Death receptor 5 agonist TRA8 in combination with the bisphosphonate zoledronic acid attenuated the growth of breast cancer metastasis

Abstract

Bone metastasis affects the majority of patients with advanced

breast cancer and no adequate therapy exists.  Bisphosphonates, like zoledronic

acid, inhibit the osteolytic component of tumor growth in osseous tissues, but

these drugs are not curative. The current study evaluated the combination of

zoledronic acid with death receptor 5 agonists in an animal model of breast

cancer bone metastasis.  Materials and Methods. Female athymic nude mice

(age 4-6 weeks, n=35) were inoculated with 200,000 luciferase-positive MDA-

MB-435 cells by injection into the left ventricle. Animals were immediately imaged

by bioluminescence technique and placed into one of the following therapy

groups: Saline, hTRA8, hTRA8 + zoledronic acid, mTRA8, mTRA8 + zoledronic

Acid, or zoledronic acid monotherapy. DR5 agonists were given at 200 µg/dose

and zoledronic acid 5 µg /dose, with mice treated biweekly for 4.5 weeks and

imaged weekly. Results. Combination therapy containing either hTRA8 or

mTRA8 with zoledronic acid significantly reduced the number of secondary

lesions (7.67+2.2 and 7.5+1.7 lesions/mouse, respectively) compared to saline

treated controls (12.1+/-1.56 lesions/mouse) as assessed by bioluminescence

imaging (p