as the potential doubling time (Tpot) and the mean and variance of the transit times in S and G2M phases, were estimated. This study revealed the presence of a substantial heterogeneity in S and G2M phases within the in vivo cell population and of a lower heterogeneity in the in vitro population. Moreover, our analysis suggests a nonnegligible effect of the BrdUrd pharmacokinetics in the in vivo cell labelling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bromodeoxyuridine / metabolism
  • Bromodeoxyuridine / pharmacokinetics
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Cycle / physiology*
  • Cell Division / physiology
  • DNA, Neoplasm / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Kinetics
  • Mice
  • Mice, Nude
  • Models, Biological*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • DNA, Neoplasm
  • Bromodeoxyuridine