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PubMedDate not supplied

Effect of arginine-enriched total parenteral nutrition on the host-tumor interaction in cancer-bearing rats.

By using a transplantable Yoshida sarcoma in a rat total parenteral nutrition model, we measured the effectiveness of an arginine-enriched amino acid solution (AI-82) in terms of leucine kinetics and nitrogen balance as indicators of host-tumor nutrition interaction compared with that of a conventional amino acid solution (Proteamin12). When tumor-bearing rats received isocaloric total parenteral nutrition solutions for 7 days, AI-82 significantly improved host nitrogen balance and significantly decreased the tumor-nitrogen trap throughout the experimental period. Leucine kinetics of whole body and tissues were also determined by a 4-hour continuous infusion of each total parenteral nutrition solution containing 14C-leucine. Significantly increased whole-body leucine oxidation (p < .01) without an increase in leucine release from normal tissues was observed in the AI-82 group. Total incorporation of 14C-leucine into whole muscle was significantly elevated (p < .05) without changes in muscle protein degradation in the AI-82 group. In the whole tumor, AI-82 tended to decrease total incorporation of 14C-leucine, but there was no difference in leucine release caused by protein breakdown between the two groups. These findings suggest that AI-82 can improve the nutritional status of the host over that of the tumor.

Animals↗

PubMedDate not supplied

Arginine-enriched solution induces a marked increase in muscle glutamine concentration and enhances muscle protein synthesis in tumor-bearing rats.

Using a transplantable Yoshida sarcoma in a rat model of total parenteral nutrition (TPN), we measured the effectiveness of an arginine-enriched amino acid solution (AI-82) on muscle glutamine concentration and muscle protein synthesis compared with that of a conventional amino acid solution (Proteamin12). After tumor-bearing rats had been given one of two isocaloric TPN regimens for 6 days, [15N]glycine (99 atom %) containing TPN solution was infused into animals at a constant rate of 8 mg of [15N]glycine per hour for 18 hours, after which the liver, skeletal muscle (gastrocnemius muscle), and tumor protein synthesis rates were measured. A significantly increased whole muscle protein synthesis rate was observed in the AI-82 group; there was no difference in the whole liver and tumor protein synthesis rates between the two groups. When each TPN solution was administered for 1 week, muscle concentrations of arginine, ornithine, glutamine, and glutamate were considerably higher in the AI-82 group than in the Proteamin12 group, and these differences were also accompanied by a decrease in the plasma branched-chain amino acid (BCAA) (leucine, isoleucine, and valine) levels in the AI-82 group. The high levels of muscle glutamine concentration in the AI-82 group were investigated in connection with the high use of exogenous branched-chain amino acids.

Amino Acids, Branched-Chain↗

PubMed1997

Antitumor effects and toxicities of carboxymethylpullulan-peptide-doxorubicin conjugates.

In vivo antitumor effects of the conjugates of doxorubicin (DXR) with carboxymethylpullulan (CMPul) through tetrapeptide spacers were compared with those of DXR against tumor-bearing rats. CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers were found to be more potent than DXR after a single intravenous injection in rats bearing Walker 256 carcinosarcoma. These conjugates were also more effective than DXR in rats bearing Yoshida sarcoma. However, CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly was less effective against Walker 256-bearing rats than DXR. Body weight loss of CMPul-DXR conjugates in rats, on the other hand, was less than that of DXR at a DXR dose of 10 mg/kg. Lethal doses of CMPul-DXR conjugates in CDF1 mice were about 3-times higher than that of DXR. These data suggest that the therapeutic index of CMPul-DXR conjugates bound through appropriate peptide spacers was increased more than that of DXR. However, CMPul-DXR conjugates tested were all less effective than DXR against Walker 256 cells in vitro. Also, 125I-labeled CMPul-DXR conjugate accumulated much less in the cells than 14C-DXR.

Animals↗

PubMed1984

Antitumor agent poly (amino acid) conjugates as a drug carrier in cancer chemotherapy.

Antitumor agent melphalan was conjugated through a carbodiimide-catalyzed reaction to poly (L-lysine) (71.3K and 2K) and poly (L-glutamic acid) (60K and 14K) at a ratio of approximately one molecule per 7-lysyl and 23-glutamate residues, respectively. These conjugates had 40-70% of alkylating activities by themselves in vitro as compared with free melphalan. Poly (glutamic acid) conjugates showed the antitumor activity in vivo against Yoshida sarcoma in rats. In addition, poly (glutamic acid) conjugates containing 3H-phenylalanine which was used as a model compound instead of melphalan had a sustained release property of radioactivity and the release rates could be regulated by exopeptidases. After subcutaneous injection as the first choice of routes of administration, moreover, the conjugates were found to be absorbed through the lymphatic transport system, probably due to the macromolecularity. These results suggest that the melphalan-poly (amino acid) conjugates are one of good candidates to attain the sustained release and targeting of drugs in cancer chemotherapy.

Absorption↗

PubMed1977

Studies on the properties of the immunologically effective anti-tumor substance from spleen cells of tumor-resistant rats.

The influence of physical and chemical treatments upon the immunologically effective subcellular fractions (5,000 X g supernatant and 105,000 X g sediment), which were prepared from the spleen cells of Yoshida sarcoma (YS)-resistant Donryu rats, was studied. The immunological activity of the 5,000 X g supernatant was stable to heating at 80 degrees C for 30 min. It was stable to alkali (pH 10) and less stable to acid (pH 2). It was labile to a ten-day storage at 4 degrees C, but relatively stable to a 30-day storage at -20 degrees C. When the 105,000 X g sediment was lyophilized and stored at -20 degrees C for 95 days, its immunological activity was well maintained. It was labile to 95% ethanol, 90% phenol and 2 M NaNO2, but relatively stable to 10% as well as 100% acetone, 10% phenol and 10% ethanol. It was labile to 0.1 M NaIO4 and relatively stable to 0.1 M K2Cr2O7 solution. It was labile to RNase but relatively stable to DNase.

Acetone↗

PubMed1979

Antimetastatic effect of triton WR 1339, a nonionic detergent, on rat ascites tumors.

The antimetastatic effect of Triton WR 1339 (TWR), a nonionic detergent, was evaluated in the rats bearing ascites tumor (Yoshida sarcoma or AH 66F). TWR did not inhibit the growth of primary tumor (ascites production). However, a marked inhibition of metastasis was observed in the lung and liver of rats treated with TWR. The results obtained suggest that TWR exerts antimetastatic effect before the entry of tumor cells into vascular channels. With other tests, it was found that TWR inhibits the release of tumor cells from tumor graft.

Animals↗

PubMed1980

UDP-N-acetylglucosamine 2'-epimerase of rat hepatoma and its comparison with the enzyme of rat liver.

UDP-N-acetylglucosamine 2'-epimerase was partially purified from Yoshida sarcoma, a strain of rat ascites hepatoma, by (NH4)2SO4 precipitation followed by TEAE-cellulose chromatography. The purified enzyme was inhibited by CMP-N-acetylneuraminic acid to similar extent to partially purified rat liver 2'-epimerase. Although the two enzymes were also similar in Km for UDP-N-acetylglucosamine, they were differentiated by chromatography on TEAE-cellulose, DEAE-Sephadex and hydroxyapatite, tumor enzyme being less tightly bound to these columns than liver enzyme. Similar chromatographic difference was also noted between 2'-epimerases of mouse liver and mouse Ehrlich asites carcinoma.

Animals↗

PubMed1989

A role of the cancer cell membrane fluidity in the cancer metastases: an ESR study.

AH66F or Yoshida sarcoma (YS) cells were transplanted intraperitoneally into male Donryu rats. Cancer cells obtained from ascites were suspended in saline solution (10(7) cells/ml) after washing. Then, 0.1 ml of each suspension obtained from both strains was injected into the tail vein of 5 rats, respectively. Each metastatic nodule, 1 mm or less in a diameter, thus obtained was then injected into the peritoneal cavity in which these metastatic cells come to free. After 10 days, cancer cells obtained from each ascites were suspended in phosphate buffered saline (Ca2+ and Mg2+ free, pH 7.2) after washing. Each suspension (10(7) cells/ml) was violently vibrated with a definite amount of 5-doxyl stearic acid and spin labeling of cancer cell membrane was done. Furthermore, each specimen thus obtained was subjected to the electron spin resonance (ESR) measurement and the order parameter was determined from the spectra. In both YS and AH66F strains, the cell membrane fluidity of the metastatic cancer cell was increased at each temperature measured from 5 degrees C through 35 degrees C. The results obtained here suggest that the change of the cell membrane fluidity of cancer cell is closely related with the cancer metastases.

Animals↗

PubMedDate not supplied

Enhanced cytotoxicity in combination of low dose-rate irradiation with hyperthermia in vitro.

We have pursued an in vitro investigation using a rodent cell line to characterize the interaction of simultaneous low dose-rate irradiation (LDRI) and hyperthermia and to determine the role of LDRI in the development of thermotolerance in a fractionated hyperthermia schedule. Yoshida sarcoma cells growing in vitro were used in this study. Cell survivals were estimated by the Courteney soft agar clonogenic assay. A treatment device for LDRI treatment, which held eight 137Cs sources and agar plus containing the cells, gave an irradiation dose of 51.8 cGy/h to the cells. In the experiment of simultaneous LDRI and hyperthermia, the LDRI cytotoxicities were enhanced by hyperthermia over a non-lethal temperature range. High synergistic effects were observed in a lower temperature range (40, 41 and 41.5 degrees C) in contrast to higher temperature (42, 43 and 44 degrees C). In the experiment of alternate LDRI and hyperthermia, thermotolerance induced by initial heating was well developed during the LDR exposure but less expressed in comparison with the cells which had no LDRI exposure. The treatment of LDRI for 8 h may have affected the thermotolerance development in our experimental condition.

Animals↗

PubMed1976

[Affinity of the elements in group VI of the periodic table to tumors and organs].

In order to investigate the tumor affinity radioisotopes, chromium (51Cr), molybdenum (99Mo), tungsten (181W), selenium (75Se) and tellurium (127mTe)--the elements of group VI in the periodic table--were examined, using the rats which were subcutaneously transplanted with Yoshida sarcoma. Seven preprarations, sodium chromate (Na251CrO4), chromium chloride (51CrCl3), normal ammonium molybdate ((NH4)299MoO7), sodium tungstate (Na2181WO4), sodium selenate (Na275SeO4), sodium selenite (Na275SeO3) and tellurous acid (H2127mTeO3) were injected intravenously to each group of tumor bearing rats. These rats were sacrificed at various periods after injection of each preparation: 3 hours, 24 hours and 48 hours in all preparations. The radioactivities of the tumor, blood, muscle, liver, kidney and spleen were measured by a well-type scintillation counter, and retention values (in every tissue including the tumor) were calculated in percent of administered dose per g-tissue weight. All of seven preparations did not have any affinity for malignant tumor. Na251CrO4 and H2127mTeO3 had some affinity for the kidneys, and Na275SeO3 had some affinity for the liver. Na2181WO4 and (NH4)299MoO4 disappeared very rapidly from the blood and soft tissue, and about seventy-five percent of radioactivity was excreted in urine within first 3 hours.

Animals↗

PubMed1977

[Relation between location of elements in periodic table and affinity for the malignant tumor (author's transl)].

Affinity of many inorganic compounds for the malignant tumor was examined, using the rats which were subcutaneously transplanted with Yoshida sarcoma. And the relations between the uptake rate into the malignant tumor and in vitro binding power to the protein were investigated in these compounds. In these experiments, the bipositive ions and anions had not affinity for the tumor tissue with a few exceptions. On the other hand, Hg, Au and Bi, which have strong binding power to the protein, showed high uptake rate into the malignant tumor. As Hg++, Au+ and Bi+++ are soft acids according to classification of Lewis acids, it was thought that these elements would bind strongly to soft base (R-SH, R-S-) present in the tumor tissue. In many hard acids (according to classification of Lewis acids), the uptake rate into the tumor was shown as a function of ionic potentials (valency/ionic radii) of the metal ions. It is presumed that the chemical bond of these hard acids in the tumor tissue is ionic bond to hard base (R-COO-, R-PO3(2-), R-SO3-, R-NH2).

Animals↗

PubMed1977

[Study of distribution of 169Yb, 69Ga and 111In in tumor tissues by macroautoradiography; comparison between viable and necrotic tumor tissues].

The localization of 169Yb, 67Ga and 111In in tumor tissues was determined macroautoradiographically. 169Yb-citrate and 111In-citrate were injected intravenously to the rats subcutaneously transplanted Yoshida sarcoma and were injected intraperitoneally to the mice subcutaneously transplanted Ehrlich tumor. These animals were sacrificed 3, 24 and 48 hours after injection. These tumor tissues were frozen in n-hexane (-70 degrees C) cooled with dry ice-acetone. After this, these frozen tumor tissues were cut into serial thin sections (10 micron) in the cryostat (-20 degrees C). One of the slice of these sections was then placed on X-ray film and this film was developed after exposure of several days. On the other hand, next slice of these sections were then stained using the hematoxylin and eosin. From the observations of these autoradiogram and H-E stained slice, the following results were obtained. Concentration of 169Yb, 67Ga and 111In was predominant in viable tumor tissue rather than in necrotic tumor tissue, regardless of time after the administration. 67Ga and 111In were distributed uniformly in viable tumor tissue, but deposition of 169Yb was observed more avidly in viabl tumor tissue neighboring to necrotic tumor.

Animals↗

PubMed1976

Cell population size dependency of therapeutic effect of divided dosage of 1-beta-D-arabinofuranosylcytosine.

A total dose of 960 mg/kg body weight of 1-beta-D-arabinofuranosylcytosine (cytosine arabinoside) was given intraperitoneally to rats bearing Yoshida sarcoma, in a single or divided doses. Single-dose therapy gave an increased life span of about 1 day irrespective of cell population size in accord with the concept of constant percentage cell kill. Tumor cell reduction was estimated to be about 70%. Divded-dose therapy, however, brought about increased life span which was reciprocally proportional to the logarithm of population size. Estimated cell reduction was 87% when population size was 10(8) cells and 99.95% at 10(4) cells.

Animals↗

PubMed1976

Predication of the effect of carcinostatic agents on tumor-bearing host by the sensitivity test using acid phosphatase activity in vitro.

For the purpose of predicting the effect of carcinostatic agents on tumor-bearing host in vitro, a sensitivity test of a drug in tumor bearers was developed. This test is based on the change in the specific activity of acid phosphatase of individual tumor and liver tissue, and the difference in them was used as an indicator of effectiveness. The value was called the "effective value." The present papar is concerned with the relationship between the effective value and effectiveness of the agents in rodents and man. The results showed that the effective value became higher with increasing concentration of Mitomycin-C incubated with tumor and liver tissues. The survival time of Ehrlich carcinoma-bearing mice, which were given Mitomycin-C intraperitoneally, was longer and increase in the dose of Mitomycin-C. In ascitic or subcutaneous form of Ehrlich carcinoma, AH-130, and Yoshida sarcoma, the effective value was parallel with the survival time of or the inhibition of tumor growth in tumor-bearing animals treated with Mitomycin-C. In 25 patients with gastric carcinoma treated with Mitomycin-C, the postoperative survival time was more closely correlated with the effective value calculated by the titers of both tumor and liver than the value of tumor alone.

Acid Phosphatase↗

PubMed1976

Bioassay of blood-born tumour cells on in vivo and in vitro systems.

Viability and biological integrity of tumour cells circulating in the blood were studied in an experimental system using bioassay methods. Results of subcutaneous and intravenous retransplantation as well as explantation of the blood obtained from tumour-bearing animals previously receiving intravenous inoculation of tumour cell suspension (Yoshida sarcoma, Walker 256 carcinosarcoma and DMBA-induced myeloid ascitic leukaemia), revealed that the tumour cells detected in the blood are not only viable at the time of their transportation in the blood-stream but are also in possession of biologic potentials to proliferate and establish metastatic growths in organs.

Animals↗

PubMed1976

The reaction of Cytembena with cellular thiol compounds.

Cytembena has been shown to undergo a rapid addition reaction with a number of thiol compounds, including glutathione and cysteine, resulting in alkylation of the sulphur. Administration of Cytembena to Yoshida sarcoma cells and to L1210 leukemia cells resulted in a loss of titratable thiol groups within the cells, though the loss of thiol groups caused by pharmacologically active doses of the drug was not sufficient to account, in itself, for the observed toxicity. The addition product of Cytembena and glutathione was isolated and tested for cytotoxicity; it was much less effective than free Cytembena. It is concluded that this reaction acts as a route of detoxification of Cytembena.

Acrylates↗

PubMedDate not supplied

Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) as an oxygen radicals scavenger and apoptosis inducer in vivo.

A stable nitroxide radical named Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) was synthesized and its antioxidant and antitumor properties were investigated and compared with these of another nitroxide derivatives previously designed in our laboratories. Three experimental models were used: xanthine/xanthine oxidase system, pulse radiolysis and experimental rat cancer (Yoshida Sarcoma) in vivo. In this work we measured the rate constant of the reactions of Metexyl with enzymatically generated O2.- or radiolytically produced .OH. For comparison, the reactions of non radical derivative (4-acetamide-2,2,6,6-tetramethylpiperidinium acetate) or nitroxide Tempace (4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl) with the above mentioned reactive oxygen radicals were also studied. The comparative ability of Metexyl to act as an inducer of apoptosis in vivo was also investigated in pharmacological test. The ring substituent (-OCH3) at position 4 of the Metexyl molecule had significant influence on its properties as antioxidant and apoptosis inducer. The results in this study suggest that Metexyl is a promising nitroxide antioxidant, which can induce apoptosis of tumor cells in vivo, thus providing a base for its further investigations in vitro and pharmacological applications.

Animals↗

PubMed1999

Inhibitory effect of combined administration with CPT-11 and 5-fluorouracil in vitro and in vivo.

Combined antitumor activity of CPT-11 and 5-fluorouracil (5-FU) was evaluated in a human cultured cell line derived from lung cancer. After 24 h culture with SN-38 followed by 5-FU 24 h, synergistic effect was observed in the cell line. In addition, the antitumor effect of this combination was studied in in vivo experiments using Donryu rat with Yoshida sarcoma cells. CPT-11 and 5-FU synergistically inhibited tumor growth. There was no significant increase of toxicity as assessed by the body weights. These results might support for the combination with 5-FU and CPT-11 in a chemotherapy for cancer.

Animals↗