Human osteosarcoma xenografts and their sensitivity to chemotherapy

Abstract

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.

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

“…Aloj et al [53] found a significant correlation between the absence of 99m Tc-sestamibi uptake and overexpression of Bcl-2 in breast cancer cell lines. Multidrug resistance-associated protein 1 (MRP1) can also be overexpressed in tumour cells, conferring drug resistance [23,54]. Decreased uptake or enhanced efflux of 99m Tc-sestamibi can be mediated by MRP1 [19,23].…”

Gene Expression Profiles Classify Human Osteosarcoma Xenografts According to Sensitivity to Doxorubicin, Cisplatin, and Ifosfamide

“…The animals were maintained, and experiments and assessment of chemotherapy response were conducted as described previously (12). In brief, the animals were 4 to 6 weeks old at the day of tumor implantation.…”

“…Ten human osteosarcoma xenografts were used, eight of which have been described previously (12), and in addition, two newly established xenografts were included. These originated from a 32-year-old male with an extremity located fibroblastic osteosarcoma of malignancy grade 4 (GKAMX) and from a 13-year-old female with an extremity located osteoblastic osteosarcoma of malignancy grade 4 (CTPX).…”

“…However, these studies cannot access genes related to individual drugs using patient's specimens. We have previously established a panel of osteosarcoma xenografts for the purpose of preclinical testing of novel drug candidates to treat osteosarcoma (12). Here, we report the results of microarray expression profiling of these xenografts to screen for potential markers for each of three of the drugs used in current clinical treatment protocols, resulting in three different subsets of genes that with high significance distinguished between poor and good responders to doxorubicin, cisplatin, and ifosfamide.…”

Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells

“…One study of GSTP1 expression in samples from pediatric patients with osteosarcoma showed that GSTP1 expression might have a bearing on the outcome of treatment with chemotherapy (14). Another study by Bruheim et al (15) showed that the GSTP1 mRNA level was inversely correlated with doxorubicin growth inhibition in human osteosarcoma xenografts.…”