SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
The movement of rat ascites tumor cells of AH66F and Yoshida sarcoma cultured in an agar medium was analyzed. Contraction occurred at the frontal fringe of each cell, and the cytoplasm and nucleus seemed to pass through the site of contraction. Morphological changes observed were similar to that of the leucoycte.
A study was undertaken to investigate the mechanism of liberation of tumor cells into the blood stream in connection with the process of tumor growth, using three strains of ascites tumor such as Yoshida sarcoma (YS) with infiltrative growth pattern, AH100B with expansive one, and AH109A with intermediate one. For this experiment, a new method for the quantitation of the number of circulating tumor cells was devised. From its results, it was concluded as follows: (1) Tumor cells appear first in the circulating blood at the transitional phase from logarithmic growth to declining growth. (2) Tumor size is a macroscopical index of the risk of the liberation of tumor cells into the blood stream. (3) Tumor necrosis is a histological sign suggesting that the tumor growth phase is declining, namely, that hematogenous dissemination of tumor cells has begun already. (4) There is a striking difference in the frequency and number of tumor cells in the venous blood among these three tumor strains. The tumour strains in order of the number of the circulating tumor cells are YS, AH109A, and AH100B. (5) In YS and AH109A, the transition of the number of tumor cells liberated into the blood stream is closely related to the growth process of tumor tissue. (6) Liberated cells of AH109A and AH100B disappear promptly from the blood stream.
Dynamic studies of kinetics of 99mTcO4, 57Co-Bleomycin, 67Ga, A2 fraction of 57Co-Bleomycin in Yoshida sarcoma bearing rats were undertaken. Then the regional variations of rate of the initial uptake of a radiopharmaceutical were examined using functional representation of the rate constants as a function of position. It was concluded that--for radiopharmaceuticals with a high initial uptake rate--the method resulted in visualization of tumor and in suppression of the blood background, within five to eight minutes after administration. This approach based on an evaluation of the parameters of the radiopharmaceutical kinetics in organs and tumor makes possible the use of short-lived radionuclides for tumor visualization and could offer some possibilities of distinguishing the tumor from other accumulating organs.
Pretreatment with thioctic acid has no negative influence on the chemotherapeutic efficacy of cyclophosphamide against i.p. transplanted Yoshida sarcoma and vincristine sulfate against i.p. transplanted Walker carcinosarcoma 256. The toxic side effects of vincristine sulfate are lowered to such a degree that an increase results in median survival time compared to animals treated only with vincristine sulfate. A diminution of the toxic side effects of cyclophosphamide due to adjuvant treatment with thioctic acid could not be proven.
Cells of a Yoshida sarcoma implanted subcutaneously in the rat are heterogeneous. Nuclei vary microscopically from regularly vesicular to irregular and hyperchromatic. Cells with hyperchromatic nuclei are in remarkably close association with stromal elements. This finding is consistent with the theory that stromal influences have a promotional effect on tumor cells. The nature of the hypothetical factor is conjectural.
5-Fluorouracil levels in Yoshida sarcoma implanted subcutaneously and some organs of rats were measured following intraarterial or intravenous administration of 5-FU at various infusion time and doses, and the relationship between 5-FU level in tumors and antitumor effect was examined. The antitumor effect following intraarterial infusion of 5-FU was superior to its systemic administration. With intraarterial infusion, higher levels of 5-FU in tumors could be expected during infusion and immediately after injection. One-shot intraarterial injection of 5-FU was much more effective than continuous infusion of 5-FU from view points of the antitumor effect. This reason might be attributed to that, 5-FU level in the tumor after one shot intraarterial injection was maintained higher for many longer period than its level during continuous infusion. 5-FU levels in the liver following and during intraaortic infusion of 5-FU showed interesting change, i.e. if 5-FU levels flowing into the liver was low, 5-FU in the liver was not detected at all, however, if high level of 5-FU was flown into, the liver 5-FU was measured even 24 hours after injection. It was supposed that the low level of 5-FU was degraded by the liver easily, but the high level of 5-FU flown into the liver could not be metabolized. From these experiments it may be concluded that infusion time of intraarterial administration of 5-FU must be as short as possible within tolerable toxicity, and infusion doses must be as high as possible that could be degraded by the liver for reduction of toxicity.
Immunopotentiators may mitigate the depression of immunological function caused by the cancer itself or by chemotherapeutics. However, it has been found that these immunopotentiators reduce the metabolic activity of the host against drugs, including "masked" chemotherapeutics, which might be activated by metabolization in the body. Reported here is the result of serial experiments carried out on the activation of cyclophosphamide (CPM) in tumor-bearing animals, pretreated with phenobarbital, a drug-metabolizing enzyme inducer, and coenzyme Q10, a physiological activator of the electron transfer system in mitochondrias, in combination with immunopotentiators. Female Donryu rats (120 g body weight) implanted with Yoshida Sarcoma cells (YS) (2.5 X 10(6) i.p.) were treated with CPM (160 mg/kg X 1 i.p.), 84 hrs after implantation; the levels of the normustard-like substances (active metabolites of CPM) were serially measured. Some of the animals were also treated with PSK (125 mg/kg X 5 i.p.), a proteinpolysaccharide immunopotentiator obtained from mycelia of the Coriolus vesicolor, or with OK-432 (10 KE/kg X 5 i.m.), a streptococcal immunopotentiator. The results obtained were as follows: The blood levels of the normustard-like substances were lowered, i.e. the CPM activation was depressed in the YS-bearing rats and the depression was markedly intensified by PSK or OK-432 administration. Phenobarbital (40 mg/kg X 3 i.p.) or coenzyme Q10 (5 mg/rat X 5 i.p.) administration could mitigate the depression of the blood levels caused by the immunopotentiators, and the combination of phenobarbital with coenzyme Q10 could recover the blood levels up to those of the YS-bearing control rats, or even higher. YS-implanted (i.p.) rats treated with CPM+ immunopotentiators+coenzyme Q10 survived longer than those treated with CPM+immunopotentiators. These findings suggest the usefulness of coenzyme Q10 for the enhancement of cancer immunochemotherapy using masked compounds combined with immunopotentiators; all the more so, because coenzyme Q10 has also an immuno-stimulating effect, moreover, it presents almost no side effects in clinical application.
A marked difference in polypeptide pattern and electron micrographs of the nuclear residual protein fraction between normal tissues /liver, kidney, spleen/ and tumors /hepatoma 27, Jensen and Yoshida sarcomas/ is revealed. While in normal tissues the polypeptides with molecular weight lower than 26 KD constituted about one half of the total residual protein, in tumors the polypeptides with molecular weight exceeding 100 KD were markedly prevailing. In electron micrographs the uniform filaments with a diameter of 4-5 nm, and periodical structure represented the bulk of the preparation from normal liver, while in the case of hepatoma 27 an amorphous granulated material was predominating.
Two bleomycin (BLM)-containing agents (BLM-PLA, BLM-SOL) were prepared, and the drug distribution and antitumor effect were studied. BLM-PLA is an agent in which BLM is incorporated into biodegradable low-molecular-weight polylactic acid, and BLM-SOL is an aqueous solution of BLM. BLM-PLA or BLM-SOL was subcutaneously administered in the back of rats. When BLM-PLA was implanted, high BLM activity of the connective tissues near the implants was maintained for 2 weeks. On the other hand, BLM activity was very low when BLM-SOL was administered. The effects of BLM-PLA, BLM-SOL and nontreatment on tumor growth and survival time were compared using subcutaneous tumor of Yoshida sarcoma in 21 rats each. The survivors and mean survival time in BLM-PLA group, BLM-SOL group and nontreatment group was 14 and 44.6 days, 5 and 23.7 days, and 0 and 11.3 days, respectively. BLM-PLA was superior to BLM-SOL in both drug distribution and antitumor effect, and consequently BLM-PLA could be a useful tool in loco-regional chemotherapy.
Solid tumor treatment was given in our animal laboratory to determine the mechanism of tumor disappearance by direct electric current, and clinical trials were done on 9 far advanced recurrent rectal cancers. Solid tumors of Yoshida sarcoma in Donryu rat were treated by 1 mA of constant direct current for 1 hour a day, for 4 days. The tumors disappeared in 13/16 within 21 days. Positive results of DNA Nick-end labeling and ladder patterns in the gel electrophoresis of DNA were observed in the regressing tumor specimen. It is considered that apoptosis is the one of the mechanisms of a disappearing tumor. As for the clinical trial concern, in 9 cases of rectal cancer, one CR and 5 PR were seen.
Fibrin seal has been used for hemostasis and sealing in operative field of tumors in the head and neck. The authors applied it for drug preparation and tried a local chemotherapy to treat residual and disseminated tumors of cellular level in the operative wound using 5-FU. The drug release rate in this therapy in vitro study was 50% after 24 hrs. When injected to rats bearing Yoshida sarcoma, it exhibited a marked antitumor effect compared to the control group given 5-FU alone. This therapy is easy to make the dosage adjustment and can apply drugs directly to the tumor residue at the high concentration. It will be clinically a useful adjuvant therapy for radiotherapy, surgery or chemotherapy.
Urokinase-type plasminogen activator (uPA) from artificially induced decidual tissue of rat has been purified to homogeneity employing chromatographic techniques and the final preparation has a specific activity of 12,084 I.U./mg. The purified preparation resolves into a single band following SDS-PAGE and has an apparent molecular weight of 45 kDa. HPLC of the purified fraction also yields a single peak at 45 kDa. Decidual uPA is immunogenic in rabbit and a monospecific antiserum raised against it does not cross react with human melanoma tPA or rat Yoshida sarcoma tPA but elicits a precipitin reaction with human uPA and extracts of rat placenta and kidney. The enzyme has a pH optimum of 7.5, a kM of 1.0 microM, is heat stable upto ten minutes at 42 degrees C and inhibited by anti-uPA IgG.
We examined the changes of the number of FdU MP binding sites of thymidylate thynthase (TS-BS) in Yoshida sarcoma after administration of 5-FU to the tumor bearing rats. We also investigated the optimal dose of CDDP for the increase of intracellular folate level. In the group received consecutive 7-days administration of UFT (U-7 group), total TS-BS was significantly increased compared with non-treatment group and the group received only UFT (U-1 group). For free TS-BS, however, there was no difference despite of UFT administration. Thymidylate synthase inhibition rate (TSIR) was, therefore, significantly high in U-7 group compared with U-1 group. It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when 5-FU chemotherapy was performed. The optimal dose of CDDP as a modulator of 5-FU was 1 mg/kg in rat when it was estimated from the changes of intracellular folate levels after administration, which was less than the dose to reveal its own anticancer effect.
AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given methionine-containing TPN and 5-FU: 2.66 +/- 0.91 versus 5.12 +/- 2.11 (p < 0.05).
Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by solvent evaporation method in oil-in-oil emulsion system. CDDP-MS and CDDP aqueous solutions (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of CDDP in 72 rats each. On 0.5, 1, 7, 14, 21 and 30 days, the omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of the CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Additionally, acute toxicity of anticancer drug in CDDP-MS group was reduced, compared with CDDP-SOL. The effects of CDDP-MS, CDDP-SOL, empty-MS and non-therapy group on survival time were compared using intraperitoneally administered Yoshida sarcoma. The survival time in CDDP-MS, CDDP-SOL, non-therapy and empty-MS group were 43 +/- 24, 11.7 +/- 4.7, 9.8 +/- 1.1, and 7.8 +/- 1.1 days each. Consequently, it was suggested that CDDP-MS is useful as a tool in loco-regional chemotherapy using drug delivery system.
Therapeutics that are selective for cancer would have a high potential for efficacy. We have previously shown that the metabolic defect of enhanced methionine dependence is a broad cancer-selective target. Methionine depletion can completely arrest the growth of methionine-dependent tumor cells in vivo with a reversible pre-mitosis cell-cycle block. Dietary methionine depletion can partially arrest the growth of methionine-dependent rodent tumors in vivo. This report demonstrates that methioninase isolated from Pseudomonas putida can arrest rodent and human tumors in nude mice with no apparent toxic side effects. Methioninase injected i.p. arrested the growth of the Yoshida sarcoma in nude mice and greatly slowed the growth of the H460 human non-small-cell-lung carcinoma in nude mice. The effectiveness of methioninase against H460 was in contrast to 5-fluorouracil and vincristine, which were inactive against this tumor. The activity of the administered methioninase did not cause weight loss for up to 10 days treatment at 40-120 units/day indicating the possibility of low toxicity. In contrast, vincristine was highly toxic despite its ineffectiveness. Methioninase also induced a tumor-specific late cell-cycle block. The tumor-selective late cell-cycle block induced by methioninase should be able to be exploited to enhance the tumor specificity of antimitotic drugs and other agents in future experiments. Thus methioninase is a highly effective antitumor agent with a new tumor-selective mode of action with minimal toxicity, demonstrating potential clinical effectiveness against solid tumors.
Cytostatic and chemical properties of two cyclophosphamide (CP) 4-peroxides, 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide anhydro-dimer, that were earlier isolated and identified after Fenton oxidation of CP, are summarized and discussed. Their cytostatic toxicities, which are quantitatively comparable to those of the primary metabolite of CP, 4-hydroxycyclophosphamide, are explained from their apparent spontaneous conversion to mono-oxidized forms of CP, both in vitro and in vivo. The conversion is shown to proceed via autocatalyzed reactions, which are thought to imply the occurrence of free radicals during deoxygenation. The point is raised whether any qualitative difference in cytotoxicity might be caused by the action of these free radicals. Current dose-effect studies of residual colony-forming ability after treatment of 3T6 mouse fibroblasts and Yoshida sarcoma cells in suspension culture are introduced. Further studies on the local toxic action of the radicals under in vivo conditions are necessary if the peroxides are to be introduced in local or regional clinical treatments.
Tumor cells were coupled with fluorecent dansyl group in aqueous medium by dansyl chloride-cycloheptaamylose complex (CDC) without destruction of the cells. C57BL/6 mice and Donryu rats pretreated respectively with dansylated EL4 leukemia cells and with dansylated Yoshida sarcoma cells acquired transplantation immunity to the corresponding tumor cells. Serum and spleen cells obtained from EL4 immune mice showed cytotoxicity to EL4 cells but not to other allogeneic leukemia cells. Hapten-specific cytotoxicity of immune serum and spleen cells was not observed in the present immune system.