Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.     

Congenital vascular lesions: clinical application of a new classification

Two hundred and ninety-seven patients with 375 pediatric vascular lesions were followed from 1967 to 1981. By history and physical examination, 96% of childhood vascular lesions can be classified as hemangiomas or malformations. Hemangiomas are often not present at birth (40%), but make their appearance during the first month. A proliferative phase, lasting an average of 3 months, is followed by a slow, but eventually complete involution. A "perfect" cosmetic result is more likely when involution is complete before age 6. Malformations are always present at birth, their growth is commensurate with the patient's, and they never involute. Analysis of clinical characteristics fails to identify a subgroup of hemangiomas destined for early involution.     

Estimates of radiation absorbed dose for intraperitoneally administered iodine-131 radiolabeled B72.3 monoclonal antibody in patients with peritoneal carcinomatoses

Using a newly available model for determining estimates of radiation absorbed dose of radioisotopes administered intraperitoneally, we have calculated absorbed dose to tumor and normal tissues based on a surgically controlled study of radiolabeled antibody distribution. Ten patients with peritoneal carcinomatosis received intraperitoneal injections of the murine monoclonal antibody B72.3 radiolabeled with 131I. Biodistribution studies were performed using nuclear medicine methods until laparotomy at 4-14 days after injection. Surgical biopsies of normal tissues and tumor were obtained. The marrow was predicted to be the critical organ, with maximum tolerated dose [200 rad (2 Gy) to marrow] expected at about 200 mCi (7.4 GBq). In patients with large intraperitoneal tumor deposits, the tumor itself is an important source tissue for radiation exposure to normal tissues. Local "hot-spots" for tumor-absorbed dose were observed, with maximum tumor-absorbed dose calculated at 11,000 rad (11 Gy) per 100 mCi (3.7 GBq) administered intraperitoneal; however, tumor rad dose varied considerably. This may pose serious problems for curative therapy, especially in patients with large tumor burdens.     

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations.

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high-dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.     

LANGERHANS' CELL GRANULOMA CONFINED TO THE BILE DUCT

Langerhans' cell histiocytosis (LCH) of the liver is uncommon. When seen, it is part of multifocal disease and can present as biliary obstruction. We present a case of sclerosing biliary disease with a solitary LCH lesion and no evidence of systemic disease. We postulate that the LCH is a secondary phenomenon, arising against a background of a complex, familial liver disease. This case also raises the possibility that some instances of idiopathic sclerosing cholangitis may follow cryptic LCH of the bile ducts.     

Increased levels of intercellular adhesion molecules and vascular cell adhesion molecules in pre-eclampsia

Objective To investigate the correlation between soluble forms of the intercellular adhesion molecule (SICAM-1) and vascular cell adhesion molecule (sVCAM-1) and the severity of pre-eclampsia or its possible consequences for fetal growth.
Design Prospective observational study.
Setting Institute of Medical Genetics, University of Oslo, Department of Medical Genetics and Haematological Research Laboratory, Ullevål University Hospital; and the Department of Obstetrics and Gynaecology, The National Hospital, Oslo, Norway.
Participants Seventy-six women with normotensive pregnancies and 157 women with pre-eclampsia divided into three subgroups: mild, severe and pre-eclampsia with fetal growth retardation.
Methods ELISA-measurements of plasma SICAM-1 and sVCAM-1 were performed in a group of healthy pregnant normotensive women and three groups of women with varying degrees of pre-eclampsia.
Results SICAM-1 concentrations were higher in the pre-eclampsia group compared with the control group, but this difference was not statistically significant. Plasma concentrations of sVCAM-1 were significantly greater ( P < 0.0001) in all pre-eclampsia subgroups (835.34, 855.25 and 964.05 ng/mL) compared with the control group (667.62 ng/mL). Within the pre-eclampsia group, plasma concentration of sVCAM-1 was significantly higher in the subgroup exhibiting fetal growth retardation ( P = 0.03) compared with mild pre-eclampsia.
Conclusion The observed increases in plasma concentrations of sVCAM-1 suggest that measurements of this adhesion molecule may be useful in monitoring pregnancies with respect to the development of pre-eclampsia or fetal growth retardation.