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PubMed1982

A further study on the number of silver stained granules of active nucleolus organizer regions in mitotic Yoshida and Zajdela rat experimental tumor cells.

Yoshida ascitic sarcoma and Zajdela ascitic hepatoma were investigated in Norway rats to provide more information on active nucleolus organizer regions (NORs) represented by silver stained granules (SSGs). Diploid Yoshida sarcoma cells were characterized by the presence of 6 (3 doublets) of SSGs in the metaphase and 3 + 3 SSGs in future daughter nuclei in the anaphase or telophase. In contrast Zajdela hepatoma cells (frequently hypoploid) possessed 6 SSGs less frequently in the metaphase and the number of anaphasic or telophasic cells with 3 SSGs in future daughter nuclei was also reduced. The number of SSGs in future nuclei of anaphasic or telophasic Yoshida sarcoma cells was usually the same, i.e. such anaphases or telophases were symetric. In Zajdela hepatoma cells the number of symetric anaphases and telophases was substantially reduced in favor of asymetric anaphases or telophases which contained different number of SSGs in future nuclei.

Animals↗
PubMed1994

Effects of fluidity and vesicle size on antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin.

The effects of fluidity and vesicle size on the antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin, an anthracycline antitumor drug, were investigated in Yoshida sarcoma-bearing rats. Liposomes composed of egg phosphatidylcholine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), cholesterol and dicetyl phosphate in a molar ratio of 5:4:1 were injected intravenously into rats 5 d after subcutaneous inoculation of Yoshida sarcoma. At non-effect dosage in free drug, HEPC-liposomes with a diameter of 58 or 142 nm showed the greatest inhibitory effect against Yoshida sarcoma among liposomes tested, whereas larger ones (272 nm) had weaker effect. Small EPC-liposomes (57 nm) had no effect. Larger HEPC-liposomes (especially 142 nm) greatly decreased the number of peripheral white blood cell compared with free drug at the same dose, indicating relatively strong myelosuppressive toxicity. However, small EPC- and HEPC-liposomes with a diameter of 57 and 58 nm, respectively, showed toxic effects comparable to that of free drug. Examination of the dose-dependency of therapeutic effects and toxicity indicated encapsulation of daunorubicin in the small HEPC-liposomes to enhance the therapeutic index about 3 times that of free drug. These findings indicate the possibility of using small HEPC-liposome as a drug carrier for targeting solid tumors.

Animals↗
PubMed1994

Tumor-derived components were responsible for suppression of ornithine decarboxylase activity in the rat wounded skin.

To elucidate the principal cause of delayed wound healing in a tumor-bearing host, the effect of Yoshida sarcoma-derived components on dermal wound healing was investigated in rats with the aid of ornithine decarboxylase (ODC) activity and in vivo bromodeoxyuridine (BrdU) labeling index. The ODC activity in the wounded skin decreased 3 and 7 days after intraperitoneal inoculation of Yoshida sarcoma cells (378.0 +/- 37.3 on Day 3, 280.0 +/- 140.0 on Day 7 vs. 809.3 +/- 109.5 pmol/mg protein/hour on Day 0). When administered 24 hours before and immediately after wounding, the crude nuclear component of the tumor cells significantly decreased the ODC activity in the wounded skin as compared with the control (185.9 +/- 159.8 vs. 534.0 +/- 59.1), but the non-nuclear component was not effective. When nuclear extracts of Yoshida sarcoma cells were intraperitoneally administered immediately after wounding, the 0.15 M or 0.35 M NaCl extract significantly suppressed ODC activity in the wounded skin (233.5 +/- 14.5 and 352.3 +/- 63.2 pmol/mg protein/hour, respectively) in comparison to the control (445.9 +/- 73.6). The BrdU labeling index of epidermal basal cells adjacent to the edge of the wound decreased up to 52% of the control by injection of the 0.15 M extract. It seems that tumor-derived nuclear components may be responsible for delayed wound healing which is commonly observed in cancer cachexia.

Animals↗
PubMed1989

Pharmacokinetic modulation of plasma 5-fluorouracil concentrations to potentiate the antitumor activity of continuous venous infusion of 5-fluorouracil.

Methods for pharmacokinetic modulation of the plasma 5-fluorouracil (5-FU) level to increase antitumor activity during continuous venous infusion (CVI) of low doses of 5-FU were examined in Yoshida sarcoma-bearing rats. These methods were additional infusion of 5-FU for a short period (4 h) or oral administration of UFT or Tegafur during long-term CVI of 5-FU that alone gave a plasma 5-FU level of about 50 ng/ml. The antitumor effect on Yoshida sarcoma was markedly potentiated when an additive dose of 5-FU combined with 3-cyano-2,6-dihydroxypyridine (CNDP), a potent inhibitor of 5-FU degradation, giving a plasma level of about 500 ng/ml, was infused for 4 h. A similar increase in the antitumor effect was observed with oral administration of a conventional dose of UFT during CVI of 5-FU without CNDP, giving a plasma level of 30 to 60 ng/ml. These results suggest that the antitumor effect of CVI of 5-FU can be potentiated by pharmacokinetic modulation of the 5-FU concentration in the blood.

Animals↗
PubMed1982

The number of nucleolar silver-stained granules of active nucleolus organizer regions in mitotic and interphase cells of rat Yoshida and Zajdela ascitic tumors.

To provide more information on the number of silver-stained granules (SSGs) of active mitotic nucleolus organizer regions (NORs) as well as interphase nucleoli, rat Yoshida ascitic sarcoma and Zajdela ascitic hepatoma cells were studied by means of standardized one-step and two-step silver-staining procedures. The number of SSGs of mitotic active NORs was relatively constant and corresponded to the number of active NORs of animals bearing the tumors investigated. Some anaphases and telophases were "asymmetric", i.e. chromosomal figures (future nuclei) in one and the same cell contained different number of SSGs (active NORs). The incidence of such asymetric anaphases and telophases was higher in aneuploid (hypoploid) Zajdela hepatoma than in euploid (diploid) Yoshida sarcoma cells. In the interphase, the number of SSGs was low in small or large cells with distinct chromocenters or chromosomes condensation presumably representing postmitotic and premitotic cells. In contrast, the highest number of SSGs was noted in nucleoli of large cells which were usually characterized by a fine chromatin structure.

Aneuploidy↗
PubMed1998

[Invention of a tumor-selective 5-fluorouracil derivative named S-1 by biochemical modulation of 5-fluorouracil].

A new oral type of 5-fluorouracil (5-FU) derivative possessed of both potent antitumor activity and less gastrointestinal (GI) toxicity was investigated and developed in the form of a combination of tegafur (FT), a masked form of 5-FU, and its two peculiar biochemical modulators. One is 5-chloro-2,4-dihydroxypyridine (CDHP), a new potent inhibitor of 5-FU degradation in vivo, and another is potassium oxonate (Oxo), a characteristic inhibitor of 5-FU phosphorylation, which distributes much higher in GI tract after p.o. administration. 5-FU levels in blood of rats following administration of FT, were markedly elevated and persisted for a long-time by co-oral CDHP corresponding to over 0.4 molar ratio to FT, like the case in continuous infusion of 5-FU, which resulted in an augmentation of antitumor efficacy in Yoshida sarcoma-bearing rats, although severe GI toxicity simultaneously occurred. To reduce 5-FU-induced toxicities such as diarrhea and body weight loss and to maintain the augmented antitumor activity, 0.5 to 2 molar Oxo was orally given to rats with one molar FT plus 0.4 molar CDHP. As a result, both severe GI injury and body weight loss were markedly inhibited by coadministration of 0.5 to 1.0 molar Oxo while high antitumor efficacy (about 90% inhibition of tumor growth) was maintained. However, such almost complete antitumor effect was reduced to about 50% inhibition of tumor growth by over 2 molar Oxo combined with one molar FT plus 0.4 molar CDHP. Based on these results, a novel 5-FU derivative, named S-1, was composed of one molar FT, 0.4 molar CDHP and one molar Oxo. S-1 showed an antitumor activity over 3-fold stronger than UFT (one molar FT plus 4 molar uracil) against Yoshida sarcoma and Sato lung carcinoma in rats and human colon carcinoma (KM12C) xenografted in nude rats when its minimum toxic dose was administered. Co-oral Oxo also significantly reduced the incidence of diarrhea and stomatitis induced by administration of FT-CDHP in beagle dogs. These results suggest that high antitumor activity and less GI toxicity of S-1 was brought about by the elevation in blood and tumor tissues and by selective decrease of 5-fluoronucleotides, an active metabolite of 5-FU, in GI tract.

Animals↗
PubMedDate not supplied

Osseous and intestinal compartments in the humoral hypercalcemia of malignancy associated to Walker 256 tumor in rats.

The objective of the present work has been to study some aspects of bone and intestinal compartments in rats with Walker 256 carcinosarcoma, an experimental model of humoral hypercalcemia of malignancy (HHM). The results have been compared to those obtained in control animals and, also, to those obtained in Yoshida sarcoma-bearing rats, which were used as tumoral controls without hypercalcemia. Urinary hydroxyproline/creatinine ratio (OHProl/creat) is increased, in both Walker 256 and Yoshida tumor-bearing animals, showing the nonspecifity of this bone marker. However, serum tartrate-resistant acid phosphatase (TRAP) levels are increased in Walker 256 tumor-bearing animals, but they are normal in Yoshida tumor-bearing animals, indicating that TRAP is a better index of bone resorption than OHProl/creat in the HHM syndrome. The decrease of bone calcium content in Walker 256 tumor-bearing rats, not shown by Yoshida-bearing rats, also reflects an increased bone resorption due to HHM. Serum and bone osteocalcin levels are similar in control, Walker 256 and Yoshida tumor-bearing rats, but we observed a decrease in serum alkaline phosphatase levels in Walker 256 and Yoshida tumor-bearing animals, which could also be a nonspecific tumor effect, due to the presence of the neoplasia. Our results support the convenience of the employment of a nonhypercalcemic tumor group as control in the HHM study, in addition to the healthy controls. We have also observed higher 1,25-dihydroxyvitamin D serum levels in Walker 256 tumor-bearing rats than in control and Yoshida tumor-bearing rats. On the other hand, we have found normal levels in the fractional rate of intestinal calcium absorption in Walker-256 tumor-bearing rats, in spite of their high calcium levels, and a significant decrease of this parameter in Yoshida sarcoma-bearing animals. These results support the concomitant contribution of intestinal compartment to hypercalcemia, in the experimental model of HHM studied.

Acid Phosphatase↗
PubMed2000

Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo.

It is known that cisplatin (CDDP) potentiates the cytotoxicity of 5-fluorouracil (5-FU), and that the biochemical mechanism is an increase in the intracellular reduced folate levels in the tumor cells. We investigated the effect of consecutive administration with lower-dose CDDP on intracellular accumulation of reduced folate and the activity of methionine synthase, a key enzyme in intracellular methionine synthesis. When CDDP (1 mg/kg) was administered i.p. to ascitic Yoshida sarcoma-bearing rats for 4 consecutive days, both the reduced folate levels and methionine synthase activity in the cells significantly increased, as the same as a single 5 mg/kg dose of CDDP. Furthermore, when Yoshida sarcoma-bearing rats were pre-treated with 1 mg/kg CDDP for 5 consecutive days, [14C]L-methionine incorporation into the isolated ascitic cells was significantly inhibited as compared to that in non-treated cells, suggesting that consecutive administration of lower-dose CDDP is capable of inducing the intracellular modulation of reduced folate levels and methionine synthase activity via inhibition of cellular uptake of methionine. In addition, 5-day administration of lower-dose (1 mg/kg) CDDP potentiated the antitumor effect of 5 mg/kg S-1, a new oral preparation of tegafur, given for 7 consecutive days, and this combined effect was almost similar to the antitumor effect of a combination of S-1 and a single conventional dose (5 mg/kg) of CDDP. Consecutive lower-dose CDDP also may be concluded to act as an important modulator of the enhancement of 5-FU cytotoxicity in experimental tumors.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Anti-tumor properties of the organometallic complex cis-dimethylbis[sulfinylbis[methane]-S]platinum(II).

The water-soluble organometallic complex cis-[Pt(Me)2(Me2SO)2] (Me = methyl; Me2SO = dimethyl sulfoxide) (cis-dimethyl platinum(II); CDMP) was evaluated for its toxicity on the rat and for its efficacy against two tumors of this animal: the Yoshida ascites sarcoma and the T8 sarcoma of Guérin. The lethal dose for 50% of normal animals was 46.4 mg/kg; the predominant toxic effects were loss of weight, decrease in leukocytes and necrosis of the kidneys after i.v. or of the liver after i.p. administration. Doses of drug varying from 2 to 40 mg/kg were administered once by i.p., i.v., i.m. and intra-tumor (i.t.) route from 1 to 7 days after i.p. injection of 10(6) Yoshida ascites sarcoma cells and s.c. implantation of approximately 300 mg of T8 sarcoma of Guérin. The compound showed anti-tumor activity increasing both the average life span and survival of the rats. A comparison between the therapeutic properties of the title complex with those of cis-[PtCl2(NH3)2] (CDDP) reveals that cis-dimethyl platinum(II) exhibits the same anti-tumor activity associated with 6 times reduced toxicity.

Animals↗
PubMed1987

[Hormonal control of zinc uptake in tumor cells].

Zinc is essential for the proliferation of tumor cells. It is suggested that tumor cell growth is inhibited by zinc deficiency in Yoshida sarcoma-bearing rats fed on a zinc-deficient diet. Clinically applicable methods for inducing a zinc-deficient condition in tumor cells were investigated for the therapeutic application of the above phenomenon. As one of these methods, the administration of progesterone to tumor-bearing rats was tried experimentally, and the changes in the zinc content of the tumor tissue and tumor growth were studied and compared with those of tumors in a control group. Progesterone is a competitive inhibitor of glucocorticoid which stimulates zinc uptake by tumor cells. In Yoshida sarcoma-or AH 109A-bearing rats, a tendency of reduction in zinc content in the tumor tissue and inhibition of the tumor growth in the progesterone-administered group was observed in comparison with the control group, although this was not very significant.

Animals↗