ZD4190: an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy.

There is evidence that vascular endothelial growth factor (VEGF) contributes to solid tumor growth through the promotion of both angiogenesis and tumor vascular permeability. To abrogate VEGF signaling, we developed a small molecular weight inhibitor of VEGF receptor tyrosine kinase (RTK) activity that was compatible with chronic oral administration. ZD4190, a substituted 4-anilinoquinazoline, is a potent inhibitor of KDR and Flt-1 RTK activity, and VEGF stimulated HUVEC proliferation in vitro. Chronic once-daily oral dosing of ZD4190 to young rats produced a dose-dependent increase in the femoral epiphyseal growth plate area, which may be attributed to the inhibition of VEGF signaling in vivo because vascular invasion of cartilage is a prerequisite to the process of ossification. Once-daily oral dosing of ZD4190 to mice bearing established (approximately 0.5 cm3) human tumor xenografts (breast, lung, prostate, and ovarian) elicited significant antitumor activity and at doses that would not be expected to have any direct antiproliferative effect on tumor cells. Prolonged tumor cytostasis was further demonstrated in a PC-3 xenograft model with 10 weeks of ZD4190 dosing, and upon withdrawal of therapy, tumor growth resumed after a short delay. These observations are entirely consistent with the proposed mode of action. ZD4190 is one of a series of VEGF RTK inhibitors that may have utility in the treatment of a range of histologically diverse solid tumor types.

Expression of growth factors and growth factor receptors in the liver of C57BL/10J mice following administration of phenobarbitone.

Liver enlargement is a common feature of non-genotoxic rodent hepatocarcinogens administered at high doses. In the present study, the expression of growth factors and growth factor receptors was investigated in the C57BL/1OJ mouse during liver enlargement induced by the non-genotoxic rodent hepatocarcinogen, sodium phenobarbitone (PB). Male mice were dosed 0-2500 p.p.m. PB in the diet for 1, 4 and 13 weeks. There was a dose and time dependent increase in liver weight. Hepatocyte replication, assessed by incorporation of bromodeoxyuridine, was increased in a dose-dependent manner at week 1 only (18-fold increase at 2000 p.p.m.) and was predominantly localized in the centrilobular region. At week 1, PB (2500 p.p.m.) caused transient increases in transforming growth factor alpha (TGFalpha) and epidermal growth factor receptor (EGFR) and decreases in transforming growth factor beta1 (TGF-beta1) and mannose-6-phosphate receptor (M6PR) in centrilobular hepatocytes which correlated with the replication in this region. At week 1, there was an increase in both hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (HGFR) which colocalized in centrilobular hepatocytes; in some mice or periportal hepatocytes in other mice. After 13 weeks, HGF and HGFR were localized in the cytoplasm of centrilobular hepatocytes of all mice but exhibited a differential intracellular distribution across the lobule. At 2500 p.p.m. PB, EGFR and HGFR mRNA were essentially unchanged over the 13 week dosing period whilst M6PR mRNA was increased 2- to 4-fold. At 2500 p.p.m. PB, EGFR protein levels from immunoblots showed a consistent decrease over the 13 weeks whilst M6PR and HGFR protein levels were essentially unchanged. The protein level and mRNA data for EGFR suggest post-transcriptional modification. Thus, phenobarbitone caused transient replication of hepatocytes and modulation of growth stimulatory and inhibitory factors and their associated receptors in terms of overall levels and regional distribution in the liver.

The topography, structure and incidence of mineralized bodies in the basal ganglia of the brain of cynomolgus monkeys (Macaca fascicularis).

Whole coronal slices from 6 levels of the brain of 16 cynomolgus monkeys (8 control and 8 treated by daily gavage with a novel pharmaceutical agent for one year) were examined histologically. Mineralized bodies were identified only in coronal sections passing through the optic chiasma and mammillary bodies. Identical mineralized structures were present in the basal ganglia of both control and treated animals. The majority were seen in the globus pallidus, occasionally in the putamen and once in the nearby caudate nucleus. These structures were partially ferruginated and also partially calcified. They appeared to arise in relation to small vessels. They are part of the naturally occurring background pathology of several species of non-human primates and the incidence in this study (3/8 control and 5/8 treated) was approximately what might be expected from reports in the literature. Mineralized bodies of the basal ganglia of primates represent a spontaneous lesion with a characteristic distribution. They may cause confusion in interpretation of toxicological studies if their natural occurrence is not appreciated.

A case of endometriosis in the macaque diagnosed by nuclear magnetic resonance imaging.

A case of spontaneous endometriosis was diagnosed in the pigtailed macaque (Macaca nemestrina nemestrina) with the aid of high-field (2.35 T), T2-weighted (TE50), C1H2-suppressed, oblique nuclear magnetic resonance imaging (MRI). Postmortem histology was obtained. A variety of endometriotic lesions was seen with MRI, including extrauterine hyperintense apparently cystic regions, extrauterine hypointense regions apparently associated with intracellular paramagnetic iron proteins, and an enlarged myometrium exhibiting adenomyosis foci.

Neuron-specific enolase immunoreactivity in rat and mouse phaeochromocytomas.

Neuron-specific enolase (NSE) was found to be consistently present in the rat and mouse adrenal medulla in the normal and neoplastic state. It is suggested that NSE immunoreactivity may be a useful tool in the differential diagnosis of phaeochromocytomas.

Tumours of the bone in C57BL/10J mice.

Tumours of the bone were found in 17 (12 females and 5 males) of 6768 (0.25%) C57BL/10J mice (3384 males and 3384 females) pooled from 14 oncogenic studies carried out from 1973 to 1987. Tumours of bone were found predominantly in female mice and were age related. The tumours were classified histologically as osteosarcoma (5 osteoblastic, 6 mixed type and 1 fibroblastic), chondroma (2), chondromyxoid fibroma (1), chondrosarcoma (1) and periosteal fibroma (1).

Fatty liver in birds at the Zoological Society of London.

The livers of 531 captive wild birds necropsied at the Zoological Society of London were examined histologically. Marked fatty infiltration of the liver was found in 13 cases. Seven of the 13 cases were from the order Psittaciformes indicating that some species (cockatoos, parakeets and parrots) in this order may be particularly susceptible to fatty infiltration of the liver. Affected livers were commonly swollen or enlarged, pale, white or yellow in colour and soft, friable or fatty at post mortem examination. Histologically, marked fatty infiltration of the liver was characterised by the presence of intracytoplasmic fat vacuoles within hepatocytes without zonal or lobular distribution throughout the sections examined. Reticulolysis and fibrosis of the hepatic parenchyma were found in association with marked fatty liver in a proportion of cases. Macroscopic or histological evidence of hepatic haemorrhages was not found in affected birds. In psittacine birds, obesity was frequently seen at post mortem examination and it was considered that nutritional and/or metabolic factors were important causes of fatty liver in this group. Fatty liver was found in association with chronic wasting diseases caused by mycotic infection in two cases.

A survey of the pathology of marmosets (Callithrix jacchus) derived from a marmoset breeding unit.

The results of a survey of the major pathological conditions encountered in an established breeding colony of common cotton-eared marmosets (Callithrix jacchus) is presented. 265 home-bred and 70 imported wild-caught marmosets were examined. A Heinz body haemolytic anaemia and skeletal muscle myopathy were the most common pathological findings and were considered to be a result of a complex nutritional deficiency involving vitamin E, selenium and protein. Inflammatory disease of the intestinal tract was also a major feature. Chronic colitis was particularly common in older marmosets. Pneumonia, otitis media, meningitis and brain abscesses were important pathological findings in home-bred marmosets and were commonly associated with bacterial infections, particularly Bordetella bronchiseptica and Klebsiella species. Trichospirura leptostoma within pancreatic ducts of wild-caught marmosets was the only significant parasitic disease encountered. Mycotic infections of the upper alimentary tract with Candida species were occasional findings in debilitated animals. No pathological features suggesting viral diseases were found.

Hepatic haemosiderosis in birds at the Zoological Society of London.

The livers of 531 captive wild birds necropsied at the Zoological Society of London were examined histologically. Significant accumulations of stainable iron pigment were found in the livers of 37 birds. Hepatic haemosiderosis was prevalent in some species in the orders Ciconiiformes, Cuculiformes, Coraciiformes and Passeriformes. Flamingos, go-away birds, hornbills and starlings were most commonly affected. Hepatic haemosiderosis was not recorded in some orders such as the Psittaciformes, Sphenisciformes, Falconiformes or Strigiformes. Hepatic haemosiderosis usually occurred in birds that had been in captivity for many years. The macroscopic appearance of affected livers varied, some were swollen or enlarged and others either yellow, brown or golden in appearance. The degree to which stainable iron was present in hepatocytes, phagocytic cells in the liver, or both, varied from case to case. Stainable iron was both granular and diffuse in hepatocytes and granular in both Kupffer cells and aggregations of haemosiderin-laden macrophages. Fibrosis was associated with haemosiderosis in one case only. Intercurrent diseases were common in affected birds and often considered to be the cause of death. Primary hepatic neoplasia was recorded in five of the 37 affected birds.

Haematological, coagulation and blood chemistry data in red-bellied tamarins Saguinus labiatus.

Haematology, coagulation and clinical chemistry data are reported for a group of male and female red-bellied tamarins (Saguinus labiatus). The tamarins were juvenile and young adults and were bred in captivity. High mean values for activities of alkaline phosphatase, alanine amino-transferase, aspartate aminotransferase and creatine kinase were noted. The findings are compared with data obtained from other members of the family Callitrichidae.

A survey of tuberculosis in birds in the Regent's Park gardens of the Zoological Society of London.

A total of 5,177 avian post mortem examinations was carried out at the Regent's Park gardens of the Zoological Society of London between 1966 and 1978 inclusive. Avian tuberculosis was found in 13 different avian orders. A total of 112 birds (2.2%) was affected; 2.1% from Regent's Park Zoo and 2.4% from other sources. The diagnosis of tuberculosis was based on the demonstration of acid-fast bacilli in association with lesions in fresh or fixed tissues stained by Ziehl-Neelsen's procedure and by cultural methods. Mycobacterium avium (including M. intracellulare) was isolated from 12 specimens, unidentified Mycobacterium spp. from 12, and M. fortuitum from one. The overall occurrence during the 13-year period of observation did not appear to decline although seasonal and yearly fluctuations were noted. No sex predilection was found and the disease generally occurred in birds that had been in captivity for many years. Avian tuberculosis was diagnosed in three free-living wood pigeons (Columba palumbus) trapped in the Zoo grounds. These birds may contribute to the transmission of the disease to other species. A high incidence of tuberculosis was found in the Anseriformes, Gruiformes and Columbiformes, but the disease appeared to be rare in the Psittaciformes, Passeriformes, Spherdsciformes and Strigiformes.

Some cases of lymphoid leukosis in captive wild birds.

A total of 1,234 post mortem examinations of captive wild birds was carried out during a 5-year observation period. Six cases of lymphoid leukosis were found and their pathological features are described.

An ovarian adenocarcinoma in a greater flamingo (Phoenicopterus ruber roseus).

An ovarian adenocarcinoma was diagnosed in a greater flamingo (Phoenicopterus ruber roseus) which had been maintained in captivity for over 32 years. Neoplastic epithelial cells showed both solid and tubular patterns of growth. Metastases were found in the lung, liver and on the peritoneal surface of the pancreas.

Pancreatic atrophy in young Beagle dogs.

Six young Beagle dogs had non-inflammatory pancreatic atrophy associated with lack of weight gain and low serum protein levels. Histologically there was severe atrophy with loss of acinar architecture and absence of islets of Langerhans (type 1), or partial atrophy with ppreserved islets (type 2). The correlation between histological type and clinical severity was poor.

The intravenous toxicity of dibekacin sulphate (DKB) to female beagle dogs.

Dibekacin sulphate (DKB), a new aminoglycoside antibiotic developed on the theory of bacterial resistance, was given by intravenous injection to groups of female Beagle dogs at dosages of 2.5, 5.0, 10.0 or 25.0 mg/kg/day for 13 weeks. Physiological saline was given as a control. Some dogs given 5.0 or 10.0 mg/kg/day were retained undosed for a further 5 weeks in order to assess recovery. Premature deaths from acute renal tubular nephrosis occurred in dogs given 25.0 and 10.0 mg/kg/day. Dogs which survived treatment at 10.0 mg/kg/day showed marked elevation of circulating urea and creatinine concentrations after 4 weeks' treatment but thereafter the increases became less obvious. Varying degrees of renal cortical tubular dilatation, basophilia, degeneration or necrosis were seen in the kidneys of all dogs examined after 13 weeks treatment although no clinical impairment of renal function was detectable at dosages up to 5.0 mg/kg/day. These changes had essentially regressed in dogs examined 5 weeks after the last dose of DKB at 5.0 mg/kg/day. All the adverse clinical and histological effects noted, following any dose level of DKB tested, could be attributed to renal changes.