Efficient blockade of akt signalling is a determinant factor to overcome resistance to matuzumab

BACKGROUND: Clinical studies have shown antineoplastic effectiveness of monoclonal antibodies (MAbs) against EGFR for different indications. Several MAbs directed to EGFR were developed recently, such as matuzumab, but there is still lack of information on preclinical data on its combination with chemo-radiation. Thus, the present study intended to examine the molecular pathways triggered by matuzumab alone or associated to chemo-radiotherapy in gynecological cell lines and its impact on cell growth and signaling. RESULTS: Combination of matuzumab with radiation and cisplatin did not enhance its cytostatic effects on A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in clonogenic assays, when compared to controls. The lack of effect was mediated by persistent signaling through EGFR due to its impaired degradation. In spite of the fact that matuzumab inhibited phosphorylation of EGFR, it had no effect upon cell viability. To analyze which downstream molecules would be involved in the EGFR signaling in the presence of matuzumab, we have tested it in combination with either PD98059 (MAPK inhibitor), or LY294002 (PI3K inhibitor). Matuzumab exhibited a synergic effect with LY294002, leading to a reduction of Akt phosphorylation that was followed by a decrease in A431 and Caski cells survival. The combination of PD98059 and matuzumab did not show the same effect suggesting that PI3K is an important effector of EGFR signaling in matuzumab-treated cells. Nonetheless, matuzumab induced ADCC in Caski cells, but not in the C33A cell line, suggesting that its potential therapeutic effects in vitro are indeed dependent on EGFR expression. CONCLUSIONS: Matuzumab combined with chemoradiation did not induce cytotoxic effects on gynecological cancer cell lines in vitro, most likely due to impaired EGFR degradation. However, a combination of matuzumab and PI3K inhibitor synergistically inhibited pAkt and cell survival, suggesting that the use of PI3K/Akt inhibitors could overcome intrinsic resistance to matuzumab in vitro. Altogether, data presented here can pave the way to a rational design of clinical strategies in patients with resistant profile to anti-EGFR inhibitors based on combination therapy

Avaliação da dose no reto em pacientes submetidas a braquiterapia de alta taxa de dose para o tratamento do câncer do colo uterino / Rectal dose assessment in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer

OBJETIVO: O objetivo deste trabalho foi desenvolver um sistema dosimétrico termoluminescente capaz de avaliar as doses administradas ao reto de pacientes submetidas a braquiterapia de alta taxa de dose para o tratamento do câncer do colo uterino. MATERIAIS E MÉTODOS: O material termoluminescente utilizado para a avaliação da dose no reto foi o LiF:Mg,Ti,Na na forma de pó. O pó foi separado em pequenas porções de 34 mg, que foram acomodadas em um tubo capilar. Este tubo foi colocado em uma sonda retal, que era introduzida no reto da paciente. RESULTADOS: As doses administradas ao reto de seis pacientes submetidas a braquiterapia de alta taxa de dose para o tratamento do câncer do colo uterino foram avaliadas com dosímetros termoluminescentes e apresentaram boa concordância com os valores planejados, com base em duas radiografias ortogonais da paciente, imagens ântero-posterior e lateral. CONCLUSÃO: O sistema de dosimetria termoluminescente utilizado no presente trabalho é simples e de fácil utilização quando comparado a outros métodos de dosimetria do reto. Ele mostrou-se eficiente na avaliação da dose no reto de pacientes submetidas a braquiterapia de alta taxa de dose para o tratamento do câncer do colo uterino.

OBJECTIVE: The present study was aimed at developing a thermoluminescent dosimetric system capable of assessing the doses delivered to the rectum of patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. MATERIALS AND METHODS: LiF:Mg,Ti,Na powder was the thermoluminescent material utilized for evaluating the rectal dose. The powder was divided into small portions (34 mg) which were accommodated in a capillary tube. This tube was placed into a rectal probe that was introduced into the patient's rectum. RESULTS: The doses delivered to the rectum of six patients submitted to high-dose-rate brachytherapy for uterine cervix cancer evaluated by means of thermoluminescent dosimeters presented a good agreement with the planned values based on two orthogonal (anteroposterior and lateral) radiographic images of the patients. CONCLUSION: The thermoluminescent dosimetric system developed in the present study is simple and easy to be utilized as compared to other rectal dosimetry methods. The system has shown to be effective in the evaluation of rectal doses in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer.