Kinetic heterogeneity of an experimental tumour revealed by BrdUrd incorporation and mathematical modelling.
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.
Bertuzzi
Alessandro
A
Istituto di Analisi dei Sistemi ed Informatica del CNR, Viale Manzoni 30, 00185 Roma, Italy. bertuzzi@iasi.rm.cnr.it
Faretta
Mario
M
Gandolfi
Alberto
A
Sinisgalli
Carmela
C
Starace
Giuseppe
G
Valoti
Giorgio
G
Ubezio
Paolo
P
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism / Q000493:pharmacokinetics; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D001973:Bromodeoxyuridine