Antitumor effects of two newly constructed oncolytic herpes simplex viruses against renal cell carcinoma

Conditionally replicating (oncolytic) herpes simplex viruses (HSVs) have shown clear potential as effective agents for the treatment of solid tumors such as renal cell carcinoma (RCC). To enhance the oncolytic capabilities of first-generation HSVs, we recently developed two new constructs. Synco-2D is derived from HSV-1 and contains two mechanisms to induce cell membrane fusion. FusOn-H2 is derived from HSV-2. It selectively targets the activated Ras signaling pathway in tumor cells and also has the ability to induce cell membrane fusion and apoptosis. We studied the in vitro and in vivo antitumor effects of both Synco-2D and FusOn-H2 against RCC. Both Synco-2D and FusOn-H2 lysed human RCC cells in vitro much more readily than did Baco-1. For in vivo studies, the oncolytic viruses were administered either intratumorally or intravenously to nude mice bearing xenografted human RCC, and the tumor growth rate and animal survival were monitored after treatment. In most instances, the results were compared with those for a first-generation non-fusogenic oncolytic HSV (Baco-1). A single intratumoral injection of either Synco-2D or FusOn-H2 produced a striking effect against xenografted human RCC, in contrast to Baco-1, which produced only moderate antitumor activity. Two intravenous injections of Synco-2D also inhibited the growth of human RCC xenografts, while Baco-1 injections via the same route lacked any measurable antitumor effect. These data demonstrate that the newly constructed oncolytic HSVs have potent activity against established RCC in animal models. Clinical trials to validate these results in cancer patients appear warranted.     

Genistein, a soybean isoflavone, inhibits inward rectifier K(+) channels in rat osteoclasts

Genistein, a soybean-derived isoflavone with an inhibitory effect on protein tyrosine kinases (PTKs), has been shown to suppress osteoclastic bone resorption. To clarify the mechanisms underlying this action, we investigated the effects of genistein on inward rectifier K(+) current (I(Kir)) in rat osteoclasts by using the whole-cell patch-clamp technique. Extracellularly applied genistein inhibited I(Kir) in a concentration-dependent manner. Physiologically attainable concentrations of genistein inhibited I(Kir). IC(50) values obtained 5 and 10 min after the application of genistein were 54 and 27 microM, respectively. The removal of genistein partially restored the current. Daidzein, an isoflavone without PTK-inhibiting activity, also showed a weak inhibitory effect on I(Kir), but genistin had no effect. Other PTK inhibitors, tyrphostin A25, tyrphostin B42, and tyrphostin B46, inhibited I(Kir), whereas herbimycin A and lavendustin A were without effect. The inactive tyrphostin, A1, showed a similar inhibitory effect as tyrphostin A25. The tyrosine phosphatase inhibitor, orthovanadate, did not affect the inhibitory potency of genistein on I(Kir). The inhibitory action of genistein was unaffected by changing intracellular Ca(2+) concentration ([Ca(2+)]i) or by pretreatment of the cell with GDPbetaS, Rp-cAMPS, okadaic acid, or staurosporine. Therefore the inhibition of I(Kir) by genistein does not depend on PTK inhibition, involvement of changes in [Ca(2+)]i, or secondary interaction with protein kinase A or protein kinase C. Genistein-induced inhibition of I(Kir) would cause membrane depolarization, elevation of [Ca(2+)]i, and inhibition of osteoclastic bone resorption.