Different susceptibility of osteosarcoma cell lines and primary cells to treatment with oncolytic adenovirus and doxorubicin or cisplatin

Abstract

Despite improvements in treatment regimens for osteosarcoma (OS) patients, survival rate has not increased over the last two decades. New treatment modalities are therefore warranted. Preclinical results with conditionally replicative adenoviruses (CRAds) to treat OS are promising. One type of CRAd that was effective against OS cells is Ad5-D24RGD. In other types of cancer, CRAds have been shown to interact synergistically with chemotherapeutic agents. Chemotherapy for OS often includes doxorubicin and cisplatin. Therefore, we explored combination treatment of OS cell lines and primary OS cell cultures with Ad5-D24RGD and doxorubicin or cisplatin. On OS cell lines, combination treatment was additive to synergistic. Surprisingly, however, on seven of eight primary OS samples no such combination effects were observed. In contrast, in many cases chemotherapy even inhibited CRAdmediated cell killing. The inhibitory effect of doxorubicin on Ad5-D24RGD in primary OS cells appeared to correlate with slow cell growth rate; reduced viral replication and absence of chemotherapy-induced G2 cell cycle arrest. Our results point to the possibility that, at least for OS, virotherapy and chemotherapy should best not be performed simultaneously. In general, our work underscores the importance of testing new genetic anticancer agents and treatment regimens on primary cancer specimens.

Novel quinazoline HMJ‐30 induces U‐2 OS human osteogenic sarcoma cell apoptosis through induction of oxidative stress and up‐regulation of ATM/p53 signaling pathway

“…In Figures 1 and 2C, HMJ‐30 triggered the shrinking and the detaching of some debris from the surface of U‐2 OS cells. The protein levels of caspases were also increased, suggesting that they might play a crucial role in the execution‐phase of apoptosis 28. These results suggest that HMJ‐30‐induced apoptosis in U‐2 OS cells is through the caspases‐dependent signaling pathway.…”

“…The reasons for the differences in sensitivities in IC 50 of different cell lines may be due to the inherent different doubling time in different cell lines. The doubling time of U‐2 OS is 16.8 h 28. However, the hFOB cells are also a normal fetal osteoblast cell line and the doubling time of those cells is around 34 h 29.…”

Characterization and comparison of the properties of sarcoma cell linesin vitroandin vivo

“…osteosarcoma cell lines, widely available from repositories such as the American Type Culture Collection [ATCC]), it is often difficult to extract appropriate baseline cell line comparative characteristics in order to make meaningful conclusions. Numerous publications (and some more recent ones 8–10 ) clearly demonstrate differential sensitivities to various treatments on osteosarcoma cell lines and these results may indeed be therapeutically meaningful. In one report 8 gemcitabine was clearly shown to be 10 times more potent in inhibiting the growth of HOS osteosarcoma cells than MG63 osteosarcoma cells.…”

Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses

“…However, there are reports of attenuated cytotoxicity of CRAds when combined with chemotherapies (for example, doxorubicin 34 ). To investigate the oncolytic activity of Ad5-RV004 or Ad5-RV004.21 in the presence of adriamycin, C4-2 cells were infected with either Ad5-RV004 or Ad5-RV004.21 (MOI=2) in the presence or absence of adriamycin (0.1 ug ml −1 ) in 96-well plates.…”