In a first stage, we have successfully improved a three compartment PK/PD model for liposomal doxorubicin proposed by Harashima et al. (1999). However, our model lacks PD complexity, since the tumor is represented as a single variable parametric model that only accounts for tumor cells.
The objective of this work is the development of a mechanistic model that accounts for the p53 gene regulation inside the tumor core; in addition, its dynamics is studied under drug administration. Researchers have focused on the importance of the p53 network in tumor control and development. p53 sits as the main hub of a wide network of intracellular and extracellular inputs (Oren et al., 2002) that control genomic integrity (Bargonetti et al., 2002), regulating caspase and apoptosis activity and tumor development. Kohn (1999) proposed a dense network for p53 while Chickarmane et al. (2005), Ciliberto et al. (2005) and Oren et al. (2002), among others, have proposed simpler sub networks for the p53 signaling pathways.
_______________________
Bargonetti, J., and Manfredi, J.J., (2002). Multiple roles of the tumor suppressor p53. Current Opinion in Oncology 14 86-91.
Chickarmane, V., Nadim, A., Ray, A., and Sauro, H.M. (2005). A p53 Oscillator Model of DNA Break Repair Control. arXiv:q-bio.MN/0510002 v1.
Ciliberto, A., Novak, B., and Tyson, J.J. (2005). Steady States and Oscillations in the p53/Mdm2 Network. Cell Cycle 4 107-112.
Harashima, H., Tsuchihashi, M., Iida, H., Doi, H., and Kiwada, H. (1999). Pharmacokinetic/pharmacodynamic modeling of antitumor agents encapsulated into liposomes, Advanced Drug Delivery Reviews 40 39-61.
Oren, M., Damalas, A., Gottlieb, T., Michael, D., Taplick, J., Leal, J.F.M., Maya, R., Moas, M., Seger, R., Taya, Y., and Ben-Ze' ev, A. (2002). Regulation of p53: intricate loops and delicate balances. Biochemical Pharmacology 64 865-871.