Tumor-Specific Transplantation Resistance in Mice after Treatment of Initial Tumors with Streptococcus thermophilus

Antitumor activity observed by treatment with Streptococcus thermophilus was further investigated. The mice cured from fibrosarcoma by treatment with heat-killed preparation of S. thermophilus, when challenged with fibrosarcoma failed to take up the tumor. However, these cured mice when challenged with sarcoma-180 or Ehrlich ascites carcinoma, did not show significant changes in tumor take and/or survival compared to their respective controls. Similarly, mice cured from sarcoma-180 were challenged with fibrosarcoma, sarcoma-180 or Ehrlich ascites carcinoma. Though there was no change in the mean survival time (MST) of the dying mice regarding sarcoma-180 or Ehrlich ascites carcinoma, there was 50 and 30% increase in the number of mice that showed total regression respectively over controls. However, there was no difference in the growth rate of fibrosarcoma. Similar observations were made with mice cured from Ehrlich ascites carcinoma, challenged with these tumors. These findings thus suggest that the antitumor response was tumor-specific and that tumor-associated antigens may have a role in imparting this specificity. Bacterial treatment non-specifically augmented this primary response.     

Oral administration of Agaricus blazei (H1 strain) inhibited tumor growth in a sarcoma 180 inoculation model.

Agaricus blazei (H1 strain) was tested for its anticancer activity using a sarcoma 180 (S180) inoculation model and the changing patterns of splenocyte subsets were examined. Its hot-water extract was administered orally to ICR and KSN nude mice that were inoculated with S180. The growth of S180 was significantly inhibited in A.blazei treated groups. Pan T cells significantly increased in all treated groups compared to controls, even in KSN nude mice. Splenocyte subset changes were slightly different between ICR and KSN nude mice. This S180 inoculation model proved to be effective in screening the antitumor effect of basidiomycetes and allowed comparisons of immunological cellular changes between the mouse strains.     

Effect of saffron on thymocyte proliferation, intracellular glutathione levels and its antitumor activity.

Liposome encapsulation of saffron effectively enhanced its antitumor activity towards Sarcoma-180 (S-180) and Ehrlich ascites carcinoma solid tumors in mice. Significant inhibition (P < 0.001) in the growth of these tumors was observed as compared with vehicle (control) mice. In the presence of phytohemagglutinin (PHA), a T cell mitogen, saffron stimulated non-specific proliferation of lymphocytes in vitro. The intracellular reduced glutathione and related enzymes, i.e. glutathione reductase and glutathione-S-transferase, of S-180 tumor cells were significantly elevated when incubated with saffron, possibly acting to maintain functional levels of other antioxidants. Our studies indicate the antioxidant activity of saffron.     

一些抗癌药物对荷瘤小鼠血清中唾液酸含量的影响

测定荷六种小鼠肿瘤S180肉瘤(实体型和腹水型),腹水肝癌(HepA),艾氏腹水瘤(EC),白血病P388和Lewis肺癌的小鼠腹水和血清中唾液酸含量,结果显示血清中唾液酸含量与肿瘤生长、肿瘤类型有关。腹水中唾液酸含量高,推测肿瘤能比正常组织产生更多唾液酸。对四种腹水肿瘤用阴离子交换树脂层析鉴定,发现HepA腹水中葡萄糖代唾液酸(NcuGc)含量明显低于其它三种腹水瘤。还研究了十几种抗癌药物对荷S180和Lewis肺癌小鼠血清中唾液酸含量的影响。发现吗丙嗪(probimane)和顺铂(DDP)能降低荷瘤小鼠血清中唾液酸含量,提示此二药物在肿瘤治疗中更具选择性。     

Plasmid DNA transfection in fibroblasts of athymic rats]

Nontumorigenic clone FR-7 cl 13 from fibroblasts of athymic rat was obtained from stroma of human colon carcinoma xenograft propagated on nude animals. Spontaneous transformation of this cells was absent after 40 passages in vitro and treatment with pSV2neo. But cells give rise to tumors in athymic mice after transfection with pEJ. This cell clone can be recommended as cells-targets for transfection.     

Tumor-specific immunity induced by somatic hybrids. I. Lack of relationship between immunogenicity and tumorigenicity of selected hybrids.

Hybrid clones were derived from fusion of TEPC-15 plasmacytoma cells of BALB/c mice with mouse L cells of C3H origin. The morphology, tumorigenicity, and immunogenicity of three representative clones were extensively studied. One clone (LTC-1) showed a morphology intermediate to that of either parental cell and possessed the highest tumorigenic and immunogenic properties. The other two clones displayed a "flat" morphology which differed significantly from that of either parent. One of these two, LTC-4, eventually induced tumors in some (BALB/c X C3H)F1 mice but failed to stimulate protective immunity against TEPC-15 tumor cells in BALB/c mice. The other hybrid clone, LTC-2, has a "very flat" morphology and did not induce tumors, although it was capable of stimulating a significant level of tumor immunity. Histologically, all the tumors induced by hybrid cells were fibrosarcomas rather than plasmacytomas. These results indicate that the morphology of hybrid cells may be correlated with the tumorigenicity as well as the histologic appearance of tumor. In addition, the degree of tumorigenicity of individual hybrid clones does not correspond to their immunogenicity in the host, suggesting that major antigens responsible for immunogenicity may not play an important role in induction of tumors.     

Tumor-inhibitory and liver-protective effects of <Emphasis Type="Italic">Phellinus igniarius</Emphasis> extracellular polysaccharides

The tumor-inhibitory and liver-protective effects of crude extracellular polysaccharides (EPS) extracted from the liquid mycelial culture of the mushroom Phellinus igniarius were studied in mice. The mice were injected with murine sarcoma S180 and murine hepatoma H22. Crude EPS at 100, 200, 400 mg kg⁻¹ body weight was administered to EPS groups each day in the twelve consecutive days. The result showed that EPS 200 mg kg⁻¹ body weight significantly inhibited S180 and H22 at 65.0 and 46.3%, respectively. Moreover, EPS could not only keep the numbers of WBC, RBC, PLT and the concentration of HGB in a normal range, but also normalize the activities of AST, ALT and ALP. For example, in EPS-treated mice, AST significantly reduced with the percentage of A/G reverse in S180 (P < 0.05) and H22 (P < 0.01) when the mice took EPS 200 mg kg⁻¹ body weight. In conclusion, it was remarkable that P. igniarius EPS exhibited antitumor activity related to dosage and protected liver function by sustaining the blood routine as well as keeping the blood biochemical indexes normal.     

Synthesis and antitumor properties of 3'-desamino-3'-dimethylformamidinorubomycin

Interaction of rubomycin (daunorubicin) chlorhydrate with dimethylformamidine diethyl acetal yielded 3'-desamino-3'dimethylformamidinorubomycin chlorhydrate (DFR). Comparative antitumor activity of DFR and rubomycin was studied on mice with respect to ascitic lymphadenosis NK/Ly and Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388 and two solid tumors i. e. lymphosarcoma LIO-I and sarcoma 180. The highest antitumor effect of DFR was observed in the mice with Ehrlich carcinoma and lymphadenosis NK/Ly after the drug intravenous administration for 4 times. By selectivity of the antitumor effect DFR was inferior to rubomycin with respect to lymphosarcoma LIO-I and sarcoma 180. It was shown that the antileukemic activity of DFR and rubomycin with respect to hemocytoblastosis La was practically the same. In the experiments with leukemia P-388 DFR was inferior to rubomycin.     

Sensitization by glycerol for CDDP-therapy against human cultured cancer cells and tumors bearing mutated p53 gene

To clarify effective chemotherapeutic regimens against cancer, we examined the effects of glycerol on apoptosis induced by CDDP treatment using cultured human cancer cells (in vitro) and transplanted tumor in mice (in vivo). Human tongue cell carcinoma (SAS) cells transfected with mutated p53 gene (SAS/m p53) showed CDDP-resistance compared with the cells with neo control gene (SAS/ neo). When those cultured cells were pre-treated with glycerol, CDDP-induced apoptosis was enhanced by glycerol in SAS/m p53 cells but not in SAS/ neo cells.In tumor-transplanted mice, the glycerol treatment to tumors enhanced growth delay induced by CDDP in mp53 tumors transplanted with SAS/m p53 cells, but not in wtp53 tumors transplanted with SAS/ neo cells. When transplanted tumors were treated with CDDP alone, the cells positive for active caspase-3, 85 kDa PARP and apoptosis were observed by immunohistochemical staining in wtp53 tumors but not in mp53 tumors. When the tumors were treated with CDDP combined with glycerol, positive cells were observed not only in wtp53 tumors but also in mp53 tumors. These results showed that the CDDP-induced growth inhibition of the tumors is p53 -dependent and that the enhanced growth delay by glycerol may be due to the increased apoptosis. Glycerol might be available for cancer chemotherapy in patients with mp53 tumors.     

Effect of epidermal chalones on the growth of transplantable tumors]

The ethanolic extract of rat skin contains epidermal G1- and G2-chalones which having been added to cell suspension of transplantable squamous-cell cornified carcinoma of mice cervix, inhibits its growth in recipients by 72,6 per cent. The same extract failed to inhibit the growth of transplantable mouse tumours of other histogenesis (hepatoma 22a, leukemia L-1210 and sarcoma 180). When added to cell suspension of transplantable carcinoma of mouse skin which had been anaplized during a long period of transplantation (over 10 years) this extract inhibits its growth by 39,2 per cent only.     

Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis

We have shown earlier that a decline in splenic natural killer (NK) activity during the development of transplanted or spontaneous tumors in mice results from an inactivation of NK lineage cells, mediated by prostaglandins (primarily PGE2) secreted by NK suppressor cells of the monocyte-macrophage lineage. In the present study we have used a C3H mouse mammary carcinoma model to examine whether this mechanism of NK suppression is conducive to tumor metastasis in vivo and whether a reversal of this suppression by a chronic indomethacin therapy can prevent metastatic spread from the primary tumor site. Three mammary tumor lines, all derived in our laboratory from a spontaneous C3H mammary tumor were employed: T-58 (uncloned parental line, having weak lung metastasizing ability from the subcutaneous site), C3 (a clone of T-58, showing high metastatic ability), and C10 (a nonmetastatic clone of T-58). Although the degree of NK susceptibility of these lines varied inversely with their metastatic potential, none was NK resistant. A chronic administration of indomethacin in the drinking water (14 micrograms/ml) to mice beginning on Day 4 after subcutaneous transplantation of 10(6) tumor cells resulted in a significant reduction in the growth rate of primary tumors in all hosts and led to a complete or nearly complete abrogation of lung metastasis in T-58- or C3-transplanted hosts examined at 1 month after tumor transplantation; C10-transplanted mice showed no metastasis in the control or the treated group. Concomitantly, there was a substantial restoration of splenic NK activity in all indomethacin-treated hosts. Plastic-adherent cells (greater than 95% macrophages) isolated from tumors growing in control mice, when coincubated for 20 hr with normal splenic effector cells caused a suppression of NK activity, reversible in the presence of indomethacin (10(-5) M) in vitro. Similar cells recovered from the residual primary tumors in indomethacin-treated mice had no suppressor ability. Chemically pure PGE2 (at concentrations of 0.5 to 1 X 10(-6) M, but not 0.25 X 10(-6) to 10(-8) M) also caused a suppression of NK activity of normal splenic effector cells, when added during the 4-hr 51Cr-release assay or allowed to interact with effector cells alone for a 20-hr incubation period; a removal of the cell-free PGE2 in the latter case prior to the NK assay did not relieve the suppression.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inflammation and Cancer. I. Rodent models of infectious gastrointestinal and liver cancer

Chronic gastrointestinal and liver infections account for a significant percentage of human cancer deaths. Rodent models help elucidate how infection can lead to malignancy. Helicobacter pylori, the leading cause of human gastric tumors, produces similar disease in Mongolian gerbils. H. pylori, H. felis, and H. hepaticus induce stomach, lower bowel, or liver tumors in susceptible wild-type and genetically engineered mice. Immune dysregulated mice recapitulate features of inflammatory bowel disease including colon carcinoma. Hepatitis B and C virus transgenic mice provide insights into viral hepatitis and hepatocellular carcinoma. Rodent models enhance our understanding of infectious cancer pathogenesis and suggest novel targets for intervention.     

Synthesis and antitumor properties of 3'-desamino- dimethylformamidine doxorubicin

Interaction of doxorubicin hydrochloride with dimethylformamide diethylacetal yielded hydrochloride of 3'-desamino-3'-dimethylformamidine doxorubicin (DFD). It was shown that with single intravenous administration to tumor-free mice DFD was 2.5 times less toxic than the initial doxorubicin. Antitumor activity of DFD was studied with respect to 6 transplantable murine tumors: lymphosarcoma LIO-1, sarcoma 180, lymphadenosis NK-Ly, Ehrlich carcinoma, hemocytoblastosis La and leukemia P-388. Selectivity of the DFD activity against all the above tumors was shown to be high and practically equal to that of doxorubicin. DFD had the highest inhibitory effect on development of Ehrlich carcinoma and lymphosarcoma LIO-1.     

Immunomodulatory Activity of 3β,6β‐Dihydroxyolean‐12‐en‐27‐oic Acid in Tumor‐Bearing Mice

3β,6β‐Dihydroxyolean‐12‐en‐27‐oic acid ( 1 ) is a pentacyclic triterpenoid isolated from the rhizomes of Astilbe chinensis. To evaluate the in vivo antitumor potential and to elucidate its immunological mechanisms, effect of 1 on the growth of mouse‐transplantable tumors, and the immune response in naive and tumor‐bearing mice were investigated. The mice inoculated with mouse tumor cell lines were orally treated with 1 at the doses of 40, 60, and 80 mg/kg for 10 days. The effects of 1 on the growth of mouse‐transplantable S180 sarcoma and H22 hepatoma, splenocyte proliferation, cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, and production of interleukin‐2 (IL‐2) from splenocytes in S180‐bearing mice were measured. Furthermore, the effect of 1 on 2,4‐dinitrofluorobenzene (DNFB)‐induced delayed‐type hypersensitivity (DTH) reactions and the sheep red blood cell (SRBC)‐induced antibody response in naive mice were also studied. Compound 1 could not only significantly inhibit the growth of mouse transplantable S180 sarcoma and H22 hepatoma, increase splenocytes proliferation, CTL and NK cell activity, and the level of IL‐2 secreted by splenocytes in tumor‐bearing mice, but also remarkably promote the DTH reaction and enhance anti‐SRBC antibody titers in naive mice. These results suggested that 1 could improve both cellular and humoral immune response, and could act as antitumor agent with immunomodulatory activity.     

Suppression of phorbol myristate acetate-triggering of macrophage H2O2 release by sarcoma 180 originating factor

A high molecular weight proteinaceous factor in the cell extract of sarcoma 180 (S-180) was found to inhibit phorbol myristate acetate (PMA)-triggering of macrophage H2O2 release. This factor (S-180 factor) was stable at 56 C for 1 hr and resistant to ultraviolet-irradiation. The S-180 factor inhibited the specific binding of PMA to macrophages and this was accompanied by a parallel reduction of PMA-triggered H2O2 release. S-180 factor preferentially depressed macrophage H2O2 release in response to phorbol diesters including PMA, 4 beta-phorbol 12 13 beta,13 alpha-diacetate, 4 beta-phorbol 12 beta,13 alpha-didecanoate, 4 beta-phorbol 12 beta,13 alpha-dibenzoate, and 4-omicron-methyl-PMA rather than the H2O2 release triggered by wheat germ agglutinin or by phagocytosis of latex particles. The S-180 factor failed to affect the PMA-elicited macrophage cell spreading and macrophage phagocytic activity against latex beads with or without PMA-mediated stimulation. A similar inhibitory factor was found in the extracts of some other murine tumor cells (Ehrlich carcinoma and thymic leukemia) and normal cells (liver, spleen, and peritoneal exudate cells).     

Effect of Lawsonia inermis on tumor expression induced by Dalton’s lymphoma ascites in Swiss albino mice

The purpose of this study was investigating experimentally the possible antitumor effect of ethanol extract of root of Lawsonia inermis against Dalton’s lymphoma ascites (DLA) bearing mice.Mice were administered with L. inermis at a dosage of 180 mg/kg of body weight for 15 days after 24 h of DLA inoculation. The ethanolic root extract of L. inermis reverted the increased number of the WBC count, platelets and lymphocytes and decreased the number of the RBC count, hemoglobin content and monocytes. The effect of root extract of L. inermis also increased the pathophysiological marker enzyme, lipid profile and decreased the enzymic and non enzymic antioxidants. A histopathological result shows the loss of liver hepatocytes and kidney architecture in DLA bearing mice. However, mice treatment with L. inermis extract improves the liver and kidney function and rearranges more or less normal architecture. The present work indicates that the ethanol extract of L. inermis exhibited significant antitumor activity.     

Behavioral effects of the aqueous extract of Guiera senegalensis in mice and rats

Behavioral effects of the aqueous extract of Guiera senegalensis on the central nervous system of mice and rats were investigated. Spontaneous motor activity, pentobarbital sleeping time, amphetamine-stereotyped behavior, exploratory activity and performance on treadmills (rota-rod) were evaluated. The results revealed that the aqueous extract of G. senegalensis reduced spontaneous motor activity in mice, prolonged the duration of pentobarbital sleeping time in rats and attenuated amphetamine-induced stereotype behavior in rats. The extract also decreased exploratory activity in mice and had no observable effects on motor coordination (rota-rod) at the doses tested. The results suggested that the crude aqueous extract of G. senegalensis possesses some biologically active principles that are sedative in nature.     

In vivo and in vitro antitumoral effects of an extract from Vibrio cholerae in different murine models. I. Effect in vivo of bacterial extract from Vibrio cholerae on the development of different murine tumoral grafts]

A bacterial extract from Vibrio cholerae, so called DGZ, is shown to prevent transplantation of sarcoma 180 and Lewis lung carcinoma. A 4 days DGZ treatment (4 x 100 micrograms) triggers reject of the graft by 40% of the mice. The mice which have rejected a graft once after treatment, cannot be grafted lately or, at least, the tumor growth is delayed. The association with cisplatinum (4 x 25 micrograms) allows to protect 90 to 95% of the mice.     

Inhibitory effects of Azadirachta indica on DMBA-induced skin carcinogenesis in Balb/c mice

Male Balb/c mice were divided into four groups on the basis of their respective treatments wherein mice of Group I served as controls. For induction of skin tumors, mice of Group II and IV were injected sub-cutaneously with 7,12-dimethylbenz(a)anthracene (DMBA). Mice of Group III and IV were administered aqueous Azadirachta indica leaf extract (AAILE) thrice a week throughout the experiment. After 14 weeks of the first DMBA injection, Group II and IV mice developed tumors. In the tumor-bearing mice that received AAILE (Group IV), a significant reduction in mean tumor burden and tumor volume was observed. The tumors were confirmed to be papillomas and interestingly, the extent of hyper-chromatia was observed to be much more in skin tumors of Group II mice vis a vis the mice receiving AAILE. An increase in the extent of lipid peroxidation was observed in tumorous tissue of Group IV when compared to that of Group II mice. Glutathione (GSH) content and the activities of GSH-based antioxidant enzymes viz. glutathione peroxidase (GPx) and glutathione reductase (GR) increased significantly in the skin tissues of all the groups of mice when compared to control counterparts. Catalase activity was found to decrease significantly in the skin of mice, which received AAILE treatment only (Group III). Activity of super-oxide dismutase (SOD) decreased significantly in all the tumorous tissues (Group II and IV mice). In light of the above observations, the role of AAILE in inhibition of DMBA-induced skin carcinogenesis is discussed in the present study.     

Preparation and biological properties of basidiomycete aqueous extracts and their mycelial compositions]

The basidiomycetes Ganoderma lucidum, Hericium erinaceus, Lentinus edodes and Trametes versicolor were used for preparation of aqueous extracts. A polysaccharide preparation (VPG) was isolated from the G. lucidum aqueous extracts. The mycelium was grown under submerged conditions according to an original procedure. Preliminary exposure of mice with tumors to cyclosphosphamide in a low dose for prolonged elimination of T-suppressors and rapid recovery of T-killers induced an increase in the efficacy of the H. erinaceus and L. edodes extracts. Investigation of the aqueous extracts and VPG on different tumor strain lines for the potential Modifiers of Biological Response (Ca755, s/c P388, s-180) demonstrated antitumor activity and satisfactory tolerabily after oral administration. Inhibition of the tumor growth by the H. erinaceus and T. versicolor extracts and VPG amounted to 88-99% and that of s-180 treated with the L. edodes aqueous extract amounted to 66-75%. Compositions 1, 2, 4 amd 5 were significantly more active by the duration and value of the effect on the animal tumor nodes as compared to the aqueous extracts and VPG included to the compositions and composition 4. Composition 5 (T. versicolor + H. erinaceus + G. Lucidum) proved to be the most efficient by all the criteria. The results of the design of the technologies for cultivation of the mycelum of the medicinal basidiomycetes, investigation of the antumor properties of the extracts and polysaccharide fraction of the mycelium and development of efficient compositions on their basis are summarized. Composition 5 proved to be the most promising for the clinical trials.