Synergistic increase in the sensitivity of osteosarcoma cells to thermochemotherapy with combination of paclitaxel and etoposide.

Osteosarcoma is a malignant bone tumor which is found most commonly in adolescents and young adults. Local perfusion thermochemotherapy has long been proposed as an alternative strategy for the treatment of osteosarcoma. As a standard anticancer drug, paclitaxel plays a significant role in the treatment of a number of tumors; however, little is known concerning its ability to promote thermochemotherapy. The aim of this study was to evaluate the cytotoxic effects of a combination of paclitaxel and etoposide on an osteosarcoma cell line in the presence of hyperthermia and to investigate the related mechanism. Our study indicated that 1 h after the application of a combination of 10 µg/ml paclitaxel and 5 µg/ml etoposide to OS732 cells at 43˚C, the survival rate of the cells was 14.52% which was significantly lower than when either 10 µg/ml paclitaxel (45.83%) or 5 µg/ml etoposide (43.31%) was applied alone (P<0.01). Moreover, changes in cellular morphology and apoptotic rates indicated that the apoptosis-inducing effect of the combination was much stronger than that of either drug applied individually. Fas expression levels in the OS732 cells were increased by the combination of paclitaxel and etoposide in the presence of hyperthermia. Therefore, paclitaxel enhances the thermochemotherapy of the osteosarcoma cell line and this is primarily accomplished by the upregulation of Fas expression and the induction of apoptosis.

Postsynaptic protein kinase C essential to induction and maintenance of long-term potentiation in the hippocampal CA1 region.

Previous studies on the effects of protein kinase C (PKC) inhibitors intracellularly introduced into the postsynaptic neuron on long-term potentiation (LTP) in the hippocampal CA1 region showed that given before the tetanic stimulation they only blocked the development of the maintenance phase of LTP and that given after the tetanus they did not affect the continued maintenance of established LTP. We now report different results in such experiments obtained by looking into the dose-effect relationship of the inhibitors given to the postsynaptic neuron and making use of a synergistic effect of two inhibitors given together. We used the following three PKC inhibitors: polymyxin B (PMB), PKC-(19-31), and H7. With the intracellular delivery of the inhibitor(s) beginning 30 min before the tetanus, PMB in adequate dosage or a combination of PMB and PKC-(19-31), each at a low dosage, could block the development of LTP completely including its initial induction phase. With the delivery beginning at the time of the tetanus, PKC-(19-31) or H7 slowly caused the established LTP to decline to the baseline; this decline was greatly accelerated when PMB and PKC-(19-31) or PMB and H7 were given together. PMB and PKC-(19-31) given together 75-90 min or even 3 h after the tetanus caused a decline of the maintained LTP similar to the decline observed when both inhibitors were given at the time of the tetanus. These results show that postsynaptic PKC is essentially involved in both the initial induction and the subsequent maintenance of LTP, contrary to current views on the subject.

The occurrence of post-denervation hypertrophy in chick slow muscle fibres after complete elimination of stretch and tension.

With the slow muscle fibres in the pure slow muscle ALD as well as in two mixed muscles, flexor metacarpi ulnaris and sartorius, it is demonstrated that the phenomenon of postdenervation hypertrophy still occurs under conditions preventing stretch of muscle after denervation or even in tenotomized muscles in shortened state relieved of tension. Striking differences between the slow fibres of the ALD and those of the mixed muscles are seen, both with respect to their histochemical property and to the degree of development of post-denervation hypertrophy. The slow fibres in the mixed muscles show the phenomenon of post-denervation hypertrophy in a much more striking form than the ALD fibres and should be made more use of in further studies on the phenomenon.