ABT-737  In allen Behandlungsarmen konnte zwischen BIBW 2669 und BIBW 2992 kein signifikanter Unterschied gefunden werden. BIBW 2669 und BIBW 2992 zeigten einen deutlichen antiproliferativen Effekt in vitro bei nur geringer Strahlensensitivierung. Die vorliegenden Daten haben erstmals die Wirkung einer kombinierten Bestrahlung und dualen EGFR/ ErbB2-Inhibition auf die Verzögerung des Tumorwachstums in vivo gezeigt. Weitere präklinische Untersuchungen mit einem fraktionierten Bestrahlungsschema und lokaler Tumorkontrolle als Endpunkt sind nötig, um ein mögliches kuratives Potential von BIBW 2669 oder BIBW 2992 in Kombination mit Strahlentherapie zu untersuchen Despite

Danusertib PHA-739358  the improvement of irradiation schedules and techniques for the treatment of head-and-neck cancers (e.g., due to the advantages of modern three-dimensional planning) 24 or combined-modality treatments 8, local recurrences of tumors often occur. Novel molecular targets are now being investigated. The epidermal growth factor receptor (EGFR, ErbB1), a member of the ErbB family of receptor tyrosine kinases (TKs), is overexpressed in many human tumors, e.g., squamous cell carcinomas of the head and neck, colorectal carcinomas, non-small cell lung cancer, breast cancer, malignant gliomas, and prostate cancer 5, 46. Elevated EGFR expression is often associated with a poor clinical prognosis and resistance to chemotherapy, hormone therapy and radiotherapy 2, 5, 46. ErbB2 (HER2) is another member of the ErbB receptor family that does not bind to known ligands. The ErbB2 receptor is the preferred and most potent heterodimerization partner for other EGFR/ErbB family members 14, 25, 44. Each receptor complex may activate different signaling pathways which regulate cell proliferation, survival, cell differentiation, and radioresistance 41, 44. Aberrant activation or overexpression of ErbB2 has been shown to correlate with poor prognosis in breast and ovarian cancer 34, 35. The strong involvements of ErbB1 and ErbB2 in cell signaling pathways make the receptors attractive targets for therapeutic intervention. Monoclonal antibodies (mAbs) as well as small molecules, tyrosine kinase inhibitors (TKIs) 3 which

target EGFR or ErbB2, have been developed Preclinical and first clinical studies with mAbs or TKIs that selectively target the EGFR showed antiproliferative and sometimes sensitizing effects in tumor cells when combined with irradiation 6, 9, 17 and, in the case of mAbs, also an improvement of local tumor control 7, 21, 27. In previous Danusertib Aurora inhibitor experiments, EGFR inhibition with the selective EGFR TKI BIBX1382BS led to decreased proliferation and slightly increased radiosensitivity of FaDu tumor cells in vitro. However, despite clear antiproliferative activity and significantly increased tumor growth delay when combined with fractionated irradiation in FaDu xenografts, local tumor control was not improved by BIBX1382BS The fact that ErbB receptor heterodimers are considered to be more potent than ErbB receptor homodimers and human cancers often show co-expression of different ErbB receptors 16, 31 has led to the suggestion that a dual inhibitor or combined treatment, targeting both EGFR and ErbB2, might have greater antitumor activity than inhibition of only one receptor 1, 26. In this study
(20 mg kg–1) until the final tumor diameter of 15 mm. Arm (b): oral application of carrier, BIBW 2669 (4 mg kg–1; later 3 mg kg–1) or BIBW 2992 (20 mg kg–1) for 3 days, followed by 20-Gy single-dose irradiation 4 h after last drug application. Arm (c): 20-Gy single-dose irradiation followed by daily applications of carrier, BIBW 2669 (4 mg kg–1; later 3 mg kg–1) or BIBW 2992 (20 mg kg–1) until the final tumor diameter of 15 mm. Animals were observed until the mean diameter exceeded 12–15 mm or until death. Animals that appeared to suffer were killed before reaching these endpoints. Tumor Danusertib FGFR inhibitor diameters were measured twice per week. Tumor volumes were determined using the

formula of the rotational ellipsoid , e.g., π/6 × a × b2, where a is the longest and b is the perpendicular shorter tumor axis. Conversion of tumor volumes to tumor mass (mg) was performed by a calibration curve based on excision weights [38]. Median tumor volumes and their 95% confidence intervals were calculated for each treatment arm and dose level as a function of time after the start of treatment. Growth delay was evaluated from tumor growth curves of the individual animals as the time needed after the start of treatment to reach twice the starting volume (GDV2)