This evaluation revealed only a slight and statistically not significant fect of BIBW 2992 and BIBW 2669 (Figure 6, Table 2). A daily application of BIBW 2669 or BIBW 2992 after a single- dose irradiation showed a clear inhibition of tumor growth in addition to the effect of irradiation alone with a significantly longer tumor growth delay after drug treatment compared to control tumors (Figures 4c and 6). In all treatment arms, the effects of BIBW 2669 were not significantly different from BIBW 2992. The body weight of the mice was PD0325901 determined daily during treatment and after the end of treatment once per week. Median

body weight decreased in the animals treated with BIBW 2669 and BIBW 2992 by ~20%. The initial weight loss was associated with a reduction in the performance status. The animals showed side effects, e.g., diarrhea and skin reactions around the muzzle. The side effects in BIBW 2669-treated animals were more pronounced than in the BIBW 2992 treated group. After dose reduction, the loss of body weight as well as the described Doramapimod p38 MAPK inhibitor side effects were equally distributed (see above). A limited number of studies investigating the effect of monotherapy with a dual EGFR/ErbB2 TKI have been published so far [30]. Lapatinib (GW572016; GW2016), a dual reversible EGFR/HER2 TKI, showed potent inhibition of tumor growth in xenografts [32, 45, 47]. Konecny et al. [18] found that the efficacy of the dual kinase inhibitor lapatinib does widely differ between individual breast cancer cell lines that express different levels of EGFR and HER2, and that lapatinib is more potent in inhibiting cell growth in cell lines that The dual irreversible EGFR/ErbB2 TKI BIBW 2992 has previously been shown to reduce growth of human tumor xenografts [36]. In a phase I study, BIBW 2992 was administered to patients with advanced solid tumors for 21 consecutive days every 4 weeks on two different dose levels.

Observed toxicities were skin rash, pruritus, mucositis, and gastrointestinal disturbances The present experiments are the first to test EGFR/ErbB2 TKIs in combination with irradiation. Since FaDu is positive for EGFR, ErbB2, and ErbB3 and negative for ErbB4, and since ErbB3 has a defective TK [28], this tumor is a well-suitable model for this approach. In our study, we found a pronounced antiproliferative effect of BIBW 2669 and BIBW 2992 on FaDu cells in vitro (Figure 1) as well as in FaDu tumors in vivo (Figure 4a) with blockade of cells in the G0/ G1-phase of the cell cycle (Figure 2). In vitro, BIBW 2669 and BIBW 2992 showed a slight radiosensitizing effect which was significant for BIBW 2992 (p = 0.006). In vivo, after drug application over 3 days, followed by single-dose irradiation, a slight effect of both drugs on tumor growth could be shown buy Doramapimod (Figure 4b). In line with the in vitro data shown above, the results suggest only little or no radiosensitizing effect of BIBW 2992 and BIBW 2669 on FaDu tumor cells in vivo.

After 20-Gy single-dose irradiation followed by daily application of BIBW 2669 and BIBW 2992, a pronounced inhibition of tumor growth by the drugs was shown (Figure 4c). Tumor growth delay was significantly longer after combined treatment compared to irradiation alone (Figure 6, Table 2). Compared to unirradiated FaDu tumors, the factors (Table 2) were even smaller between BIBW 2992- and BIBW 2669-treated tumors and control tumors after single-dose irradiation suggesting an additive effect for combinations with radiotherapy. These data imply that BIBW 2669 or BIBW 2992 have a good purchase Doramapimod antiproliferative potential and can enhance time to recurrence after radiotherapy. From the only marginal radiosensitizing effects it might be hypothesized that simultaneous drug application during radiotherapy has little effect on local control on FaDu tumors. However, it has to be considered that mechanisms other than cellular radiosensitivity can be influenced by EGFR inhibitors.