Kinetic heterogeneity of an experimental tumour revealed by BrdUrd incorporation and mathematical modelling |
| |
Authors: | Alessandro Bertuzzi Mario Faretta Alberto Gandolfi Carmela Sinisgalli Giuseppe Starace Giorgio Valoti Paolo Ubezio |
| |
Affiliation: | (1) Istituto di Analisi dei Sistemi ed Informatica del CNR, Viale Manzoni 30, 00185 Roma, Italy;(2) Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milano, Italy;(3) Istituto di Medicina Sperimentale del CNR, Viale Marx 43, 00137 Roma, Italy;(4) Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Gavazzeni 11, 24125 Bergamo, Italy |
| |
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 (T pot) 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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|