Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma.

Background: The clinical challenge for the application of rapamycin and its derivatives as anticancer drugs is the ability to prospectively identify which tumors will be sensitive to mammalian target of rapamycin (mTOR) inhibition. The present study is designed to explore mTOR signaling in peripheral-blood mononuclear cells (PBMCs) from renal transplant recipients with Kaposi sarcoma and ascertain whether it would reflect deregulation of the AKT-mTOR pathway in skin cancer tissue and might help identify which patients would benefit from rapamycin treatment, as well as to monitor their clinical response.

Methods: We measured basal and in vivo stimulated AKT and P70 S6 kinase (P70(S6K)) phosphorylation in PBMCs from 37 cyclosporine A-treated patients, 10 of whom had Kaposi sarcoma, before and 6 months after conversion to rapamycin therapy.

Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes?

Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin.

Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus.

Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic beta cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled.

Simultaneous determination of free mycophenolic acid and its glucuronide in serum of patients under mycophenolate mophetil therapy by ion-pair reversed-phase liquid chromatography with diode array UV detection.

An high performance liquid chromatography (HPLC)-UV method for the simultaneous determination of the free forms of mycophenolic acid (MPA) and its phenol glucuronide (MPAG) in human serum samples was developed for the first time. Chromatographic separation was performed on octadecylsilane based stationary phase in combination with a mobile phase of methanol/buffered tetrabutylammonium (TBA) salt mixture. Sample pretreatment consisted of an ultrafiltration step followed by clean-up/enrichment on a C(18) solid-phase extraction (SPE) cartridge.

Cyclosporin exposure correlates with 1 year graft function and histological damage in renal transplanted patients.

Background: Cyclosporin (CsA) level obtained 2 h after the morning dose (C(2)) has been shown to accurately predict total CsA exposure and acute rejection (AR) risk, whereas conventional trough levels (C(0)) do not. The impact of C(2) monitoring on long-term kidney graft function, independent from AR risk, is still unclear, however, and it was assessed in the present study.

Methods: We enrolled 39 CsA-treated renal transplant recipients and used 1 year graft function and histological structure as surrogate markers of graft outcome.