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We have studied the levels of sialo-glycoprotein in the serum of Yoshida sarcoma-bearing rats, with the aim of exploring its possible value as a tumour marker and the influence upon it of non-neoplastic factors.
The distribution of (3)H-chlorambucil following its administration by subcutaneous injection to Yoshida ascites tumour-bearing rats has been examined, in an attempt to elucidate the metabolic fate and mode of action of this drug.Drug uptake into the body tissue was rapid, with a high level of radioactivity being associated with the plasma and ascitic fluid during the initial 6-hour period after treatment. Previous studies in vitro had shown that chlorambucil-resistant cells accumulated less drug than their sensitive counterparts: this discrepancy was also observed after in vivo drug treatment and was reflected in the two-fold difference in extent of binding of tritium to DNA, RNA and protein isolated from the 2 cell strains. These results might in part explain the observed difference in metabolism of chlorambucil by the resistant and sensitive strain of Yoshida ascites sarcoma cells.
Changes in the leucocytes, lymphocytes and peripheral blood lymphocyte nucleoli of Yoshida ascitic sarcoma bearing rats untreated and treated with cyclophosphamide were studied. In the course of the growth of Yoshida ascitic sarcoma lymphocytes with "active" nucleoli (compact nucleoli and nucleoli with nucleolonemas) first increased and then, in the terminal stage of the disease, decreased in number. The number of lymphocytes with ring-shaped nucleoli ("reversibly inactive") and micronucleoli was rising throughout the disease. The increase in numbers of micronucleoli in the lymphocytes produced increased values of nucleolar coefficient. After administration of cyclophosphamide to rats with transplanted tumour the number of lymphocytes with both "active" and "reversibly inactive" nucleoli decreased and the number of lymphocytes with micronucleoli increased. The increase in the proportion of micronucleoli also led to increased values of nucleolar coefficient. After cessation of cyclophosphamide treatment and when the signs of the neoplastic disease had disappeared, the changes observed in the white blood cell picture returned to the values before sarcoma transplantation.
Erythrocytes from the circulation of rats bearing Yoshida ascites sarcoma exhibit higher concanavalin A (ConA)-mediated agglutinability than those from normal animals. A tetrameric glycoprotein of subunit molecular mass 170 kDa, purified from the cell-free ascites fluid, was found to confer higher ConA-mediated agglutinability on erythrocytes in vitro. An antiserum to this tumour-derived protein failed to detect any cross-reactive component in normal rat plasma or in any of the normal tissues examined. An immunoreactive protein was, however, detected in blood plasma when the acute-phase reaction was stimulated by injection of turpentine. The cross-reactive acute-phase protein was purified by ConA-affinity, gel-filtration and ion-exchange chromatography, and identified as alpha2-macroglobulin. The acute-phase protein and the protein obtained from the ascites fluid have identical or very similar native and subunit molecular masses, subunit arrangement and pI. They both are able to inhibit trypsin and, as a consequence, acquire greater mobility in native PAGE. In addition, the two proteins bind to rat erythrocytes non-specifically, and in similar amounts. However, despite these similarities, the acute-phase protein is unable to enhance the agglutinability of erythrocytes. The two proteins differ in their carbohydrate content, but this differential glycosylation is not the cause of the difference in their surface modification activity. The chemically deglycosylated proteins show a small but consistent difference in the size of their polypeptides. Their tryptic peptide maps, although largely similar, show some differences, as do their amino acid compositions. It is probable that the proteins are independent members of the same (alpha-macroglobulin) family. The rat embryo is also found to express a soluble protein consisting of a 170 kDa polypeptide that cross-reacts with the antibody to the tumour-derived protein. The purified embryo protein is able to alter the ConA-mediated agglutinability of erythrocytes in vitro, and also yields a tryptic peptide map that is identical to that of the tumour-derived protein. The modification of the host cell surface in the tumour-bearing rats is thus caused by what appears to be a tumour (oncofetal?) variant of alpha2-macroglobulin.
Spontaneous mammary tumours of the rat with various degrees of malignancy exhibit similar tissue pH distributions. The mean pH (+/- s.d.) of dysplasia is 7.05 +/- 0.20. In benign tumours the mean pH is 6.95 +/- 0.19 and in malignant tumours it is 6.94 +/- 0.19. In contrast, tumours with the same degree of malignancy but different histologies show different pH distributions. Benign tumours with a higher percentage of fibrous tissue exhibit less acidic pH values than those with larger portions of epithelial cells (delta pH = 0.38 pH units). The pH distribution in the benign tumours is independent of the tumour wet weight up to stages of very advanced growth. In the malignant tumours, a trend towards more acidic pH values is observed as the tumour mass enlarges. However, in tissue areas within a malignant tumour with gross, long-established necrosis the pH distribution is shifted towards more alkaline pH values. The pH distributions in spontaneous rat tumours are not significantly different from those obtained in isotransplanted Yoshida sarcomas (6.87 +/- 0.21). In the Yoshida sarcomas, mean pH values do not correlate with tumour size. However, a pH gradient from the rim to the centre of the tumours is found which coincides with the development of small, disseminated necroses in the tumour centre. It is concluded that pathology-related variations of tumour pH may be more important than the mode of tumour origin or the degree of malignancy.
The plasminogen activator was purified to the extent of 150-fold from 20,000 x g supernatant of Yoshida ascites Sarcoma by ammonium sulphate precipitation at 33% saturation followed by affinity chromatography on p-aminobenzamidine-Sepharose 4B. The specific activity of the purified activator was 10,260 IU/mg expressed in terms of International units of urokinase, the known activator of plasminogen. The activator was homogeneous by polyacrylamide slab gel electrophoresis with an apparent molecular weight 75 kDa by gel filtration on Sephadex G-100. Analysis by SDS-polyacrylamide gel electrophoresis under reducing conditions, revealed the presence of two subunits of about 48 and 29 kDa. The activator displayed binding preference to fibrin and was immunologically distinguishable from urokinase, indicating that it could be of non-urokinase origin. The preparation further revealed similarity to standard tissue plasminogen activator with respect to fibrin binding and immunological cross reactivity.
Prostaglandin E1 (2.5 mug/ml) enhanced the level of cyclic adenosine 3':5'-monophosphate (cyclic AMP) three to four times in Yoshida ascites sarcoma (YS) cells cultured in vitro. When Ricinus communis toxin (RC-toxin) was added 30 min after the addition of prostaglandin E1, the enhanced level of cyclic AMP in the YS cells decreased rapidly. Of RC-toxin, 0.2 mug/ml was enough to produce the maximum effect. By addition of 5 mM lactose with RC-toxin, approximately 60% of the RC-toxin effect on the levels of cyclic AMP was abolished. This indicates that the specific binding of RC-toxin on the surface membrane is largely responsible for the observed decrease of the cyclic AMP level. The toxin treatment did not induce either leakage of cyclic AMP from the cell or change in the activity of cyclic AMP phosphodiesterase. However, the treatment of YS cells with RC-toxin caused a decrease of adenylate cyclase activity when the activity was measured at a substrate concentration of 0.15 mM ATP. In contrast, there was little difference with the control when the activity was assayed at a higher ATP concentration, 0.24 mM. It was found that the K-m of adenylate cyclase for ATP was changed by RC-toxin from 0.1 to 0.25 mM, and that the Mg2+ activation of the enzyme observable in untreated cells disappeared. These results suggested that the decrease in the level of cyclic AMP in YS cells induced by RC-toxin can be explained in terms of the change in K-m of the adenylate cyclase activity.
A purified antitumor protein from the proteinaceous crystal of Bacillus thuringiensis subsp. thuringiensis inhibits the growth of Yoshida ascites sarcoma both in vivo and in vitro. Exogenous respiration of the tumor cells was unaffected by the protein at a concentration as high as 500 mug/ml. The antitumor protein inhibits the uptake and incorporation of labeled precursors into macromolecules. However, the ratio of incorporation over uptake is not affected by the protein. Further, the protein brings about the leakage of 260-nm-absorbing material, proteins, and (32)P-labeled cellular constituents from the Yoshida ascites sarcoma cells. The results show that the action of the antitumor protein appears to alter the cellular permeability of the tumor cells.
As a model for the development of paraneoplastic syndromes, we have studied the mechanism by which erythrocytes in the circulation of rats bearing intraperitoneal Yoshida ascites sarcoma acquire higher agglutinability with concanavalin A (Con A). The in vitro incubation of erythrocytes from normal animals with the cell-free ascites fluid or the plasma of tumour-bearing animals is able to confer an enhanced agglutinability on the cells. Fractionation of the ascites fluid has yielded three subfractions that are active in vitro. Two of these, occurring in small amounts, are a particulate fraction rich in plasma-membrane markers and a soluble fraction containing protein of molecular mass equal to or less than 50 kDa. These two are, however, unable to affect the agglutinability of erythrocytes in vivo, i.e. when injected intraperitoneally into normal rats. The third, and major, fraction consists of proteins of molecular mass equal to or greater than 680 kDa, and is able to modify the erythrocyte agglutinability in vivo. From this fraction, by using a combination of Con A affinity chromatography, gel filtration, (NH4)2SO4 fractionation and DEAE-Sephadex chromatography, an active protein has been purified to apparent homogeneity. It yields a subunit of 310 kDa in the presence of SDS and further breaks down into a polypeptide of 170 kDa when reduced with 2-mercaptoethanol. It has a pI of 5.35. The protein is rich in Glx, and appears to contain hybrid-type N-linked oligosaccharides. The protein is also present in the blood plasma of tumour-bearing, but not normal, rats. The radioiodinated protein binds to the erythrocyte surface adding about 7400 molecules/cell. The study unequivocally demonstrates that a protein from the tumour fluid can appear in the circulation, interact with host cells that are not in contact with the tumour and modify their properties.
AIM: To clarify the effects of the activities of hepatic enzymes in liver, hepatoma, and malignant tumor on 67Ga accumulation in lysosome. METHODS: 67Ga-citrate solution was prepared from carrier-free 67Ga-citrate solution 0.08 mol.L-1 and sodium citrate solution 0.08 mol.L-1, and was injected iv 0.4 ml to the rats. Subcellular fractions of the liver were measured for radioactivity of 67Ga by a well-type scintillation counter (Aloka JDC-701). Glutamate dehydrogenase, choline oxidase, and G-6-P activities were calculated as described by Shimizu H, Ikuta S, and Baginski E, respectivily. RESULTS: 67Ga radioactivity in normal liver lysosome (55%) was significantly higher than those in hepatoma AH 109A (32%) and Yoshida sarcoma (18%). Glutamate dehydrogenase activities were 1830 +/- s 320 U.L-1 in normal liver while 23 +/- s 6 U.L-1 in hepatoma AH 109A, and 7 +/- s 2 U.L-1 in Yoshida sarcoma. Choline oxidase activities were 46 +/- s 10 U.L-1 for normal, 25.0 +/- s 0.4 U.L-1 for hepatoma AH 109A, and 2.0 +/- s 0.4 U.L-1 for Yoshida sarcoma. G-6-P activities were 2550 +/- s 180 U.L-1 in normal, 84 +/- s 14 U.L-1 in hepatoma AH 109A, and 78 +/- s 13 U.L-1 in Yoshida sarcoma. CONCLUSION: Lysosome of normal rat liver in which hepatic enzymes work actively played a major role in the tissue concentration of 67Ga, but the role diminishes with the neoplastic transformation into hepatoma. The lysosome of Yoshida sarcoma does not play any role in 67Ga accumulation because it does not possess any features of liver.
The continuous administration of physiological doses of the branched-chain amino acids leucine, isoleucine, and valine (Leu-Ile-Val) to Yoshida sarcoma-bearing rats caused a significant increase in the survival time by 32% and a significant reduction of tumor size after 3 weeks of growth by 33%. The shift of the nitrogen balance to negative values during the cachectic stage was delayed but not prevented. On the average, less nitrogen (-47 mg/day) were lost by Leu-Ile-Val treated rats compared with untreated tumor-bearing animals (-91 mg N/day). It appeared that Leu-Ile-Val increased the synthesis of carcass proteins, while it left the proteolysis rate unchanged, since the excretion of urea and creatinine was unaffected by these amino acids. The daily excretion of alpha-ketoglutarate, which is correlated with tumor size during the early stage of growth, was decreased during the first 2 weeks by Leu-Ile-Val, but remained for a longer period on a high level than in untreated tumor bearers. The results point to an improvement of the metabolic resistance against carcass protein depletion of the tumor-bearing host by the administration of branched-chain amino acids.
The etiology of anemia in cancer is not fully understood. A possible cause of the anemia of tumor-bearing animals could be a decreased activity in the enzymes of the heme-pathway. We report the enzyme activity of porphobilinogen-synthetase in the liver of Yoshida sarcoma-bearing rats. PBG-synthetase activity in the whole liver, is higher in tumor-bearing rats than in controls, although the enzyme activity by a gram of wet liver is decreased. Hence PBG-synthetase activity is not a limiting factor in the biosynthesis of heme in tumor-bearing animals.
Changes in blood glucose in response to glucagon and epinephrine administration, in rats bearing Yoshida solid sarcoma and Walker-256 carcinosarcoma have been studied, and in rats carrying Yoshida tumor which had received previously intraperitoneal glucose. The response to glucagon by tumor-bearing rats follows the control pattern but at a lower level of blood glucose. Rats which had received glucose before glucagon administration responded to this hormone as the control animals. These results indicate that glycogen metabolism in the host liver is not diturbed by the presence of the tumor.
A proton NMR analysis of an in vitro culture of cells in heavy water has been made. The relaxation times of L-strain cells 929, He-La, transformed and normal embryonic human cells, C3H mice and isolated Yoshida sarcoma tumour cells, as well as of Yoshida sarcoma tumour tissue were determined. It turned out that spin-lattice (T1) and spin-spin (T2) relaxation times are characteristic of every cell and fairly different from those of corresponding tissues, which may be used for NMR identification of cells (NMR cytology). Furthermore, it has incontestably been proved that there is an ordered water fraction of cells, which is very slowly exchanged with surrounding heavy water.
The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.
Comparing platelet adhesiveness and cancer cell stickiness under the conditions of the so-called Fibre test showed that: 1. Platelets aggregate in the first few seconds only, whereas Yoshida sarcoma cells accumulate continuously. 2. Platelets show a characteristic velocity profile. Platelet adhesiveness shows a maximum at a velocity of 7 cm/sec. Yoshida sarcoma cells adhere better at low flow velocity. 3. An experimentally induced electric current (streaming electric current) of ca. 40 mV augments platelet adhesiveness to twice the basal value, whereas Yoshida sarcoma cells remain uninfluenced by the current. These results suggest an interaction between platelets and vessel wall, whereas Yoshida sarcoma cells adhere passively.
Microspheres containing cisplatin (CDDP) embedded in poly-d,l-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS) were developed to improve treatment of malignant effusions. In vitro studies demonstrated that CDDP was released continuously for more than 4 weeks from CDDP-PPMS without initial burst. CDDP-PPMS was compared with CDDP aqueous solution (CDDP-SOL) by i.p. administration in rats for 1) tissue distribution, 2) toxicity and 3) therapeutic effects against Yoshida sarcoma. We found that the CDDP concentration in the omentum was maintained at a higher level than in the CDDP-SOL group, while the particles of CDDP-PPMS were observed in the stomata of the omentum by electron microscopy. Concentrations of CDDP in the lung, liver, kidney and blood were lower in the CDDP-PPMS group than in the CDDP-SOL group. All rats given CDDP-PPMS containing < or = 28 mg/kg were alive, whereas in the CDDP-SOL group, all rats given > or = 16 mg/kg died from side effects. The LD50 of CDDP-PPMS and CDDP-SOL were 32.8 and 14.8 mg/kg, respectively. The survival of rats with peritoneal metastasis was better in the CDDP-PPMS group than in the CDDP-SOL group.
A Yoshida sarcoma cell line (YR/cyclo) showing decreased sensitivity to metabolically activated cyclophosphamide in vitro has been shown to be cross-resistant to phosphoramide mustard, the ultimate alkylating agent formed from cyclophosphamide. Resistance to these alkylating agents has been shown to be associated with increased activity of the glutathione S-transferase group of enzymes, and with elevated levels of glutathione, the cosubstrate of the enzyme. The resistant cell line shows lower levels of cellular damage, as measured by alkaline elution following treatment with phosphoramide mustard, than the parental (YS) line. The mechanism of resistance is ascribed to increased deactivation of potentially damaging metabolites of cyclophosphamide by the glutathione S-transferase enzymes, resulting in decreased cellular damage in the resistant cell line.