Gefitinib in combination with capecitabine as second-line therapy in patients with advanced colorectal cancer (aCRC): a phase I/II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: This phase I/II study was conducted to assess the maximal tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of gefitinib in combination with capecitabine in patients with advanced colorectal cancer (aCRC). PATIENTS AND METHODS: After failure of a 1st-line therapy, patients with aCRC received escalating doses of gefitinib once daily in combination with capecitabine twice daily: dose level (DL) 1: gefitinib 250 mg and capecitabine 1,000 mg/m(2), DL 2: gefitinib 250 mg and capecitabine 1,250 mg/m(2), DL 3: gefitinib 500 mg and capecitabine 850 mg/m(2). DLTs were determined after 6 weeks of treatment. RESULTS: A total of 16 patients were enrolled. On DL1 (n = 6), 1 patient developed a DLT (hand-foot syndrome, HFS n = 1). On DL2 (n = 7), DLTs were observed in 3 patients (exanthema n = 2, HFS n = 1), and on DL3 (n = 3), DLT occurred in 1 patient (HFS n = 1) resulting in recruitment stop at DL3. No patient showed an objective tumor response. Disease stabilization was observed in 6 patients. CONCLUSION: The combination of gefitinib and capecitabine resulted in significant skin toxicities such as exanthema and HFS. As 2nd-line treatment of patients with aCRC, this combination showed no substantial efficacy.

PKCmu prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells.

Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumour progression. Protein kinases C (PKC) have been shown to be important in the regulation of proliferation and apoptosis. In this report, we investigated the role of the PKC-like kinase PKCmu in the control of these processes in pancreatic adenocarcinoma cells. We demonstrate that in these cells, PKCmu expression strongly correlates with resistance to CD95-induced apoptosis. Inhibition of PKCmu with Goe6983 sensitized resistant cells to CD95-induced apoptosis. In CD95-sensitive Colo357 cells, forced overexpression of PKCmu strongly reduced CD95-mediated apoptosis, an effect that could be reversed by pretreatment with Goe6983. In addition, PKCmu overexpression led to a strongly enhanced cell growth and to a significant increase of telomerase activity. In an attempt to identify the signalling pathways affected by PKCmu, we identified the antiapoptotic proteins c-FLIPL and survivin to be strongly upregulated in PKCmu overexpressing cells. Immunohistochemical analysis of pancreatic tumour tissue of 48 patients and 10 normal pancreatic tissues revealed marked overexpression of PKCmu in tumours. In conclusion, we showed that PKCmu controls proliferative, as well as anti-apoptotic, signalling pathways and therefore plays an important role in acquiring the malignant phenotype of pancreatic tumours.