Mode of antitumor action of recombinant human tumor necrosis factor on the sarcoma Meth A transplanted in the mouse

The mode of antitumor action of rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation with respect to time course, dose-response relationships and selectivity of the effects. The maximal cytotoxic effect on tumor cells revealed by inhibition of DNA synthesis and maximal lesional effect on tumor vasculature revealed by change in blood pool-size in the tissue were detected at 30 min and I h after administration of rHu-TNF, respectively. The dose-response relationship between cytotoxic and tumoricidal effects of rHu-TNF was irrespective of administration route. ED₅₀s of these antitumor effects afteri.v. administration of rHu-TNF were about 50 times as high as ED₅₀s afteri.t. administration. ED₅₀ ofi.t. given rHu-TNF for vascular effect was about 20 times as high as that for cytotoxicity while ED₅₀ ofi.v. rHu-TNF for vascular effect was only 2–3 times as high as that for cytotoxicity. The whole body autoradiographies with [¹²⁵I] HSA giveni.v. to see the blood influx into tumor tissue and [¹⁴C]thymidine given i.v. to see DNA synthesis in the whole body after administration of rHu-TNF revealed that the distribution of radioactivity was markedly changed in the tumor alone without any detectable change in other whole body tissues.In conclusion, thein vivo antitumor effect of rHu-TNF giveni.t. ori.v., appears to be exerted through the direct action on Meth A sarcoma rather than indirectly on tumor vasculature. Under present conditions, the effect of rHu-TNF in the whole body tissues seems rather selective on cells and vasculature of the tumor.     

Immunocytochemical detection of estrogen receptors in a hormone-unresponsive mammary tumor

Summary A combination of two monoclonal antibodies and high resolution immunocytochemical technique was applied to label estrogen receptors in spontaneous mouse mammary tumors. Protein A-colloidal gold complex was used as an electron opaque marker. With this procedure estrogen receptors were labelled in the nuclei of cancer cells, predominantly over heterochromatin. In the cytoplasm a slight tagging of the rough endoplasmic reticulum was detected, apparently related with the sites of receptor biosynthesis. Other organelles and the mammary tumor viruses (MuMTV) were not stained immunocytochemically.The immunocytochemical procedure applied in this investigation allowed the detection of low levels of estrogen receptors in an estrogen-unresponsive mammary carcinoma. The presence of estrogen receptors with a specific distribution in estrogen-independent tumors suggests the need of a reevaluation of their capacity as indicators of hormone-dependence in mammary carcinomas.     

Acute effects of unsaturated fatty acids in splanchnic artery occlusion shock

Diets enriched with omega-3 unsaturated fatty acids are associated with decreased hypercholesterolemia and decreased risk of ischemic and atherosclerotic diseases. We studied the acute intravascular effects of some of these unsaturated fatty acids (i.e., eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) along with omega-6 unsaturated fatty acids, (i.e., linoleic and linolenic acid) in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes followed by reperfusion usually resulted in a fatal outcome 90-120 minutes after releasing the clamps. SAO shock rats treated with the omega-3 unsaturated fatty acid, EPA, exhibited an improved survival time and rate (p less than 0.05 from vehicle) compared to those receiving only vehicle (i.e., 50% ethanol). EPA and DHA treated SAO rats also exhibited lower plasma activities of the lysosomal protease, cathepsin D, free amino-nitrogen compounds, and the cardiotoxic peptide, myocardial depressant factor. These results indicate that omega-3 unsaturated fatty acids, especially EPA, have some acute beneficial effects in SAO shock in rats.     

Praziquantel-induced secretion of proteolytic enzyme from Schistosoma mansoni cercariae

The effect of praziquantel (PZQ) on secretion of proteolytic enzyme by Schistosoma mansoni cercariae was examined using an azocoll assay. The cercariae secreted proteolytic enzyme in various concentrations of PZQ (0.1, 1, and 10 micrograms/ml), but secretion of enzyme was highest at the lowest concentration. PZQ-induced secretion of proteolytic enzyme was partially inhibited by treatment with verapamil and ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetra-acetic acid but not by calmodulin antagonist W-7 and protein kinase C inhibitor H-7.     

Close linkage of MEN2A with RBP3 locus in Japanese kindreds

Summary The gene responsible for multiple endocrine neoplasia type 2A (MEN2A) has recently been assigned to the pericentromeric region of chromsome 10 in European Caucasian kindreds by linkage analysis using a DNA marker, interstitial retinol-binding protein 3 (RBP3). We have found tight linkage between the MEN2A and RBP3 loci in Japanese MEN2A kindreds. The maximum lod score is 5.19 at a recombination fraction of 0.00. This result suggests that mutation of a certain gene close to RBP3 is responsible for MEN2A irrespective of ethnic backgrounds.     

Intravesical treatment of bladder cancer with recombinant human interferon-β

Summary In order to examine its clinical efficacy, recombinant human interferon- (rIFN-) was instilled intravesically into 51 patients with superficial bladder cancer. Ten patients, who received intermittent intravesical instillation at a dose of (3–36) × 10⁶ U rIFN- on days 1–3 every week, showed no response. Thirty-two patients received intravesical instillation at a dose of (3–36) × 10⁶ U every day for 10–20 days. Eight patients showed partial response, indicating an efficacy rate of 25%. Nine patients received divided doses of 18 × 10⁶ U twice a day every day for 10–20 days. Six patients showed partial response, indicating an efficacy rate of 67%. This value was significantly higher than that obtained by administering divided doses. The response to intravesical instillation therapy with rIFN- varies with treatment protocol. Frequent and longer exposure to rIFN- may induce better regression of superficial bladder cancer. Six incidences of side-effects were found in five cases (9.8%): pollakiuria in one, pain on micturition in two, fever in two, and eruption in one case. All of these side-effects were slight and reversible after drug withdrawal. Laboratory tests showed only a few changes with low severity. Thus, rIFN- is potentially a new drug for instillation therapy of superficial bladder cancer, in view of the absence of adverse effects.     

Factors contributing to cerebral hypomyelination in the growth hormone-deficientlittle mouse

We attempted to delineate the events leading to hypomyelination in the brain of thelittle mouse, a promising murine model of isolated growth hormone deficiency. At 20 days of age, the mutant mouse brain weighed less than its normal counterpart, and this difference in brain weight persisted. Increase in CNPase activity was found to be suppressed in the cerebrum throughout the developmental stage, but not in the other parts of the brain. Differences in cerebral DNA content between thelittle and normal mice first became apparent on the 10th day of age. Thereafter, the rate of increase in thelittle brain consistently lagged behind the normal. [³H]Thymidine incorporation into the DNA fraction in vivo on the 7th day of age, when glial cell proliferation in the normal cerebrum is most active, was approximately half that of the controls in all parts of thelittle brain. These findings indicate that the hypomyelination of the mutant cerebrum might result from reduced oligodendroglial proliferation due to growth hormone deficiency.