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

Alessandro Bertuzzi, Mario Faretta, Alberto Gandolfi, Carmela Sinisgalli, Giuseppe Starace, Giorgio Valoti, Paolo Ubezio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)355-384
Number of pages30
JournalBulletin of Mathematical Biology
Volume64
Issue number2
DOIs
Publication statusPublished - Mar 2002

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

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