Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins

This study shows a strong association between cell attachment to substratum and activation of beta 1-integrin-signaling with resistance to the camptothecin derivative topotecan (TPT) in breast cancer cells. We propose a mechanistic-driven approach to sensitize the cells to camptothecins. ZR-75-1 anchorage-dependent breast cancer cell line, its derivative 9D3S suspension cells (9D3S-S), and 9D3S cells attached to fibronectin-coated plates (9D3S-A) were treated with TPT (1 microM) or CPT-11 (40 microM) for 48 h. Programmed cell death (PCD), as shown by poly(ADP-ribose) polymerase (PARP), pro-caspase-3 and pro-caspase-9 cleavage, was observed in 9D3S-S cells but not in ZR-75-1 or 9D3S-A cells. Because p125 focal adhesion kinase (FAK) is a transducer in the beta 1-integrin signaling pathway, it is essential to cell adhesion and it is overexpressed in metastatic breast cancer, we hypothesized that attenuation of FAK might enhance the sensitivity of breast cancer cells to camptothecins. Moreover, inhibition of FAK gene expression by a phosphorothioated antisense oligodeoxynucleotide targeting the portion of the gene encoding amino acids 262-268, increased the sensitivity of ZR-75-1, MDA-MB-231 and MCF7 breast cancer cells to treatment with TPT or CPT-11.

Improvement of cardiac function by short atrioventricular delay and diastolic mitral regurgitation in patients implanted with DDD pacemakers

Efficacy of short atrioventricular (AV) delay and diastolic mitral regurgitation (MR) were studied in 16 patients (70.2 mais ou menos 10.5 SD years old) with implanted DDD pacemakers. AV delay was set at 0.215 and 0.115 sec. In 10 of the 16 patients, diastolic MR was not observed when the AV delay was set at both 0.215 and 0.115 sec. Cardiac output (CO) and pulmonary capilary wedge pressure (PCWP) did not change.In 6 of the 16 patients, diastolic MR was observed when the AV delay was set a 0.215 se However, diastolic MR was not observed when the AV delay was set at 0.115 sec. CO increased from 3.6 mais ou menos 0.7 to 3.9 mais ou menos 0.8 I/min (p menor que 0.05). PCWP was decreased in 5 of the 6 patients (83 por cento, p menor que 0.05 vs. 10 por cento in patients without diastolic MR at 0.215 sec of AV delay). Cardiac function may be improved by shortening AV delay when the diastolic MR was observed. On the other hand, short AV delay may not be effective for patients in whom diastolic MR was ntobserved.