Objective determination of the oncolytic potency of conditionally-replicating adenoviruses using mathematical modeling.
BACKGROUND
Conditionally-replicating adenoviruses (CRAds) infect and replicate in tumor cells, releasing viral progeny upon lysis of the cell. This is a dynamic and inherently exponential process and, thus, the assessment of CRAds should incorporate these dynamics. In vitro experiments are therefore prone to subjective assessment because no validated assay exists that truly appreciates the dynamics of the process. An objective assay could simplify experiments and reduce the number of CRAd variants required to enter a full preclinical evaluation.


METHODS
We developed a simple and practical mathematical model incorporating easily obtainable parameters of the interaction between replicating viruses and growing tumor cells in vitro and, in the present study, validate this model by fitting the predicted values to experimentally-derived values.


RESULTS
From the exponential curves of cellular growth and the viral propagation rate in glioma cells, we derive the four parameters needed in this model and show a robust fit to experimental data. Because the initial infection conditions appear to significantly influence the final outcome of CRAd experiments, these conditions are determined using the same cells and correlated with the expression of the primary adenovirus receptor CAR (coxsackie and adenovirus receptor).


CONCLUSIONS
The results obtained shed light upon the method of action of CRAds and provide an objective and practical model and assay for determining and predicting CRAd activity in tumor cells.
Idema
Sander
S
Neurosurgical Center Amsterdam, Neuro-Oncology Research Group, Amsterdam, The Netherlands. s.idema@vumc.nl
Dirven
Clemens M F
CM
van Beusechem
Victor W
VW
Carette
Jan E
JE
Planqué
Robert
R
Noske
David P
DP
Lamfers
Martine L M
ML
Vandertop
W Peter
WP
D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000821:virology; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D050504:Oncolytic Viruses / Q000502:physiology*; D011991:Receptors, Virus / Q000378:metabolism; D015203:Reproducibility of Results; D014779:Virus Replication / Q000502:physiology*
D011991:Receptors, Virus; C085301:adenovirus receptor