Woodchuck hepatocellular carcinoma has been successfully transplanted into nude (athymic) mice. The morphology of heterotransplanted tumor is similar to that of naturally occurring hepatocellular carcinoma before transplantation. The growth rate of transplanted tumor was very slow compared with those of other transplanted tumors. During the first month, only two tumors appeared. However, definitive tumor growth was noted in 6 of 20 nude mice about 3 months later. Seventeen of 20 nude mice exhibited sustained tumor growth after 6 months. The woodchuck hepatocellular carcinoma in nude mice provides an in vivo model for the study of oncogenesis of human hepatocellular carcinoma related to hepatitis B virus.

Animals↗

PubMedDate not supplied

Establishment of a cell line from a woodchuck hepatocellular carcinoma.

A new cell line derived from a woodchuck hepatocellular carcinoma serially transplanted in athymic nude mice has been established and named WH257GE10. The original tumor in the nude mouse system produces woodchuck hepatitis surface antigen and albumin. In addition, woodchuck hepatitis virus DNA is integrated into cellular DNA. Adaptation of the cells to the in vitro culture condition was completed after 15 months with the doubling time of 40 hr. The morphologic features of the cell by light microscopy are of an epithelial type. The modal chromosome number is 36 and the karyotype is mainly metacentric, similar to that observed in normal woodchuck liver cells. Ornithine and tyrosine aminotransferase activities were detected. Production of albumin was demonstrated in the cytoplasm by indirect immunofluorescence. Integration of woodchuck hepatitis virus DNA was shown by Southern blot analysis, although the secretion of woodchuck hepatitis surface antigen was not detected. This cell line provides an excellent in vitro model to study human hepatocellular carcinoma related to hepatitis B virus.

Albumins↗

PubMedDate not supplied

Efficacy of long-term treatment with nipradilol, a nitroester-containing beta-blocker, in patients with mild-to-moderate essential hypertension.

The effects of long-term treatment with nipradilol, a nitroester-containing beta-blocker, on casual and 24-hour blood pressures were studied in 70 patients with mild-to-moderate essential hypertension. Antihypertensive effects of nipradilol on casual blood pressure were observed in 68% of patients. Nipradilol reduced pulse rates, but no bradycardia was observed. The usefulness of nipradilol in the present study was 65%. The results of ambulatory blood pressure monitoring indicated that nipradilol reduced systolic blood pressure more than diastolic blood pressure, and reduced blood pressure during waking more than during sleep. These results suggest that nipradilol is a safe and useful long-term antihypertensive drug in both young and older patients with mild-to-moderate essential hypertension. When administered twice daily, nipradilol is effective throughout a 24-hour period.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Mechanisms of insulin-induced relaxation of the canine proximal stomach after proximal gastric vagotomy.

The aim of this study was to determine whether insulin-induced relaxation of the proximal stomach after proximal gastric vagotomy is mediated by vagal release of antral gastrin. In six conscious, fasted dogs following proximal gastric vagotomy, the effects of intravenous insulin (1 U/kg) and intravenous gastrin (1 microg/kg) on proximal gastric motility, as measured by a gastric barostat, on plasma glucose, and on plasma gastrin, as measured by radioimmunoassay, were assessed 1 hour before and for 2 hours after injection. The effects of a cholecystokinin (CCK)-A receptor antagonist and a CCK-B receptor antagonist on insulin-induced or gastrin-induced relaxation of the proximal stomach and on plasma glucose and gastrin were also determined. Intravenous insulin decreased plasma glucose (before [mean +/- SD], 97 +/- 5 mg/dl vs. after, 45 +/- 3 mg/dl; P <0.05), increased plasma gastrin (before, 240 +/- 59 pg/ml vs. peak after, 387 +/- 85 pg/ml; P <0.05), and relaxed the proximal stomach (100% +/- 0% barostat volume vs. 202% +/- 15% volume; P <0.05). Exogenously administered gastrin also relaxed the proximal stomach without decreasing plasma glucose. CCK-B blockade diminished, but did not abolish, the gastric relaxation caused by insulin or gastrin, whereas CCK-A blockade had little effect. It was concluded that insulin-induced relaxation of the proximal stomach after proximal gastric vagotomy is mediated, in part, by vagal release of antral gastrin.

Animals↗

PubMedDate not supplied

Colony-forming ability in vitro and clonology of colorectal cancer.

One hundred and twenty-three specimens (83 primary and 40 metastatic) of colorectal cancers from 102 patients were subjected to the human tumor clonogenic assay (HTCA) to determine the clonogenicities of tumor specimens stratified by the degree of histological differentiation and of tumor progression. No statistically significant differences in the clonogenicity were observed among the tumors with different histological differentiation. Viable malignant cells were abundant in the primary tumor specimens with submucosal (sm) and muscular layer (pm) invasion, and decreased significantly in number per gram of wet specimen as the tumors progressed (P less than 0.05). Clonogenicity was also higher in "sm" and "pm" primary tumor specimens, and decreased as the tumors advanced (P less than 0.05). These findings suggest that, at the onset or in the relatively early phase of the tumor progression, tumors are medullary and have a large fraction of clonogenic cells, and that they then develop more stroma while losing the clonogenic cell fraction by tumor progression. HTCA appears to be still valuable for analysis of the changes in biological properties over time in large bowel tumors.

Colorectal Neoplasms↗

PubMedDate not supplied

Response characteristics of amygdaloid neurons provoked by emotionally significant environmental stimuli in cats, with special reference to response durations.

Extracellular single or multiple neuronal activities were recorded from the basolateral portion of the amygdala of wild adult cats under an unanesthetized, freely moving condition, and neuronal responsiveness to neutral, aversive, and appetitive stimuli was studied. Of 71 units, 47 (66%) responded to some of the stimuli. The patterns of neuronal responses were classified into three types on the basis of response duration. Of the responses sampled, 9% rapidly attenuated and disappeared before termination of stimulus presentation (pattern A), 58% of responses were maintained during the period of the stimulus presentation but disappeared abruptly after termination (pattern B), and 33% of responses markedly outlasted the stimulus presentation period (pattern C). Pattern A responses habituated readily and were most prominent when neutral stimuli were presented, so this type of response was considered to underlie altering or orienting responses. Pattern B responses were observed equally for the three kinds of stimuli, and were suggested to be predominantly involved in perception of the environmental stimuli. Pattern C responses habituated least and tended to be elicited more frequently by aversive stimuli. This type of response was interpreted to reflect emotional arousal. These findings were considered to be compatible with the hypothesis that the amygdala plays an important role in converting environmental stimuli into emotions such as rage or fear.

Amygdala↗

PubMedDate not supplied

Cytotoxic activity of synthetic aza alkyl lysophospholipids against drug sensitive and drug resistant human tumor cell lines.

The anti-tumor cytotoxic activity of four newly synthesized aza alkyl lysophospholipids (AALP), namely BN 52205, BN 52207, BN 52208 and BN 52211, was investigated. Using the 51Cr release assay, the four compounds were endowed with cytotoxic activity, in a concentration-dependent fashion, against various human tumor cell lines of different histological origin. Two different mechanisms appear to be involved in the AALP-mediated cytotoxicity. A rapid membrane damaging effect was observed in less than one hour's incubation of tumor cells with AALP and cytotoxicity was temperature-independent when AALP were used at greater than or equal to 200 micrograms/ml. A slower cytotoxic mechanism was observed after 18 hours incubation at 37 degrees C when AALP were used at concentrations of 30-100 micrograms/ml. The pattern and magnitube of the cytotoxic activity achieved with all the 4 AALP compounds tested were similar and the cytotoxicity mediated by combination of two compounds was additive. In addition to the cytotoxic effect, the AALP compounds also exerted a cytostatic anti-tumor effect, as assessed by inhibition of 3H TdR incorporation. Using a variety of human tumor cell lines as targets, the cytotoxic effect observed with the AALP was noted with tumor cells that were either sensitive or resistant to TNF-alpha and/or chemotherapeutic drugs such as mitomycin C, adriamycin and cis-platinum. The LD50 toxicity in mice was 100-125 mg/kg. The present findings demonstrate that AALP are cytotoxic to a variety of human tumor cell lines and do not appear to discriminate between drug/cytokine sensitive or resistant cells. Thus the present study suggests that some aza alkyl lysophospholipids may be considered as potential anticancer agents.

Drug Screening Assays, Antitumor↗

PubMedDate not supplied

Splenectomy abolishes antitumor effect of immunotherapy with streptococcal preparation, OK-432, on mouse liver tumors.

In the present study, we investigated the therapeutic effects of oral and subcutaneous administration of OK-432 prior to or following the transplantation of murine liver tumors. In addition, the effect of splenectomy on the antitumor activity of OK-432 was investigated. Mice which received OK-432 orally prior to tumor transplantation exhibited significantly lower tumor weight and significantly improved survival, when compared to the control mice. Prior subcutaneous injection of OK-432 did not show any antitumor activity. On the other hand, both oral and subcutaneous administration of OK-432, subsequent to tumor transplantation, led to a significant improvement of survival and a decrease in the number of lung metastases, although tumor weight was not affected. The anti-tumor effect of OK-432 required the presence of the spleen, since the survival of the mice with liver tumors was not improved by OK-432 if splenectomy and tumor transplantation were performed simultaneously. These results suggest that immunotherapy with OK-432 may beneficial in the treatment of liver tumors and that these effects are dependent on the presence of the spleen.

Animals↗

PubMedDate not supplied

Relationship of in vivo antitumor activities of fluorinated pyrimidines to thymidylate synthase activity and intratumoral concentrations of 5-fluorouracil and uracil.

MOPC-104E plasmacytomas were subcutaneously transplanted into BALB/c mice and after 7 days the mice were administered different fluorinated pyrimidines at 4 times the clinical doses, 5-fluorouracil (5-FU, 15 mg/kg), tegafur (FT, 100 mg/kg) or UFT (FT, 20 mg/kg + uracil, 44.8 mg/kg) daily for 7 days. Tumor growth was most effectively inhibited in the UFT group. The % inhibition of tumor growth on day 14, while not correlating with the concentration of 5-FU in the tumor, negatively correlated with the concentration of uracil, which was lowest in the UFT group. The activity of thymidylate synthase (TS) was measured using a 5-fluoro-deoxyuridine monophosphate (FdUMP) binding assay. The total and free TS activities in the tumor negatively correlated with the % inhibition of tumor growth, and were lowest in the UFT group. However, the % inhibition of TS activity in the tumor, which was about 80% in all 3 groups, did not correlate with the tumor-inhibitory effect. These results suggest that uracil in the tumor may play an important role in the metabolism of fluorinated pyrimidines, and that exogeneously administered uracil may decrease the amounts of uracil and TS in the tumor, and subsequently cause 5-FU accumulation.

Animals↗

PubMedDate not supplied

In vitro and in vivo antineoplastic activity of a new platinum antineoplastic agent, (R)-(-)-1,1-cyclobutanedicarboxylate (2-aminomethylpyrrolidine)-platinum (II) (DWA2114R) on freshly separated human tumor cells and human tumor xenografts transplanted in nude mice--a comparison with cis-diammine-dichloroplatinum (CDDP).

The in vitro antimetabolic effect of a newly synthesized platinum antineoplastic agent, DWA2114R, on 72 fresh human tumors was compared with that of cis-platinum (CDDP). DWA2114R is reported to have a lower nephrotoxicity than CDDP, but is as strong an inhibitor of DNA synthesis as CDDP. In vitro IC50 was assessed in 10 tumors; the IC50 of DWA2114R ranged between 9.2 and 107 microM (mean +/- S.D., 45.9 +/- 36.6) and that of CDDP ranged between 0.9 and 40 microM (18.3 +/- 15.1). DWA2114R had an antitumor spectrum similar to that of CDDP. Primary esophageal and pancreatic cancers were sensitive to DWA2114R, and cells separated from malignant effusion or metastatic lymph nodes were more sensitive than those from primary lesions. Nude mice were transplanted with 3 kinds of human tumor xenografts (esophageal, pancreatic and bile duct cancer lines), and were then treated with CDDP or DWA2114R at 4 times the clinical doses. CDDP significantly inhibited the growth of all the 3 lines, and DWA2114R inhibited the growth of 2 of the lines. The effect of DWA2114R on body weight was smaller than that of CDDP. These results suggest that DWA2114R may be less potent than CDDP but may be useful as a new platinum antineoplastic agent with lower grade of side effects than CDDP.

Adenocarcinoma↗

PubMedDate not supplied

In vivo inhibitory effect of a conjugate of immunoglobulin G and melphalan, K18, on human tumors transplanted in nude mice.

Various human tumor lines, including gastric, colonic, esophageal, pancreatic, lung and breast cancer, were transplanted in nude mice, and the effect of K18 (IgG conjugated melphalan) on them was assessed and compared with that of melphalan. Melphalan (1 mg/kg) or K18 (100 mg/kg) were administered to mice for 28 days. The tumor growth was significantly inhibited in 5 out of 6 tumors by both agents, although only the esophageal line was insensitive to both agents. Significant loss of body weight was observed in mice after treatment. K18 had no influence on body weight. These results suggested that K18 may be useful in cancer chemotherapy.

Animals↗

PubMedDate not supplied

Case of small hepatocellular carcinoma in the caudate lobe detected after interferon caused disappearance of hepatitis C virus.

The high prevalence of antibodies to hepatitis C virus (HCV) in patients with hepatocellular carcinoma (HCC) in Japan suggests that the virus has a close relationship to hepatocarcinogenesis (1-4). HCV causes chronic inflammation of the human liver and HCC may finally develop, by way of an unknown mechanism. Interferon (IFN), which has an antiviral effect, is widely used for treatment of chronic hepatitis C infection (5). In Japan, about 40% of such patients have been cured of the infection by IFN therapy (6). The most suitable criteria for identification of a complete response to IFN are the most rigorous: both the disappearance of HCV RNA, verified by the polymerase chain reaction (PCR), and alanine aminotransferase activity in the normal range for at least six months after the end of the therapy. In the cured patients, the liver disorder and hepatocarcinogenesis are thought to stop progressing. However, few such patients have been monitored for years following the treatment (7-8). In this article, we describe a patient with small HCC in the caudate lobe after complete response to IFN therapy for chronic hepatitis. We suggest the necessity for regular liver checks for patients from whom HCV is eliminated by IFN therapy.

Antiviral Agents↗