Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still die due to their disease. Further improvements in the management of osteosarcoma may rely on a more individualised treatment strategy, as well as on the introduction of new drugs. To aid in the preclinical evaluation of new candidate substances against osteosarcoma, we have established 11 human osteosarcoma xenograft lines and characterised them with regard to response to five different reference drugs. Doxorubicin, cisplatin methotrexate, ifosfamide and lomustine were effective in 3/11, 3/11, 1/10, 5/11 and 4/11 of the xenografts, respectively. Five xenografts were resistant to all compounds tested. We also assessed the mRNA expression levels of the xenografts for the O(6)-Methylguanine DNA Methyltransferase (MGMT), DNA topoisomerase II- (Topo II)-alpha, Gluthathione-S-transferase (GST)-pi, Multidrug-resistance related protein (MRP) 1 and Multidrug-resistance (MDR) 1 genes. There was an inverse correlation between the transcript levels of GST-pi and doxorubicin growth inhibition (r=-0.66; p<0.05), and between the transcript levels of MGMT and the effect of lomustine (r=-0.72; p<0.01), whereas the expression of MRP1 and cisplatin growth inhibition was positively correlated (r=0.82; p<0.005). This panel of xenografts should constitute a good tool for pharmacological and molecular studies in osteosarcoma.
Arylalkylidenebisphosphonates labeled with nca [(125)I or (131)I] have been synthesized and their biological function investigated. The label was attached to the aromatic group in high yield and under mild conditions by means of iododesilylation. The bone affinities of the radioactive compounds were investigated in normal Balb/C mice. The compound 1-hydroxy(m-iodo[(125,131)I]-phenylethylidene)-1,1-bisphosphonate was found to possess superior bone affinity compared to others, and its in vivo deiodination was insignificant. The uptake in femur 24h after injection was 850 +/- 265% and 986 +/- 118% of injected dose per gram tissue times gram body weight in mice and rats, respectively. The therapeutic potential of the compound was investigated in two tumor models in athymic (nude) rats, one model for mixed lytic/sclerotic metastatic bone-lesions originating from breast cancer and the other model simulating osseous osteosarcoma. The effects in these models compare favorably to those observed for established treatment modalities. The experiments demonstrate that radioiodinated bisphosphonates may have a potential for diagnosis and therapy of malignant osseous lesions.
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