Biomedical subjects
Publications and source records attributed to W Z Gu.
We report a case in which malignant melanoma of the vagina showed some MR signal changes after radiotherapy. Before radiotherapy, the tumour had slightly high signal intensity on T(1) weighted images and was enhanced after gadolinium-DTPA administration. After radiotherapy, the signal intensity of the tumour increased conspicuously on both T(1) weighted images and fat suppression T(1) weighted images.
Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC(50) 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC(50) 3000 nM) and squalene synthase (SSase) (IC(50)>10000 nM). A-176120 inhibited ras processing in H-ras-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED(50) 1.6 and 0.5 microM, respectively). The anti-angiogenic potential of A-176120 was demonstrated by a decrease in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the secretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespan of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-176120 also had an additive effect in combination with cyclophosphamide in nude mice inoculated with K-ras NIH3T3 transformed cells. Overall, our results demonstrate that A-176120 is a potent FPP mimetic with both antitumour and anti-angiogenic properties.
Ras oncogenes can contribute to tumour development by stimulating vascular endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since farnesylation of Ras is required for its biological activity. In this paper we evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis. Human umbilical vein endothelial cell (HUVEC) tube formation and VEGF secretion were used to assess the effect of A-170634 on angiogenesis in vitro. In vivo, nude mice were injected with the K-ras mutant colon carcinoma cell line HCT116 and treated subcutaneously with A-170634 using osmotic minipump infusion for 10 days. The effect of A-170634 on corneal angiogenesis in vivo was assessed using pellets containing hydron, VEGF, A-170634 or vehicle. In vitro, A-170634 selectively inhibited farnesyltransferase activity over the closely related geranylgeranyltransferase I, inhibited Ras processing, blocked anchorage-dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC capillary structure formation, decreased VEGF secretion from tumour cells and HUVEC growth stimulating activity in a dose-dependent manner. In vivo, tumour growth was decreased by 30% and vascularisation in and around the tumours was reduced by 41% following drug-treatment with no apparent toxicity to the animals. VEGF-induced corneal neovascularisation was reduced by 80% following A-170634 treatment for 7 days. The data presented here demonstrated that A-170634 was a potent and selective peptidomimetic CAAX FTI with anti-angiogenic properties. These results implied that A-170634 may affect tumour growth in vivo by one or more antitumour pathways.
Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long-term clinical trials with encouraging preliminary results as a chemopreventive agent for breast cancer. The effect of Tam on ER-negative cancers, however, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4-HT) have a synergistic cytotoxic effect on the ER-negative colon cancer cell line HCT15, which is refractory to paclitaxel alone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiproliferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel concentrations used for HCT15, 4-HT and paclitaxel also showed synergistic effect on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the single treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G2/M population and resulted in the increase of apoptosis in both cell lines. Enhanced early release of cytochrome c from mitochondria may be the apoptotic pathway activated in the combination treatment in HCT15 cells.
The effects of purified triptolide, a diterpenoid triepoxide compound derived from the Chinese traditional anti-rheumatic medicinal plant extract, Tripterygium wilfordii Hook f (TWHf), were determined in type II collagen-induced arthritis (CIA) in rats. Lewis rats were immunized with bovine type II collagen and treated with purified triptolide 0.1 mg/kg/day or control (vehicle for triptolide) by daily gavage feedings for 28 days. Triptolide was well-tolerated with no evidence of toxicity. Treatment with triptolide resulted in significant delay in time to onset of arthritis (P = 0.039), as well as significantly decreased arthritis incidence (P = 0.024), clinical arthritis severity score (P < 0.0001), histopathological arthritis severity score (P < 0.0001), and in vivo cell-mediated immunity to collagen (P = 0.0004). Triptolide appeared to be a potent immunomodulatory inhibitor of CIA in rats and this may account for the previously observed anti-rheumatic properties of crude extracts of TWHf, although more extensive studies will be needed to confirm these effects.
RATIONALE AND OBJECTIVES: Percutaneous methods have been used to treat primary and secondary hepatic neoplasms. In the current study, we evaluated the potential of bipolar radiofrequency (RF) electrocautery to increase in vitro liver tissue destruction when compared with monopolar RF electrocautery. METHODS: Two needles (electrodes) were placed into fresh bovine liver tissue for use with bipolar electrocautery. Needle tip exposure was kept constant at 3 cm while other parameters, including treatment time, power (wattage), interneedle distance, and needle tip temperature, were changed. Pathologic and histologic correlation was performed, and tissue necrosis was weighed in grams for individual parameters. RESULTS: There was a minimal threshold of approximately 45 degrees C where tissue coagulation occurred. Tissue coagulation increased the longer treatment went on. Increasing temperature, wattage, or both increased tissue coagulation such that necrosis was too rapid and char formation occurred, which prevented further coagulation. For all wattages and temperatures, there was increasing tissue necrosis with increasing needle separation, until a point at which further needle separation produced less tissue necrosis. Optimizing parameters allowed tissue coagulation of greater than 30 g. CONCLUSION: Bipolar RF electrocautery shows promise for increasing the tissue coagulation in fresh bovine liver compared with the previously described monopolar technique.
Crude extracts derived from the root of Tripterygium wilfordii Hook f (TWHf) have previously been demonstrated to have immunosuppressive properties and have been used as anti-rheumatic therapy in Chinese traditional medicine. Although these extracts contain a large number of chemical components, the precise nature of the compound(s) responsible for this therapeutic effect has not been established with certainty. An aqueous extract of TWHf was resolved into chemical components by medium-pressure and high-performance liquid chromatography. Immunosuppressive fractions were identified with a mixed lymphocyte reaction (MLR) and chemically characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. Two major peaks of immunosuppressive activity were identified. These were the closely related diterpenoid triepoxides, triptolide and tripdiolide. No other immunosuppressive compounds were identified using MLR as the biologic screening assay. Triptolide and tripdiolide may be responsible for the anti-rheumatic properties of crude aqueous extracts of TWHf and represent a novel class of immunosuppressive drugs with potential clinical utility.
OBJECTIVE: Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. METHODS: Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. RESULTS: Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. CONCLUSION: TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-lpr/lpr mice.
The potential of percutaneous radio-frequency (RF) electrocautery hepatic ablation was evaluated in the animal model. RF hepatic ablation was performed under ultrasound (US) guidance in the liver of 10 swine with use of a specifically designed needle. The needle was placed through the liver capsule, and ablation was performed after isolating the liver at laparotomy. Animals were killed immediately (n = 4), at 1 week (n = 1), 2 weeks (n = 3), or at 5 weeks (n = 2). The US findings were correlated with the pathologic results in the animal livers. RF hepatic ablation was successfully performed in the animal model without complications. Lesions in the animal livers were typically 1 x 2 cm, which initially appeared highly echogenic on US scans. These images corresponded to an area of hepatic necrosis. The lesions became less echogenic shortly after initial treatment but could still be visualized with US at 5 weeks. At histologic study at 5 weeks, the treated livers showed central debris, a larger area of necrotic liver, and a zone of granulation tissue surrounded by a fibrotic capsule. No complications were encountered. RF hepatic ablation shows future promise in treatment of hepatic neoplasms.
Preparations of polyacrylonitrile (PAN) are now being considered as possible new therapeutic embolization agents. This study evaluated two different liquid PAN formulations and a solid particle form (particle diameters, 100-400 microns). Eighteen rabbits underwent unilateral renal embolization with one of the three different preparations (n = 6 in each group). PAN was effective in causing infarcts in all embolized kidneys, which were documented with both angiograms and pathologic findings. These preliminary results show that PAN may have promise as an effective agent for clinical renal embolizations.
The effects of Tripterygium wilfordii Hook f (TWHf), a Chinese herbal remedy, on type II collagen induced arthritis (CIA) in DBA/1LacJ mice were determined. Mice were divided into 4 groups receiving oral treatment for 63 days: Group A, sham feedings; Group B, TWHf (78 mg/day); Group C, TWHf (140 mg/day); Group D, TWHf (140 mg/day) starting 21 days after collagen immunization. Arthritis incidence was reduced and day of onset delayed in Groups B and C compared with A. Arthritic joint counts, arthritic severity scores, and anticollagen antibody titers were decreased in Groups B, C, and D compared with A. Histopathology revealed destructive arthritis only in Group A. Our results indicate that TWHf is a potent immunosuppressive inhibitor of CIA, even when treatment is begun 3 weeks after immunization.
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