Quote:
|
after cells are treated with epidermal growth factor, heparanase moves to the cell's nucleolus, the site of ribosome production in the nucleus. In that structure, high levels of heparanase activate an enzyme called topoisomerase 1, which is essential for DNA replication and transcription (translation of the genetic message into protein). Heparanase-induced activation of topoisomerase 1 results in a significant increase of cell proliferation.
|
So...EGF inhibitors like Lapatinib to stop things from the start? Or..Heparanese inhibitors?
Cancer Chemother Pharmacol. 2010 Mar;65(4):743-53. Epub 2009 Jul 25.
Population pharmacokinetic model of PI-88, a heparanase inhibitor.
Hudachek SF,
Eckhardt SG,
Hicks B,
Gustafson DL.
Animal Cancer Center, Department of Clinical Sciences, Colorado State University, 1620 Campus Delivery, Fort Collins, CO 80523-1620, USA.
susan.hudachek@colostate.edu
PURPOSE: The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer. METHODS: A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery. RESULTS: Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%). CONCLUSIONS: This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.
PMID: 19633850 [PubMed - indexed for MEDLINE]