Future direction of nanomedicine in gastrointestinal cancer]

Cancer is one of the leading causes of death in human, and among various cancers, gastrointestinal cancers occupy more than 55%. Gastric cancer is the first leading cause of cancer-related mortality in the world and the number of pancreas and colon cancers are increasing remarkably during last two decades which will continue to increase in the future. Even though the clinical importance of gastrointestinal cancers is very high and endless efforts has been made to develop novel diagnostic and therapeutic methods to improve the patient's quality of life and survival, the realistic advance in the actual survival benefit of the cancer patients are still strongly required. Nanotechnology has the power to radically change the way of cancer diagnosis and treatment. Currently, there is a lot of researches on novel nanodevices capable of detecting cancer at its earliest stage, pinpointing its location within the body, and delivering anticancer drugs specifically to the malignant cells. Nanoscale devices can readily interact with biomolecules both on the cell surface and within the cell. In addition, nanoscale devices are already proven that they can deliver therapeutic agents to target cells even within specific organelles. Major areas in which nanomedicine is being developed in cancer include early detection and proteomics, imaging diagnostics and multifunctional therapeutics. Because nanotechnology would provide a technical power and tool that enable new diagnostics, therapeutics, and preventives to keep pace with today's explosion in knowledge in the future, it would be very useful to know the perspectives in the direction of nanotechnology as a major clinician responsible for the patients with gastrointestinal malignancies.     

Particle size and morphology of UHMWPE wear debris in failed total knee arthroplasties--a comparison between mobile bearing and fixed bearing knees.

Osteolysis induced by ultrahigh molecular weight polyethylene wear debris has been recognized as the major cause of long-term failure in total joint arthroplasties. In a previous study, the prevalence of intraoperatively identified osteolysis during primary revision surgery was much higher in mobile bearing knee replacements (47%) than in fixed bearing knee replacements (13%). We postulated that mobile bearing knee implants tend to produce smaller sized particles. In our current study, we compared the particle size and morphology of polyethylene wear debris between failed mobile bearing and fixed bearing knees. Tissue specimens from interfacial and lytic regions were extracted during revision surgery of 10 mobile bearing knees (all of the low contact stress (LCS) design) and 17 fixed bearing knees (10 of the porous-coated anatomic (PCA) and 7 of the Miller/Galante design). Polyethylene particles were isolated from the tissue specimens and examined using both scanning electron microscopy and light-scattering analyses. The LCS mobile bearing knees produced smaller particulate debris (mean equivalent spherical diameter: 0.58 microm in LCS, 1.17 microm in PCA and 5.23 microm in M/G) and more granular debris (mean value: 93% in LCS, 77% in PCA and 15% in M/G).     

多粘菌素B琼脂糖层析柱清除体液中内毒素

用多粘菌素B琼脂糖亲和层析法清除内毒素,结果表明:5ml多粘菌素B层析柱的总吸附内毒素能力为450 μg,用此法可完全清除体液或各种液体中的内毒素,对血清及腹水中的内毒素也有明显的吸附作用,而其他各种主要成分(除内毒素外)经过处理后无明显改变。去氧胆酸是一种强有力的去污剂,可使已饱和的柱子复活,复活率达85％左右。该方法有简便,可靠,吸附能力大,柱子的复活率高等优点。本方法的建立为内毒素血症的治疗展示了新的前景。     

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit

Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min^–1 kg^–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml^–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation     

Quantitative structure-activity relationships in MAO-inhibitory 2-phenylcyclopropylamines: Insights into the topography of MAO-A and MAO-B

Ten (E)-and (Z)-isomers of 2-phenylcyclopropylamine (PCA), 1-Me-PCA, 2-Me-PCA, N-Me-PCA, and N, N-diMe-PCA and fifteeno ⁻, m⁻, p⁻ isomers of (E)-PCA with substituents of Me, Cl, F, OMe, OH were synthesized in this laboratory and tested for the inhibition of rat brain mitochondrial MAO-A and MAO-B. The effects of substituents, their positions, and stereochemistry on the inhibition were assessed for the compounds with substituents at cyclopropyl and amino groups and QSAR analyses were performed using the potency data of ring-substituted compounds. The best correlated QSAR equations are as follows: pI₅₀=0.804 Π² Blo−1.069 Blm+0.334 Lp−1.709 HDp+7.897 (r=0.945, s=0.211, F=16.691, p=0.000) for the inhibition of MAO-A; pI₅₀=1.815 π-0.825 Π² R+0.900 Es²+0.869 Es³+0.796 Es⁴−0.992 HDp+0.562 HAo+3.893 (r=0.982, s=0.178, F=23.351, p=0.000) for the inhibition of MAO-B. Based on the potency difference between stereoisomers of cyclopropylamine-modified compounds and on QSAR results, it is proposed that the active sites of MAO-A are composed of one deep hydrophobic cavity near para position, two hydrophobic cavities interacting with Me group, a hydrophobic area accomodating phenyl and cyclopropyl backbone, steric boundaries, a hydrogen-acceptor site near para position, and an amino group binding site and that in addition to the same two hydrophobic cavities, hydrophobic area, steric boundaries, hydrogen-acceptor site, and amino group binding site, another steric boundary near para position and a hydrogen donating site near ortho position constitute active sites of MAO-B.     

Changes of Intestinal Caicitonin Gene-related Peptide in Acute Intestinal Radiation Sickness in Rats

The characteristic distribution of calcitonin gone-related peptide(CGRP)inthe small intestine of rats and its changes in acute intestinal radiation sickness(AIRS)were studied with immunocytochemistry(whole mount stretch preparations of the smallintestine and cryostat sections)and radio-immunoassay.It was found that in all the lay-ers of the intestinal walls,there were large amounts of CGRP immunoreactive(CGRP-I)nerve fibers which existed in especiaUy high density in the myenteric,submucosal andmucosal plexuses.There was also a rather high density of the nerves around the smallvessels of the small intestine and the intestinal crypts.Some CGRP-I neurons were seenin the myenteric and submucosal plexuses.In AIRS,the intestinal CGRP showed a dip-hasic change,in a lower level in the 24th h and a higher level in the 48th and 72nd h af-ter irradiation.The results indicate that CGRP may be related to the regulation of the motility,se-cretion,absorption,sensation,and regional blood flow of the gastrointestinal tract.Pro-bably,CGRP is released under the stress of AIRS and participates in the mechanism ofinjury through many ways especially through the influence on the regional blood flowand the increase of the permeability of blood vessels.     

Fatty acid profiles in response to soybean oil lipid emulsion infusions in essential fatty acid-deficient miniature swine

The ability of soybean oil lipid emulsions to affect essential fatty acid deficiency (EFAD) and plasma fatty acid distribution was studied in neonatal pigs. The test animals were maintained on a fat-free diet prior to administration of lipid emulsion. Plasma and red blood cell (RBC) membrane levels of essential [linoleic (C-18:2 omega 6) and arachidonic (C-20:4 omega 6)] and nonessential [palmitic (C-16, palmitoleic (C-16:1 omega 7), stearic (C-18), and oleic (C-18:1 omega 9)] fatty acids and the triene:tetraene ratio [5,8,11-eicosatrienoic acid (C-20:3 omega 9):arachidonic acid (C-20:4 omega 6)] were monitored to ascertain the establishment of EFAD and its correction. Nonessential fatty acids were studied, as these components of lipid therapy have received little attention. Results indicate that soybean oil emulsions are effective in reversing fatty acid profiles found in EFAD, and both essential and nonessential fatty acids are under strict metabolic control.     

Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs

Summary The blood-brain barrier penetration of amsacrine and its analogs 9-({2-methoxy-4-[(methylsulfonyl)-amino]phenyl}amino)-,5-dimethyl-4-acridine carboxamide (CI-921) and M-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (AC) was measured in the barbiturate-anesthetized mouse. After intracarotid administration, AC was almost completery extracted (90%) in a single transit through the brain capillaries, whereas CI-921 (20%) and amsacrine (15%) were moderately extracted. AC is retained in the brain; no loss of AC from the brain was apparent at 1, 2, 4, or 8 min after injection. In contrast, after intraportal administration, 75% of the AC, 94% of the CI-921, and 57% of the amsacrine was extracted in a single transit through the hepatic vasculature. Rather than being retained in the mouse liver, these acridine antitumor agents show time-dependent loss (t _1/2=10 min for amsacrine and AC, 24 min for CI-921). We conclude that unlike most antitumor agents, these acridine drugs appear to penetrate the blood-brain barrier readily.This study was supported by the Auckland Medical Research Foundation (New Zealand), by the Medical Research Foundation (New Zealand), by the National Science Foundation (United States/New Zealand Cooperative Science Program), by the United States Veterans Administration, and by NIH grant NS 25554