bibx-1382bs and Neoplasms

The pyrimido-pyrimidine BIBX 1382 BS inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), thus specifically reverting the aberrant enzymatic activity from overexpressed and constitutively activated EGFR. A phase I and pharmacokinetic study of this new specific molecule was carried out. After initially performing an accelerated titration design from the first toxicities onwards, a modified Fibonacci scheme was used to escalate the daily oral dose. The following dosages and cycles (defined as treatment during 28 days) were applied: 25 mg: 6; 50 mg: 3; 100 mg: 6; 200 mg: 7; 150 mg: 3. Over a 10 months accrual phase, 11 patients (pts) (7 females, 4 males) with a median age of 63 years (range 50-73 years), World Health Organization Performance Status (WHO PS) 0:5 pts, 1:6 pts and miscellaneous solid tumours were entered. The median number of cycles applied per pt was 2 (range 1-7). Reversible, dose-dependent increase of liver enzymes (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3) occurred. Oral medication yielded plasma levels far below those expected to be efficacious. In conclusion, target plasma levels could not be reached via the oral route at a reasonable dosage. Meanwhile, a preclinically unknown metabolite was identified from the urine of one patient. Subsequently, this metabolite was found to be abundant in patient plasma. The metabolite was demonstrated to be pharmacologically inactive. Due to a dose-limiting increase of liver enzymes, low bioavailability of BIBX 1382 BS and the detection of a pharmacologically inactive metabolite, this trial was discontinued.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Enzyme Inhibitors; ErbB Receptors; Female; Follow-Up Studies; Hematologic Diseases; Humans; Male; Middle Aged; Neoplasms; Organic Chemicals; Treatment Outcome

To investigate the cellular and molecular consequences of antagonizing radiation-induced EGFR-activation in vitro.. The effect of the EGFR tyrosine kinase inhibitor BIBX1382BS on radiation sensitivity was determined after single- and fractionated-dose irradiation in human cell lines of bronchial carcinoma (A549), breast adeno-carcinoma (MDA-MB-231), pharyngeal squamous-cell carcinoma (FaDu), squamous-cell carcinoma of cervix (HTB-35) as well as normal (HSF-7) and transformed (HH4-DED) human skin fibroblasts. Applying immuno-precipitation and western blotting pattern of radiation-dependent activation of different components of EGFR-signaling after pre-treatment with and without BIBX1382BS or other tyrosine kinase inhibitors was analyzed.. Autophosphorylation of EGFR which occurred 1-5 min after irradiation (IR, 2 Gy) or treatment with EGF (100 ng/ml) could be inhibited in all cells tested by pre-treatment with BIBX1382BS for 30 min. Combination of drug treatment with fractionated irradiation (4x2 Gy) led to a strong radiosensitizing effect in Ras-mutated A549 and MDA-MB-231 cells, but not in normal Ras presenting cell lines FaDu and HTB-35 or normal and transformed human skin fibroblasts. Both BIBX1382BS as well as the PI3 kinase inhibitor LY294002 led to a blockage (for A549 cells) or reduction (for FaDu cells) of radiation-induced P-AKT. In contrast to FaDu cells, treatment of A549 cells with LY294002 resulted in a significant decrease of post-irradiation survival of A549 cells. Furthermore, only in Ras-mutated cells, but not in normal Ras cells clonogenic survival and phosphorylation of AKT was sensitive to pre-treatment with TGF-alpha-neutralizing antibody indicating an important role of TGF-alpha in regulating radiation-induced EGFR signaling.. Enhancement of radiation sensitivity by the specific EGFR-tyrosine kinase inhibitor BIBX1382BS is not generally achieved in human tumor cells, but depends most likely on the Ras genotype of the cell lines tested.

Topics: Adenocarcinoma; Breast Neoplasms; Carcinoma, Squamous Cell; ErbB Receptors; Female; Genes, ras; Genotype; Humans; Lung Neoplasms; Male; Neoplasms; Organic Chemicals; Pharyngeal Neoplasms; Phosphorylation; Radiation Tolerance; Tumor Cells, Cultured; Uterine Cervical Neoplasms