Biomedical subjects

Yong Lin

Publications and source records attributed to Yong Lin.

21 records · Page 2Linked to original sources

PubMed2002

A phase I trial of a potent P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), administered orally in combination with doxorubicin in patients with advanced malignancies.

PURPOSE: The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes. EXPERIMENTAL DESIGN: Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m(2). Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells. RESULTS: A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m(2). Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells. CONCLUSION: Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Expression of E-selectin in Endothelial Cells Effects of Wild Type p53 Gene.

To investigate expression of E-selectin in endothelial cells(EC)and effect of wild type p53 gene transduction on its expression, flow cytometry and RT-PCR were employed to measure the E-selectin protein and mRNA, respectively. The effects of TNFalpha stimulation and p53 gene transduction on the expression of E-selectin was studied. Flow cytometric analysis revealed that there was no E-selectin expression on the surface of resting EC, although its mRNA was detectable by RT-PCR. TNFalpha (10-1 000 ku/L)induced E-selectin expression on the surface of EC in a concentration-dependent manner. The level of E-selectin mRNA was also increased with the increasing concentrations of TNFalpha. The expression of E-selectin protein was notable after 2 h of TNFalpha stimulation and reached a peak at 4-6 h, then rapidly declined to around the basic level by 12 h. Transduction of p53 gene inhibited TNFalpha-induced EC expression of E-selectin. The E-selectin positive cell proportion was reduced from(21.31+/-1.06)% to(11.83+/-0.98)%, (n = 3, P < 0.001). The E-selectin mRNA level was also reduced correspondingly. In resting EC, neither E-selectin nor its mRNA level was affected by the transduction of p53 gene. The results indicated that p53 gene inhibited TNFalpha-induced expression of E-selectin on the surface of EC, at least partially, by reducing its mRNA level.

Journal Article↗

PubMedDate not supplied

Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis.

PURPOSE: Based largely on in vitro investigations and animal studies, investigators believe that disruptions of transforming growth factor-beta (TGF-beta) signaling contribute to the development and progression of human colorectal cancer. The purpose of this study was to directly assess the status of the TGF-beta signaling pathway in colorectal cancer and determine the effects of its disruption on clinical behavior and outcome. MATERIALS AND METHODS: Smad proteins are the principal intracellular components of the TGF-beta signaling pathway. We conducted a high-throughput analysis of the expression patterns of Smad2, phosphorylated (activated) Smad2 (pSmad2), and Smad4 in more than 600 human colorectal cancer specimens assembled in tissue microarrays. RESULTS: The vast majority (93.8%; 95% CI: 92%-96%) of colorectal cancers expressed phosphorylated Smad2, indicating the ability of the tumors to survive and proliferate within a microenvironment that contains bioactive TGF-beta. Twelve of 633 (1.9%; 95% CI: 1%-3%) cases failed to express Smad2, and 15 of 641 (2.3%; 95% CI: 1%-4%) cases failed to express Smad4. Moreover, 29 of 615 (4.7%; 95% CI: 3%-7%) of cases expressed Smad2 but not its activated form (pSmad2), suggesting the presence of a TGF-beta receptor defect. Based on an analysis of 577 cases for which clinical outcome information was available, failure to express Smad2, pSmad2, or Smad4 was associated with advanced-stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months). DISCUSSION: Loss of Smad activation and/or expression occurs in approximately 10% of colorectal cancers. This subset has a poor prognosis because of its association with advanced disease and the presence of lymph node metastases at diagnosis.

Cell Division↗