Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival

Abstract

Chondrosarcoma is a difficult musculoskeletal tumor to treat. Surgical treatment leads to severe disability, with high rates of local recurrence and life threat. No adjuvant therapy is effective in differentiated chondrosarcomas. Bisphosphonates (BPs) are a class of molecules which is effective in malignant bone diseases. The aim of the present study was to determine the effects of zoledronic acid (ZOL) on chondrosarcoma tumor progression. ZOL was tested in vivo (s.c. 100 lg/kg, twice a week) in a rat chondrosarcoma model and in vitro (10 27 -10 24 M) on cells derived from this model. Two types of animal models were assessed, the first simulated development after intralesional curettage, the second nonoperative development of the tumor. Cell proliferation, caspase-1, -3 activities and cell cycle analysis were studied. The results revealed that ZOL slows down primary tumor development, tumor progression after intralesional curretage and increases overall survival. ZOL inhibits cell proliferation and increases cell death, with no significant variation of caspase-1 and -3 activities and cell cycle profiles. The present study demonstrates for the first time that in addition to surgery, the therapy of chondrosarcoma with BPs might be beneficial. Because of these first results, new therapeutic approaches of chondrosarcoma must be considered, mainly for low grade chondrosarcoma when disabling operation is planned and when only intralesional resection can be undertaken. ' 2006 Wiley-Liss, Inc.

First Preclinical Imaging of Primary Cartilage Neoplasm and Its Local Recurrence Using 99mTc-NTP 15-5 Radiotracer

“…The SRC model is a tumor tissue line derived from a tumor that arose spontaneously in the thoracic and lumbar vertebrae of a female Sprague-Dawley rat. The SRC tissue line has been maintained over the years by serial subcutaneous injections, and its histochemical characteristics have remained stable in successive transplants: it is a well-differentiated chondrosarcoma with mild cellular atypia (grade II) (24,25).…”

“…These fragments were immediately stored in cold a-minimum essential medium and manually calibrated to 10 mm 3 . Allograft transplantation of a 10-mm 3 SRC fragment was performed on the right paw, the other paw being used as the contralateral reference (24,25).…”

“…Using a lateral approach, the cortical surface of the diaphysis was scarified laterally over 10 mm, a 10-mm 3 SRC fragment was placed contiguous with the scarified surface, and the muscular and cutaneous wounds were sutured (24,25). The same procedure was performed for the contralateral paw, but no tumor fragment was implanted.…”

“…The relevance of 99m Tc-NTP 15-5 imaging for the diagnosis of primary chondrosarcoma and its local recurrence was assessed in the Swarm rat chondrosarcoma (SRC) model, using 2 experimental approaches: primary paratibial tumor development, and local tumor recurrence after intralesional curettage (24,25). These first experimental results suggest that 99m Tc-NTP 15-5 scintigraphy may be useful for the evaluation of the tumoral pathology of cartilage.…”

Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents

“…Recently, many investigators have reported that bisphosphonates can directly inhibit the growth of various malignant cells, including multiple myeloma (4,5), leukemia (6), prostate cancer (7), and chondrosarcoma (8,9). Bisphosphonates are effective inhibitors of bone resorption and have been used for the last three decades in the treatment of (10).…”