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PubMed1984

Nicotinamide methylation. Tissue distribution, developmental and neoplastic changes.

The distribution of cytosolic activity of nicotinamide:S-adenosylmethionine methyltransferase (nicotinamide methylase, EC 2.1.1.1) in normal tissues from adult rat and mouse and in tumors and the change in the enzyme activity during the development of rat tissues were studied. (1) Rat liver exhibited the highest nicotinamide methylase activity among all adult tissues tested; other rat tissues, like adrenal, pancreas, kidney, brain and mouse tissues, had only less than 15% of the adult rat liver activity. (2) 3 days before birth, fetal liver showed a very low nicotinamide methylase activity (2% of adult rat liver), which, however, increased already 1 day before birth and reached the adult level on the day 28 after birth. (3) In a variety of hepatomas and ascites tumors, an inverse correlation, with some exceptions, between tumor growth rate and nicotinamide methylase activity could be seen. In all hepatomas, with the exception of Morris hepatoma 5123tc, nicotinamide methylase activity was significantly decreased in comparison to normal adult rat liver. The highly malignant Zajdela hepatoma, Yoshida sarcoma, sarcoma 180 and Ehrlich ascites tumor methylated nicotinamide only at a negligibly low rate. (4) Cultured RLC cells (an established rat liver cell line) from the stationary growth phase or G1-arrested RLC cells had about half of the adult rat liver activity, yet the activity was 70% higher than that of the logarithmically growing RLC cells.

Aging↗

PubMed1989

2-Deoxy-2-[18F]fluoro-D-galactose as an in vivo tracer for imaging galactose metabolism in tumors with positron emission tomography.

The feasibility of 2-deoxy-2-[18F]fluoro-D-galactose ([ 18F]FdGal) for imaging galactose metabolism in tumors with positron emission tomography (PET), was investigated using two hepatomas, Yoshida sarcoma, or glioma in rats, and mouse mammary carcinoma. In hepatoma-bearing rats the highest uptake of [18F]FdGal was observed in the liver followed by the kidney and tumor. The tumor uptake increased with time, and the high uptake ratios of tumor to organ were observed except for the liver and kidney. Tumor uptake was also measured in all tumors. As main metabolites in all tumors, [18F]FdGal 1-phosphate and UDP-[18F]FdGal were found by HPLC. Two hepatomas showed a slightly higher uptake and a larger percentage of UDP derivative than the other three tumors. By autoradiography the brain tumor was visualized clearly. These results indicate that [18F]FdGal has potential as a tracer for imaging galactose metabolism in tumors with PET.

Animals↗

PubMed1970

Growth inhibition of tumour implants by associated surface active agents.

Whereas dilute solutions of surface active agents modify the properties of cell membranes, particularly in relation to their electrical behaviour, moderate and strong solutions provoke more serious structural damage of the membrane, leading to an increase of its permeability and, finally, to cytolysis. These phenomena have inspired some authors to apply detergents as possible cancer chemotherapeuticals so far, however, with only poor results. The disintegrating effect of tumour emboli into single cells by certain detergents, and the ingenious discovery that the mutual adhesiveness between cancer cells is much less than between normal cells, have led the present authors to investigate the action of some biological surface active agents, alone as well as in some of their associations on the "take" of Yoshida sarcoma implants. Certain associations showed, in contradistinction to the separately applied components, surprisingly favourable activity. It could be established that a correlation actually exists between inhibitory effect and surface activity.

Animals↗

PubMed1980

Criteria for the selection of second-generation platinum compounds.

Our selection of a potential second-generation platinum compound began with an initial short list of 8 compounds selected on the basis of antitumour and toxicity studies in mice. We now report further, more detailed investigations of the renal toxicity and antitumour activity of one of these compounds, cis-dichloro trans-dihydroxy bis isopropylamine platinum (IV) (CHIP), in comparison with cis-dichloro diammine platinum (II) (Neoplatin). CHIP was a more effective anti-tumour agent against both alkylating-agent sensitive and resistant strains of the Yoshida sarcoma (YSS and YSR respectively) than was Neoplatin. In addition CHIP produced negligible kidney toxicity as measured by blood urea levels. We have also compared the effects of these two drugs on nuclear-protein phosphorylation, in an attempt to gain insight into their molecular mode of action. Both Neoplatin and CHIP induced increased nuclear-protein phosphorylation in the YSS tumour cells, and loss of condensed chromatin. However, CHIP also induced increased nuclear-protein phosphorylation and loss of condensed chromatin in the YSR tumour cells. These changes correlated well with cell death. In addition Neoplatin, but not CHIP, treatment caused increased nuclear-protein phosphorylation in kidney tissues. This correlated with kidney damage as measured by blood urea levels. These selection criteria suggested that CHIP would be a more selective antitumour agent than Neoplatin, and will provide a basis for its comparison with the other 7 compounds.

Animals↗

PubMed1982

Modulation of the toxicity and antitumour activity of alkylating drugs by steroids.

The steroids prednisolone and progesterone significantly altered the therapeutic indices of the alkylating agents, nitrogen mustard, melphalan, cyclophosphamide, phenyl acetic mustard and chlorambucil. For nitrogen mustard, chlorambucil and phenyl acetic mustard, prednisolone reduced host toxicity in the rat and enhanced the antitumour effectiveness against alkylating-agent-resistant strains of the Yoshida sarcoma and Walker carcinosarcoma. Progesterone also increased the therapeutic index of chlorambucil in the rat by decreasing its systemic toxicity. Two other alkylating agents, melphalan and cyclophosphamide, exhibited lower therapeutic indices in combination with prednisolone against alkylating-agent-sensitive tumours. This was due to the greater host toxicity of the combination than of the alkylating agent alone. In alkylating-agent-resistant tumours, however, a significant increase in growth delay was achieved if prednisolone was combined with the alkylating agent.

Alkylating Agents↗

PubMed1997

Increased growth and incidence of lymph node metastases due to the angiogenesis inhibitor AGM-1470.

Using the rat tumour cell line LY80, a subline of Yoshida sarcoma, the effects of AGM-1470 on the growth of primary tumour and the incidence of regional lymph node metastasis were evaluated. AGM-1470 (30 mg kg(-1)) was administered subcutaneously or intravenously. Subcutaneous (s.c.) and intravenous (i.v.) injections were repeated for 8 days and 7 days respectively. Tumour growth of a primary region tended to be suppressed by AGM-1470. The s.c. tumours after sacrifice were much smaller in the AGM-1470-treated group (s.c. injection) than in the control groups. However, the growth of metastatic foci in the lymph nodes was prompted markedly by AGM-1470. All six of the AGM-1470-treated rats had developed swollen axillary lymph nodes and/or brachial lymph nodes on day 19 after tumour implantation (the 7th day after the last treatment) compared with one of six saline-injected rats and three of six vehicle-alone treated rats with swollen axillary lymph nodes. The weight of lymph nodes after sacrifice in the AGM-1470-treated rats was much heavier than that of the other two groups. Histological examination showed that in the AGM-1470-treated group, the cortex and the medulla of the axillary lymph nodes were almost entirely replaced by tumour cells while, in the vehicle alone group, a notable hyperplasia of the lymph nodes due to BT cell proliferation tended to be induced. In the saline group, although a slight hyperplasia of lymph nodes was observed, there were only a few lymph node metastases. In the case of i.v. injection of AGM-1470, similar results were obtained. It is thought that LY80 cells spread to regional lymph nodes at a comparatively early stage by some change or other in which AGM-1470 participated. From the present experiment, it is concluded that application of AGM-1470 alone to patients should be carried out with great caution.

Animals↗

PubMed2002

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs.

In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2x10(6)) were injected into the lateral tail vein, and AC7700 at 10 mg x kg(-1) was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

Animals↗

PubMed2003

Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis.

We previously reported that a novel combretastatin A-4 derivative, AC7700, has remarkable antitumour effects because of an irreversible stasis of tumour blood flow (TBF) and subsequent loss of nutrient supply to tumour tissue. Since early 2002, under the new designation AVE8062, AC7700 has undergone clinical trials in Europe and the US. Questions remain, however, concerning how AC7700 blocks TBF and why the TBF stasis does not recover. In this study, using a rat tumour LY80, a variant of Yoshida sarcoma, we examined whether TBF cessation after AC7700 administration is due to a direct action of the agent on tumour blood vessels. We constructed electrodes that can drop a small quantity of the drug solution directly at the site of blood flow measurement and inserted them subcutaneously and into the tumour. We compared the blood flow responses of normal vessels and tumour vessels after administration of 10-microl doses of various concentrations (0.2, 1, 10, and 50 mg ml(-1)) of the AC7700 solution. In addition, we assessed TBF stasis after i.v. and intra-arterial 10 mg x kg(-1) AC7700 administration in an LY80-induced kidney tumour. To determine why the TBF stasis is irreversible, we observed AC7700-induced changes in host arterioles and the tumour vascular network of the Sato lung carcinoma using a vital microscopic rat transparent chamber. Since an increase in tumour interstitial fluid pressure brings about a decrease in TBF, we also measured 10 mg x kg(-1) AC7700-induced changes in this pressure. The sensitivity of the blood flow response after intratumoral application of AC7700 was markedly higher in normal vessels relative to tumour vessels. Intra-arterial administration of AC7700 did not have stronger effects on TBF stasis than did i.v. administration. Intravital microscopy showed that AC7700 induced a powerful and long-lasting constriction of host arterioles, so that complete stasis of blood flow occurred in downstream vessels, which supplied blood to tumours. Owing to this stasis, the lumens of numerous tumour vessels narrowed or completely disappeared, and numerous erythrocytes stagnated in drainage vessels of the tumour vascular network. Haemolysis of these erythrocytes occurred after 2-3 h, resulting in complete thrombosis. There was no indication of reperfusion in vessels showing haemolysis. This haemolysis is thought to be the main cause for the irreversibility of TBF stasis. Since the tumour interstitial fluid pressure decreased after i.v. AC7700 administration, the possibility of stasis of TBF being caused by tumour vascular compression was excluded. All these results strongly suggest that the main target of AC7700 is host arterioles and that the stasis of TBF induced by AC7700 is not triggered by a direct action of the drug on tumour vessels.

Animals↗

PubMed2000

Day-night pattern of energy expenditure and body temperature in cachectic tumour-bearing rats.

The implication of an increase in energy expenditure in cancer cachexia, which seems to be related to the type of tumour, remains unclear. We therefore investigated the energy metabolism and body temperature in anorectic and cachectic rats bearing the Yoshida sarcoma (TB), in comparison with pair-fed (PF) and ad-libitum fed (AL) control rats. The resting energy expenditure was higher in the TB than in the two control groups when corrected for the modifications of body composition. However, the total energy expenditure did not differ between the TB and the AL, presumably because of the drop of activity in TB. There was a temporal distribution of differences in energy expenditure with higher energy expenditure in TB than in AL during the diurnal phase and a lack of difference during the nocturnal phase. The TB presented a fever, which was limited to the diurnal period. Moreover, the acrophase of the body temperature rhythm was delayed in the TB. These results highlight the circadian effects of tumour development on the energy metabolism of the host and hint to the possible implication of cytokines.

Adipose Tissue↗

PubMed1993

3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.

Alanine↗

PubMed1994

Selective increases in isoform PP1 alpha of type-1 protein phosphatase in ascites hepatoma cells.

The amounts of four isoforms of the catalytic subunit of type-1 protein phosphatases, PP1 alpha, PP1 gamma 1, PP1 gamma 2, and PP1 delta, have been determined in extracts of rat ascites hepatomas, AH131A, AH13, AH13NMOR, AH143A, and Yoshida sarcoma, and compared to those of rat liver by Western blot analysis. The amount of PP1 alpha was increased over three times in all five hepatomas. The amount of PP1 gamma 1 was increased over two times in AH13, AH13NMOR, and AH143A. The amount of PP1 delta was selectively increased about 4 times in AH131A and AH143A. The PP1 gamma 2 protein was undetectable in both liver and hepatomas. There was good parallelism between the general increase in only PP1 alpha protein in the hepatomas and the previous data demonstrating the general increase in PP1 alpha mRNA in numerous ascites hepatomas. These results suggest that PP1 alpha plays important roles in the expression of malignant phenotype, that its amount is under strict control at the transcription level, and that PP1 gamma 1 and PP1 delta play different roles in the expression of some phenotype(s) of the ascites hepatomas.

Amino Acid Sequence↗

PubMed1994

Effects of intravenous infusion of dopamine on tumor blood flow in rat subcutis.

To determine the effects of intravenous administration of dopamine hydrochloride (DA) on tumor blood flow (TBF), we measured the blood flow of normal subcutaneous tissue and subcutaneous tumor (LY-80, a variant of Yoshida sarcoma) in enflurane-anesthetized male Donryu rats using a hydrogen clearance method. Measurements were made before and during intravenous infusion of DA at a rate of 5 micrograms/kg/min, while recording the mean arterial blood pressure of the rats. Under mild hypertension induced by DA, the blood flow of normal subcutis decreased and TBF increased significantly. SCH-23390, an antagonist of the DA1 receptor, inhibited the enhancement of TBF by DA; while domperidone, an antagonist of the DA2 receptor, did not modify the effects of DA. In experimental chemotherapy against the tumor using adriamycin (ADM) 5 mg/kg i.v., only the combination of DA and ADM significantly inhibited the tumor growth. Moreover, DA reduced the weight loss caused by ADM. These results indicate that DA could have a role in increasing TBF and possibly enhance drug delivery to tumors. Moreover, it appears that the DA1 receptor contributes, at least in part, to the enhanced blood flow in rat subcutaneous tumor following DA administration.

Animals↗

PubMed1994

Oral administration of BOF-A2 to rats with lung transplanted tumors results in increased 5-fluorouracil levels.

A new tumor model was developed in which solid Yoshida sarcoma tissue injected intravenously developed into tumors in the lungs of about 30% (13/42) of the inoculated rats. Histological examination revealed that alveoli were occupied with tumor cells and the tumors were similar to those obtained by subcutaneous inoculation. Using this model, the concentrations of 5-fluorouracil (5-FU) in tumor tissue 12 h after oral administration of 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)-benzoyl]-1-ethoxy methyl- 5-fluorouracil (BOF-A2, 36 mumol/kg) or a combination of tegafur and uracil in a molar ratio 1 to 4 (UFT, 50 mumol/kg) were found to be 129.8 ng/g and 19.2 ng/g, respectively. Thus, compared to treatment with UFT, BOF-A2 resulted in higher levels of 5-FU in lung tumor tissues. Increased concentrations of 5-FU should have a superior anti-tumor effect and so BOF-A2 merits clinical trial in the treatment of patients with lung cancer.

Administration, Oral↗

PubMed1995

Stimulation of brown adipose tissue activity in tumor-bearing rats.

Despite anorexia, cancer development is frequently accompanied by an increase of energy expenditure. Considering the pivotal role played by brown adipose tissue (BAT) in the energy metabolism of small mammals, we investigated the functional and compositional modification in BAT of anorexic tumor-bearing (Yoshida sarcoma) and pair-fed control rats. BAT thermogenic activity (assessed by maximal mitochondrial GDP binding) was 1.8-fold greater in tumor-bearing rats than in controls, while the thermogenic capacity (assessed by measurement of uncoupling protein) was unchanged. This suggests that tumor bearing had induced an unmasking of uncoupling protein sites. BAT hypertrophy and hyperplasia, characteristic of full-fledged BAT activation, did not occur. The mitochondrial oxidative capacity of BAT (assessed by cytochrome c oxidase activity) was 1.6-fold lower in tumor-bearing than in control rats. The main compositional modification observed in BAT of tumor-bearing rats was an increase in the saturation of cardiolipin fatty acids. These results suggest that the BAT stimulation induced by tumor bearing after 10 days is almost exclusively functional and that the tissue development is limited, probably by anorexia. However, a suppressive effect of anorexia inhibition by tumor bearing cannot be excluded.

Adipose Tissue, Brown↗

PubMed1993

Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats.

Regional hypothalamic concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), respectively a stimulant and an inhibitor of feeding behavior, were investigated in hypothalamic nuclei in rats carrying the Yoshida sarcoma. Tumor-bearing rats (n = 10), non-tumor-bearing controls (n = 10), and food-restricted rats (n = 10), which did not carry tumors but were pair-fed to match the reduced food intake of the tumor-bearing group, were studied after 10 days. NPY concentrations in the arcuate nucleus (ARC, the main site of NPY synthesis) were significantly increased above controls (P < 0.01) in both tumor-bearing and food-restricted groups. However, NPY concentrations in the paraventricular nucleus (PVN, an NPY-sensitive site of NPY release) showed opposing changes, with a 25% decrease (P = 0.052) in the tumor-bearing but a 48% increase (P < 0.01) in the food-restricted group. CRF concentrations in both the PVN and the ARC were significantly reduced (P < 0.01) in the food-restricted group, but remained close to control values in the tumor-bearing group (P not significant). Changes in hypothalamic appetite-regulating neuropeptides in cancer anorexia, which may result from the action of cytokines produced by a host defense response or the tumor itself, may account for reduced feeding. Such changes may include impaired activity of NPY or failure of CRF activity to be suppressed after underfeeding and weight loss.

Adipose Tissue↗

PubMed1994

Influence of various fatty acids on tumour growth in total parenteral nutrition.

The aim of parenteral nutrition in tumour patients is to offer an alternative nutritional support to the patient without accelerating the growth of the tumour. For this purpose we fed a total of 100 rats, divided into five groups of 20 animals each (10 with and 10 without tumours), for a total period of 15 days with various nutritional regimes. Group 1 received glucose, group 2 long-chain triglycerides, group 3 medium-chain triglycerides (MCT), group 4 omega-3 fatty acids, and group 5 an oral diet. On the 10th day the Yoshida sarcoma in its ascites form was implanted into the tumour-bearing rats. In animals receiving MCT or omega-3 fatty acids tumour growth was considerably smaller than in the other groups (group 1 vs. groups 3 and 4; p < 0.05). Unfavourable effects of the administration of these fatty acids on the general condition of the animals were not observed [muscle nitrogen content (mg/kg body weight): MCT = 82.3, omega-3 fatty acids = 65.25]. The impulse cytophotometric measurements did not demonstrate any influence on the pattern of cell division (p > 0.05). We think that modulation of the immune system by feeding with MCT or omega-3 fatty acids was responsible for the reduced tumour growth in relation to the other groups. The extrapolation of these results to the clinical situation, however, may not be possible.

Animals↗

PubMed1980

[In vitro resistance testing of tumors in relation to cytostatics. 1. Animal experiments].

By studying rat Yoshida sarcoma and Walker carcinoma, pertinent results have been obtained for chemotherapy drug (CD) resistance of human tumors. The incorporation rates of tritiated metabolic precusors of DNA and RNA synthesis could be shown to be reproducible in ascites tumor cells and in solid tumor cells, in the absence as well as in the presence of CDS. Fraction of proliferation cells, cell cycle phase duration and tumor generation time were equal before and after explanation. The in vitro CD concentration used did not promote cell death within the first 4 h post-explantation, as shown by supravital stain (with Lissamin green and Trypan blue) and by 51Cr-release studies.

Animals↗

PubMedDate not supplied

Evaluation of the effect of arginine-enriched amino acid solution on tumor growth.

To investigate the effect of arginine-enriched solution on tumor growth and metastasis, rats were infused with solutions containing 5.5 and 0.66% arginine for 8 days. Infusions were started at the same time of subcutaneous transplant of Yoshida sarcoma. Arginine-rich solution suppressed tumor growth at an early stage and prevented metastases to the liver and kidney. In addition, arginine supplements enhanced the phagocytic activity of alveolar macrophages. It also resulted in maintenance of a positive nitrogen balance and prevented the increases in the levels of several amino acids observed in the control group. The suppressive effect of arginine-enriched solution on tumor growth may be due to its activation of the immunologic system, in which the phagocytic activity of macrophages probably participates.

Adjuvants, Immunologic↗