A significant issue in
drug efficacy studies is animal study design. Here we hypothesize that when evaluating new or existing
therapeutics for the treatment of
cancer, the location of disease burden will influence
drug efficacy. To study this, Female NCr nude mice were inoculated with
luciferase-positive human
breast cancer cells (LCC6WT-luc) orthotopically (o.t.), intraperitoneally (i.p.) or intracardiacly (i.c.) to create localized,
ascites or disseminated disease, respectively.
Tumor development was monitored using bioluminescence imaging.
Docetaxel (Dt) pharmacokinetics and distribution to sites of
tumor growth were determined.
Disease progression was followed in animals treated with Dt alone and in combination with
QLT0267, an
Integrin Linked Kinase inhibitor.
Tumor related morbidity was most rapid when cells were inoculated i.c., where
disease progression was observed in brain, ovaries, adrenal glands, and lungs. Dt pharmacokinetics were comparable regardless of the model used (mean plasma AUC0-24 hrs 482.6 ng/ml*hr), however, Dt levels were lowest in those tissues developing disease following i.c. cell injection. Treatment with low dose Dt (5 mg/kg) increased overall survival and reduced
tumor cell growth in all three models but the activity was greatest in mice with orthotopic
tumors. Higher doses of Dt (15 mg/kg) was able to prolong survival in animals bearing i.p.
tumors but not i.c.
tumors. Addition of
QLT0267 provided no added benefit above Dt alone in the disseminated model. These studies highlight a need for more comprehensive in vivo efficacy studies designed to assess multiple disease models and multiple endpoints, focusing analysis of
drug parameters on the most chemoresistant disease.