A novel quinoline derivative, TAS‐103 (6‐[[2‐(dimethyIamino)ethyl]amino]‐3‐hydroxy‐7H‐indeno[2,l‐c]quinolin‐7‐one dihydrochloride), was developed as an anticancer agent targeting topoisomerases (topo) I and II, with marked efficacy in solid tumors. TAS‐103 inhibited topo I and II (IC50: 2 μM, 6.5 μM) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50,: 0.0011 μM, 0.0096 μM). TAS‐103 stabilized topo I and II‐DNA cleavable complexes in KB cells, generating a similar amount of topo II‐DNA complex to that induced by etoposide (VP‐16) but a smaller amount of topo I‐DNA complex than that produced by camptothecin (CPT). In the in vivo study, intermittent i.v. administration was markedly effective against s.c.‐implanted murine tumors. Furthermore, TAS‐103 had marked efficacy against various lung metastatic tumors, and a broad antitumor spectrum in human tumor xenografts (derived from lung, colon, stomach, breast, and pancreatic cancer). The efficacy of TAS‐103 was generally greater than that of irinotecan (CPT‐11), VP‐16, or cis‐diamminedichloroplatinum (CDDP).
The aortic wall is perfused by the adventitial vasa vasorum (VV). Tissue hypoxia has previously been observed as a manifestation of enlarged abdominal aortic aneurysms (AAAs). We sought to determine whether hypoperfusion of the adventitial VV could develop AAAs. We created a novel animal model of adventitial VV hypoperfusion with a combination of a polyurethane catheter insertion and a suture ligation of the infrarenal abdominal aorta in rats. VV hypoperfusion caused tissue hypoxia and developed infrarenal AAA, which had similar morphological and pathological characteristics to human AAA. In human AAA tissue, the adventitial VV were stenotic in both small AAAs (30–49 mm in diameter) and in large AAAs (> 50 mm in diameter), with the sac tissue in these AAAs being ischemic and hypoxic. These results indicate that hypoperfusion of adventitial VV has critical effects on the development of infrarenal AAA.
Abdominal aortic aneurysm (AAA) is a common disease among elderly individuals. However, the precise pathophysiology of AAA remains unknown. In AAA, an intraluminal thrombus prevents luminal perfusion of oxygen, allowing only the adventitial vaso vasorum (VV) to deliver oxygen and nutrients to the aortic wall. In this study, we examined changes in the adventitial VV wall in AAA to clarify the histopathological mechanisms underlying AAA. We found marked intimal hyperplasia of the adventitial VV in the AAA sac; further, immunohistological studies revealed proliferation of smooth muscle cells, which caused luminal stenosis of the VV. We also found decreased HemeB signals in the aortic wall of the sac as compared with those in the aortic wall of the neck region in AAA. The stenosis of adventitial VV in the AAA sac and the malperfusion of the aortic wall observed in the present study are new aspects of AAA pathology that are expected to enhance our understanding of this disease.
Abdominal aortic aneurysm (AAA) is a vascular disease involving the gradual dilation of the abdominal aorta. It has been reported that development of AAA is associated with inflammation of the vascular wall; however, the mechanism of AAA rupture is not fully understood. In this study, we investigated the mechanism underlying AAA rupture using a hypoperfusion-induced animal model. We found that the administration of triolein increased the AAA rupture rate in the animal model and that the number of adipocytes was increased in ruptured vascular walls compared to non-ruptured walls. In the ruptured group, macrophage infiltration and the protein levels of matrix metalloproteinases 2 and 9 were increased in the areas around adipocytes, while collagen-positive areas were decreased in the areas with adipocytes compared to those without adipocytes. The administration of fish oil, which suppresses adipocyte hypertrophy, decreased the number and size of adipocytes, as well as decreased the risk of AAA rupture ratio by 0.23 compared to the triolein administered group. In human AAA samples, the amount of triglyceride in the adventitia was correlated with the diameter of the AAA. These results suggest that AAA rupture is related to the abnormal appearance of adipocytes in the vascular wall.
The velocity (SOS), attenuation slope (BUA) and stiffness index in the os calcis were measured using the 'Achilles' ultrasound bone densitometer (Lunar, Madison, WI). We evaluated the basic attributes of this ultrasound bone densitometer, and showed the age-related changes in ultrasound values in normal Japanese women. The precision was measured in vivo on ten occasions over a 2-week period in 5 subjects. The short-term precision errors (CVs) in vivo were 0.6% for stiffness index, 0.3% for SOS and 1.0% for BUA. Spine, femur neck and total body BMD using dual X-ray absorptiometry (DXA) were highly correlated with stiffness index (r = 0.80, 0.77 and 0.78, respectively) in 194 subjects. Ultrasound values for patients with osteoporosis were significantly lower than those for the normal controls. The Z-score compared with young normals was significantly higher for spine bone mineral density (-4.4) than for stiffness index (-3.5); BUA and SOS gave significantly lower Z-scores -2.9 and -3.0, respectively). Ultrasound values were also lower compared with age-matched normal controls. The Z-score for stiffness index (-2.1) was significantly superior to that for either SOS or BUA (-1.5). Age-related change in ultrasound values was evaluated in 842 normal women. There was a decline in stiffness index of about 24% from the values in young adulthood to those of women in their seventies, about 75% of which occurred from age 44-49 years onward. These findings seem to indicate that the menopause affected the change in ultrasound values.(ABSTRACT TRUNCATED AT 250 WORDS)
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