RESUMO
Irinotecan, a standard of care therapy for CRC, elicits cytotoxic effects by generating double strand breaks resulting in DNA damage. The activation of the ATM pathway plays a fundamental role in regulating the cellular response and repair to DNA damage. The objective of this preclinical study was to determine whether ATM inhibition would enhance sensitivity to irinotecan treatment. Treatment effects of AZ31, irinotecan or AZ31 + irinotecan were investigated in CRC cell lines and CRC patient derived xenografts. Activation of ATM and downstream targets p-RAD50 and p-H2AX were evaluated by immunohistochemistry. Combinational effects were demonstrated in 4 out of 8 CRC explants. Interestingly, each of the combinational sensitive CRC PDX models were shown to be more resistant to irinotecan single agent therapy. Treatment with irinotecan significantly elevated the ATM pathway evident by an increase in the activation of H2AX and RAD50. Combinational therapy reduced the activation of H2AX and RAD50 when compared to irinotecan alone in the combination sensitive CRC098. AZ31 + irinotecan was effective at reducing tumor growth in tumors that exhibited resistance to irinotecan in our CRC PDX model. These findings support further investigation of this combinational therapy for the treatment of CRC patients.
Assuntos
Insuficiência Cardíaca/diagnóstico , Coração Auxiliar , Prótese de Quadril/efeitos adversos , Falha de Prótese , Choque Cardiogênico/diagnóstico , Cobalto/efeitos adversos , Cobalto/sangue , Diagnóstico Diferencial , Dispneia/etiologia , Ecocardiografia , Fadiga/etiologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Transplante de Coração , Ventrículos do Coração/patologia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Desenho de Prótese , Choque Cardiogênico/terapiaRESUMO
BACKGROUND: We hypothesized that hepatocellular carcinoma (HCC) patients with higher Body Mass Index (BMI) might have more microvascular invasion (MVI) in their tumors. METHODS: Records from 138 consecutive patients who underwent surgery at Columbia University Medical Center from January 1, 2002 to January 9, 2008 were evaluated. RESULTS: 40 patients (29%) had MVI, including 14% with BMI <25, 31% with BMI = 25-30, and 40% with BMI >30 (p = .05). However, only maximum alpha-fetoprotein was significantly associated with overall mortality in a Cox model. CONCLUSIONS: MVI was associated with obesity. A better understanding of the mechanism of this association may lead to interventions for the treatment and prevention of HCC.
