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Bisphosphonates have recently been introduced in the therapeutic armamentarium for long-term treatment of patients with multiple myeloma. These pyrophosphate analogs not only reduce the occurrence of skeletal events but also provide clinical benefit to patients and improve the survival of some of them. The existence of these capabilities raises the possibility that these compounds may have a direct antiproliferative effect on tumor cells. To investigate whether these drugs exert a direct antitumor effect, we exposed human myeloma cell lines ARH-77 and RPMI-8226 to increasing concentrations of zoledronic acid (ZOL) in vitro. A concentration- but not time-dependent cytotoxic effect was detected with drug treatment of ARH-77 and RPMI-8226 cell lines (30% and 60% at 48 hours and 38% and 62% at 72 hours, respectively, for 50 microM of ZOL). Cytotoxicity was not due to ZOL-induced chelation of extracellular calcium as shown by control experiments with the calcium chelator ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid. Addition of the competitive inhibitor of the nitric oxide synthase N omega-nitro-L-arginine methyl ester did not modulate ZOL-induced cytotoxicity. However, a decrease in the number of apoptotic cells was detected when protein kinase C was inhibited by addition of staurosporine to ZOL-containing cultures. Cytotoxicity also was increased by addition of dexamethasone (Dex) and thalidomide (Thal) to ARH-77 and RPMI-8226 cultures. We demonstrated that exposing myeloma cell lines ARH-77 and RPMI-8226 to ZOL inhibits cell growth in a dose-dependent but not a time-dependent manner and that combination of Dex and Thal with ZOL induces apoptotic cell death, providing a rationale for potential applications in vivo.

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SUMMARYThe prognostic significance of white coat hypertension (WCH) remains controversial. Consecutive patients (955 cases, 566 females) aged between 15 and 70 years were divided into 3 groups, those with sustained normotension (NT), WCH, and hypertension (HT), and the prevalences of obesity, impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM), coronary heart disease (CHD), and dyslipidemia were compared among the groups. Although the prevalences of all of the disorders showed significant progression from the sustained NT group towards the WCH and HT groups, the prevalence of dyslipidemia was significantly higher in the WCH group (P < 0.05 for all). Due to the gradually increased prevalences of obesity, IGT or DM, and CHD from the sustained NT group towards the WCH and HT groups and the highest prevalence of dyslipidemia in the WCH group, WCH should preferentially be accepted as an alarming sign of a deterioration in health rather than being a predisposing factor of HT or atherosclerosis alone. The significantly higher prevalence of dyslipidemia in the WCH group than in the HT group may be explained by the increased amount of adipose tissue in the HT cases, since the prevalence of obesity was the highest in the HT group. Thus, the high prevalence of WCH even in early decades may represent increased susceptibility to future weight gain, and dyslipidemia in patients with WCH may be a preliminary sign of obesity. Therefore, the management of WCH should focus on the prevention of dyslipidemia and excess weight gain. (Int Heart J 2008; 49: 87-93)