The growth-inhibitory effect of ATO in SCCHN cells with acquired cetuximab and cisplatin resistance Cisplatin (CDDP) and cetuximab are the two major components of concurrent radiochemotherapy for first-line treatment of primary selleck chemical Nintedanib SCCHN. Since the 5-year recurrence rates after radiochemotherapy are still considerably high and since treatment most probably selects for tumor cells with resistance to the respective agents, we evaluated the potential of ATO for treatment of recurrent disease in two SCCHN models of acquired resistance to CDDP and cetuximab. These models had been established by long-term treatment with increasing concentrations of these drugs. Assessment of viability using the MTT assay after long-term drug treatment revealed that the phenotype of acquired resistance was stable up to a minimum of 6 months after stopping the selection process by removing the drug from the cultures.

A significant difference in the sensitivity of resistant subclones (UT-SCC-9CET-R, FaDuCDDP-R) compared to the parental cells (UT-SCC-9CET-S, FaDuCDDP-S) could be observed (Figures 6 A, B, right panels). In the model of acquired cetuximab resistance we observed a significant and pronounced increase in the sensitivity of cetuximab-resistant SCCHN cells to ATO treatment (Figure 6 A). In contrast, CDDP-resistant FaDuCDDP-R cells were cross-resistant to ATO treatment (Figure 6 B). Figure 6 CDDP-resistant SCCHN cells show cross-resistance to ATO whereas cetuximab-resistant cells display increased ATO sensitivity.

Discussion In this study, we could demonstrate that ATO at doses below the clinically achieved plasma levels of current ATO-containing treatment regimens in APL [30] displayed significant growth-inhibitory and cytotoxic activity preferentially in p53-deficient SCCHN cells and increased the inhibitory effect of ionizing radiation on clonogenic survival in an additive manner. The addition of ATO to current treatment regimens could thus represent a potential treatment strategy to improve the therapeutic outcome of SCCHN patients with p53-deficient tumors. Although mutations within the TP53 gene are considered the most frequent [31], [32] and one of the earliest genetic alterations [33], [34] in the carcinogenesis of SCCHN their prognostic value is still a matter of debate.

This is mainly due to the small number of patients, the lack of a focus on a particular AV-951 tumor site and the methodological differences in the assessment of TP53 mutations in the majority of the published studies so far precluding a conclusive meta-analysis [35]. Nonetheless, there is accumulating evidence that patients presenting with tumors harboring disruptive [13], truncating [15] or loss-of-function mutations in the TP53 gene [36] belong to a group of patients with poor prognosis and increased risk of treatment failure [13], [15], [16], [36].