Development and characterization of a clinically useful animal model of epithelial ovarian cancer in the Fischer 344 rat.

OBJECTIVE: Our purpose was to develop and characterize a spontaneously arising, nonimmunogenic experimental animal model of epithelial ovarian cancer. STUDY DESIGN: NuTu-19 is a cell line derived from a poorly differentiated adenocarcinoma formed in a female athymic mouse after subcutaneous injection of spontaneously transformed Fischer 344 rat ovarian surface epithelial cells. This cell line was injected intraperitoneally into naive, immunocompetent Fischer 344 rats to determine tumor growth and animal survival. Immunogenicity of this cell line was determined by repetitive vaccination of naive rats with either mitomycin C-treated or irradiated (5000 cGy) NuTu-19 cells, followed by intraperitoneal rechallenge with viable tumor cells. Kaplan-Meier survival analysis was used to analyze survival data. Major histocompatibility complex class I and class II and intercellular adhesion molecule-1 cell surface antigens were determined by fluorescence-activated cell sorting analysis. RESULTS: NuTu-19 cells injected intraperitoneally grew progressively as numerous serosal nodules (peritoneum, omentum, diaphragm, liver, bowel), exhibited local tissue invasion and formed malignant ascites in a manner typical for human ovarian epithelial carcinomas. Animal survival was dosage dependent where as few as 10(4) cells were fatal when introduced intraperitoneally; mean animal survival was noted to be approximately 49 days when 10(5) cells were injected intraperitoneally. Repetitive immunizations of animals with large doses (10(7)) of inactivated NuTu-19 cells did not confer immunity to the animals, which all died on subsequent challenge with viable parental tumor cells. NuTu-19 cells expressed high levels of major histocompatibility complex class I and intercellular adhesion molecule-1 cell surface antigens and very low levels of major histocompatibility complex class II antigens. CONCLUSION: This is the first report of a reliable, spontaneously arising, nonimmunogenic epithelial ovarian cancer animal model. Because this model exists in an immunocompetent animal, it will be useful for studying the biologic and immunologic features of ovarian cancer.

Development and characterization of an IL-4-secreting human ovarian carcinoma cell line.

Human ovarian carcinoma cell lines were genetically engineered to secrete the cytokine interleukin-4 (IL-4) by retroviral-mediated gene transduction. These cells were transduced with the LXSN retroviral vector containing the human IL-4 gene and the neomycin resistance selection marker. Numerous IL-4-secreting clones were isolated from different papillary serous carcinoma cell lines, including SKOV-3, UCI-101, and UCI-107, and one clone derived from UCI-107 extensively characterized. This clone, termed UCI 107E IL-4 GS, was shown to constitutively express high levels of IL-4 (i.e., 900 to 1300 pg/ml/10(5) cells/48 hr) for over 35 passages and 6 months of study. Like the parental cell line (UCI-107), UCI 107E IL-4 GS cells expressed MHC class I and Her-2/neu surface antigens but did not express detectable MHC class II, ICAM 1, CA 125, or IL-4 receptors. No increase in expression of surface proteins was noted between parental and UCI 107E IL-4 GS. The morphology of this clone did not differ from that of the parental or LXSN vector control cells; however, parental cells had a faster growth rates than transductants. UCI 107E IL-4 GS was sensitive to gamma irradiation since as little as 2500 rad killed most of the cells within 10 days of irradiation. However, after irradiation, IL-4 secretion continued until about Day 8. The potential use of these IL-4-secreting ovarian carcinoma cells as vaccines for woman with advanced ovarian cancer will be discussed.

Peripheral dopamine receptors in the antihypertensive action of dihydroergotoxine in humans.

The effect of the intravenous administration of dihydroergotoxine (6 micrograms/kg) on arterial blood pressure, heart rate, and plasma concentrations of norepinephrine and 3,4-dihydroxyphenylacetic acid (the deaminated dopamine metabolite) was studied in 20 subjects with essential hypertension (8 men and 12 women aged 32-68 years old, World Health Organization Class I-II). In supine resting subjects, dihydroergotoxine significantly decreased systolic blood pressure (from 175 +/- 5 to 156 +/- 4 mm Hg; p less than 0.001), diastolic blood pressure (from 109 +/- 4 to 95 +/- 3 mm Hg; p less than 0.001), and heart rate (from 71 +/- 2 to 63 +/- 2 beats/min; p less than 0.001) as compared with the results of placebo treatment. Moreover, dihydroergotoxine reduced plasma levels of norepinephrine (from 368 +/- 39 to 238 +/- 33 pg/ml; p less than 0.001) and 3,4-dihydroxyphenylacetic acid (from 1.57 +/- 0.21 to 1.22 +/- 0.13 ng/ml; p less than 0.01). The time course of the blood pressure decrease paralleled that of plasma norepinephrine concentration. Dihydroergotoxine did not suppress the cardiovascular and plasma norepinephrine concentration. Dihydroergotoxine did not suppress the cardiovascular and plasma norepinephrine response to standing. The effect of domperidone, a peripheral presynaptic dopamine receptor antagonist, on dihydroergotoxine response was studied in six of the 20 subjects (3 men and 3 women 48-64 years old). The intravenous administration of domperidone (0.3 mg/kg) prevented the dihydroergotoxine-induced reduction in blood pressure and heart rate and the fall in plasma norepinephrine and 3,4-dihydroxyphenylacetic acid levels. Domperidone administered alone failed to significantly modify any measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromocriptine reduces plasma noradrenaline and 3,4-dihydroxyphenylacetic acid in normal and hypotensive subjects.

The effect of a single oral dose of bromocriptine 2.5 mg was evaluated in 11 normotensive and 6 hypertensive volunteers. 150 min after drug administration, a significant decrease in plasma noradrenaline concentration from 202 to 124 pg/ml in normotensive and from 197 to 119 pg/ml in hypertensive patients was observed. Plasma 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine, fell from 1132 to 956 pg/ml in normal subjects and from 1242 to 807 pg/ml in hypertensives. No change in plasma adrenaline was found. At the same time, mean arterial pressure showed a significant decrease from 90 to 81 and from 132 to 111 mmHg in normotensive and hypertensive subjects, respectively. Bromocriptine also inhibited the increase in noradrenaline level that occurred when the subjects changed from the supine to the standing position. The inhibition was more evident in hypertensive subjects. It is suggested that the hypotensive effect of bromocriptine is mediated by the inhibition of noradrenaline release due to the stimulation of dopamine receptors on noradrenergic nerve terminals.

[Pulmonary ventilation during passive leg movements]. / La ventilazione polmonare durante il movimento passivo degli arti inferiori.

Passive leg movements induced in man at a frequency of 1 Hz by an electric cycle increase pulmonary ventilation after a delay of 200-400 msec. No chemical stimuli can account for this effect since a longer delay of 1 to 5 respiratory acts (7) is required for them to drive the respiratory system. Consequently the hypothesis is made that a neural mechanism, put into action by the moving legs, provides the adequate stimuli.

[Respiration during isometric contraction of the flexor or extensor muscles of the arm in humans]. / La ventilazione durante la contrazione isometrica dei muscoli flessori o estensori del braccio nell'uomo.

An increase in the instantaneous pulmonary flow and a decrease in the respiratory frequency has been found in man as a consequence of isometric contraction of either flexor or extensor muscles of the elbow. The delay of 200 to 900msec between the onset of the muscle contraction and the beginning of the flow increment suggests that the respiratory system increases its activity due to the proprioreceptor activation. As there is no significant difference in the results obtained during flexor or extensor contraction, the contribution of the two different receptor groups appears to be the same.

[Effects of passive movement of the arm on respiration in humans]. / Effetti del movimento passivo del braccio sulla respirazione nell'uomo.

Cyclic passive movements of the right arm at 1Hz induce an increase in pulmonary ventilation in man. This results from an increase in frequency of the respiratory cycles, mainly due to a shortening of the expiratory phase, and from an increase of the instantaneous flow. The delay between the beginning of the arm movements and the onset of the increase in flow is about 450msec.

Respiratory ventilation during muscular contraction in man.

Brief contraction of arm muscles affects respiratory ventilation either by increasing respiratory frequency or by increasing the instantaneous flow. Both these changes occur at a time subsequent to muscle contraction and can be attributed to a reflex mechanism originating from the muscles.