High Antimetastatic Activity of Platin Liposomal Form after Lyophilization and Storage.

Antimetastatic activity of Platin in lyophilized liposomes stored for 7 years after fabrication was evaluated. The main flaw of liposomes as vehicles for drug delivery to the tumors is their high affinity for the liver, which accumulates a great amount thereof. This property of liposomes can be used for adjuvant therapy of operable primary tumors metastasizing to the liver. It is shown on the model of mouse GA-1 tumor metastases in the liver that platinum(II) complex compound Platin in phosphatidylcholine-cholesterol liposomes, stored for 7 years after lyophilization, causes complete cure of 40% animals, while free Platin prolongs the lifespan of mice with tumors by only 31.7% vs. control (no treatment).

A galactomannan polysaccharide from Punica granatum imparts in vitro and in vivo anticancer activity.

Galactomannan polysaccharide (PSP001) was isolated from the fruit rind of Punica granatum and was previously reported to have excellent antioxidant and immunomodulatory properties. The cytotoxicity of PSP001 was evaluated in the human cancer cell lines A375, HCT116, and HepG2 as well as the murine cancer cell lines DLA and EAC over a wide range of concentrations. PSP001 exhibited significant cytotoxicity against cancer cells through the induction of apoptosis with no in vivo toxicity up to a concentration of 2000 mg/kg body weight when assessed in BALB/c mice. The antitumor efficacy of PSP001 was tested in DLA and EAC murine ascites and EAC solid tumor mouse models. PSP001 alone and in combination with doxorubicin produced a significant reduction in the tumor burden and increased life span in both models compared to the controls. The results suggest that PSP001 has the potential to be developed as an anticancer agent either alone or as an adjuvant to chemotherapy.

Anticancer activity of Acacia nilotica (L.) Wild. Ex. Delile subsp. indica against Dalton's ascitic lymphoma induced solid and ascitic tumor model.

The aim of the present investigation was to evaluate the effect of A. nilotica extract against Dalton's ascitic lymphoma (DAL) induced solid and ascitic tumors in BALB/c mice. Experimental animals received A. nilotica extract (10 mg/kg.bw) intraperitoneally for 10 and 14 consecutive days before induction of solid and ascitic tumors, respectively. Treatment with A. nilotica extract significantly decreased the development of tumor and percentage increase in body weight when compared to DAL induced solid tumor control group, also increasing the life span, restoring the total white blood cell count and hemoglobin content and significantly decreasing the levels of serum aspartate transaminase (SGPT), alanine transaminase (SGOT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and nitric oxide (NO) when compared to DAL induced ascitic tumor controls. The treatment also reduced significantly the cellular glutathione (GSH) and nitric oxide levels in treated animals. Histopathological studies also confirmed protective influence. The outcome of the present work indicates that A. nilotica extract could be used as natural anticancer agent for human health.

Antitumor efficacy and amelioration of oxidative stress by Trichosanthes dioica root against Ehrlich ascites carcinoma in mice.

CONTEXT: Trichosanthes dioica Roxb. (Cucurbitaceae) is a dioecious climber, traditionally used in India for several medicinal purposes. OBJECTIVE: The present study assessed the hydroalcoholic extract of T. dioica root (TDA) for antitumor effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. METHODS: Twenty four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 5 and 10 mg/kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and liver antioxidant parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT); and the rest were kept alive for assessment of increase in life span. The antitumor effect of TDA was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, median survival time and percentage increase in life span of EAC bearing mice. RESULTS AND DISCUSSION: TDA exhibited dose dependent and significant (p < 0.001) decrease in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC bearing hosts. Hematological profiles were significantly (p < 0.001) restored near to normal in TDA treated mice as compared to EAC control. TDA treatment significantly (p < 0.001) modulated the aforesaid liver antioxidant parameters as compared to EAC control. CONCLUSION: The present study demonstrated that TDA possessed promising antitumor efficacy in mice, plausibly mediated by amelioration of oxidative stress by multiple mechanisms.

Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1 cell cycle arrest in EAC cells.

The objective of this work is to report the antiproliferative effect of P. cupana treatment in Ehrlich Ascites Carcinoma (EAC)-bearing animals. Female mice were treated with three doses of powdered P. cupana (100, 1000 and 2000 mg/kg) for 7 days, injected with 10(5) EAC cells and treated up to day 21. In addition, a survival experiment was carried out with the same protocol. P. cupana decreased the ascites volume (p = 0.0120), cell number (p = 0.0004) and hemorrhage (p = 0.0054). This occurred through a G1-phase arrest (p < 0.01) induced by a decreased gene expression of Cyclin D1 in EAC cells. Furthermore, P. cupana significantly increased the survival of EAC-bearing animals (p = 0.0012). In conclusion, the P. cupana growth control effect in this model was correlated with a decreased expression of cyclin D1 and a G1 phase arrest. These results reinforce the cancer therapeutic potential of this Brazilian plant.

Anticancer effects of a tertiary sulfonium compound, dimethylsulfoniopropionate, in green sea algae on Ehrlich ascites carcinoma-bearing mice.

The saline and dimethylsulfoniopropionate (DMSP) solutions at 5, 10 and 20 mM were preliminarily injected intraperitoneally every other day into two control and three DMSP groups of mice (n=8) for 2 wk and thereafter Ehrlich ascites-carcinoma (EAC) cells were peritoneally injected to one control and three DMSP groups of mice, leaving one control group without the EAC injection. Then, the body weight and survival time of all mice were examined over a long rearing time up to 300 d. All EAC-bearing mice, especially the carcinoma control and 5 mM DMSP-carcinoma group mice, rapidly increased their body weights early and then died by day 50 and day 90, respectively. In contrast, the administration of 10 and 20 mM DMSP solutions prolonged the lives of EAC-bearing mice at the survival rate of 50 and 63% respectively up to 300 d without any side effects. Furthermore, the administration of 10 mM DMSP solution proved to activate the delayed-type hypersensitivity of EAC bearing-mice, and the DMSP solutions over the concentrations of 5 to 30 mM to slightly reduce the dead cells in EAC cells on the synthetic medium. Accordingly, the preliminary supplementation of 10 and 20 mM DMSP solutions to EAC-bearing mice was proven to maintain their lives at high survival rates without direct damage to EAC cells for a long time, probably due to the activation of the immune system without any side effects.

In vivo antitumor activity of ZYD88, a Chinese herbal medicine, in animal models with S180 sarcoma and Ehrlich tumor.

Cancer is a leading cause of death in the world. The continuous development of effective and nontoxic therapeutic agents is a major task in the battle of cancer. We report the in vivo effects of a Chinese herbal medicine, ZYD88, on the inhibition of tumor growth in an S(180) xenograft animal model and the improvement of animal survival in the Ehrlich tumor model. Oral administration of ZYD88 in mice with the xenograft S(180) sarcoma significantly inhibited tumor growth in a dose-dependent manner. Moreover, ZYD88 given to the animals with Ehrlich ascitic tumors by gavage significantly prolonged the life span compared with that of animals treated with saline. In both animal models, the effects of ZYD88 were comparable to those of a standard chemotherapeutic agent, cyclophosphamide, although it had few side effects. These results clearly demonstrated the in vivo anticancer activity of ZYD88 in two different animal models and suggest that ZYD88 is a potential agent for the clinical management of cancer and warrants further preclinical and clinical investigations.

Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment.

The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.

Antitumor effectiveness of different amounts of electrical charge in Ehrlich and fibrosarcoma Sa-37 tumors.

BACKGROUND: In vivo studies were conducted to quantify the effectiveness of low-level direct electric current for different amounts of electrical charge and the survival rate in fibrosarcoma Sa-37 and Ehrlich tumors, also the effect of direct electric in Ehrlich tumor was evaluate through the measurements of tumor volume and the peritumoral and tumoral findings. METHODS: BALB/c male mice, 7-8 week old and 20-22 g weight were used. Ehrlich and fibrosarcoma Sa-37 cell lines, growing in BALB/c mice. Solid and subcutaneous Ehrlich and fibrosarcoma Sa-37 tumors, located dorsolaterally in animals, were initiated by the inoculation of 5 x 10(6) and 1 x 10(5) viable tumor cells, respectively. For each type of tumor four groups (one control group and three treated groups) consisting of 10 mice randomly divided were formed. When the tumors reached approximately 0.5 cm3, four platinum electrodes were inserted into their bases. The electric charge delivered to the tumors was varied in the range of 5.5 to 110 C/cm3 for a constant time of 45 minutes. An additional experiment was performed in BALB/c male mice bearing Ehrlich tumor to examine from a histolological point of view the effects of direct electric current. A control group and a treated group with 77 C/cm3 (27.0 C in 0.35 cm3) and 10 mA for 45 min were formed. In this experiment when the tumor volumes reached 0.35 cm3, two anodes and two cathodes were inserted into the base perpendicular to the tumor long axis. RESULTS: Significant tumor growth delay and survival rate were achieved after electrotherapy and both were dependent on direct electric current intensity, being more marked in fibrosarcoma Sa-37 tumor. Complete regressions for fibrosarcoma Sa-37 and Ehrlich tumors were observed for electrical charges of 80 and 92 C/cm3, respectively. Histopathological and peritumoral findings in Ehrlich tumor revealed in the treated group marked tumor necrosis, vascular congestion, peritumoral neutrophil infiltration, an acute inflammatory response, and a moderate peritumoral monocyte infiltration. The morphologic pattern of necrotic cell mass after direct electric current treatment is the coagulative necrosis. These findings were not observed in any of the untreated tumors. CONCLUSION: The data presented indicate that electrotherapy with low-level DEC is feasible and effective in the treatment of the Ehrlich and fibrosarcoma Sa-37 tumors. Our results demonstrate that the sensitivity of these tumors to direct electric current and survival rates of the mice depended on both the amount of electrical charge and the type of tumor. Also the complete regression of each type of tumor is obtained for a threshold amount of electrical charge.

Treatment with Alstonia scholaris enhances radiosensitivity in vitro and in vivo.

The radiosensitizing effect of 5 micrograms/mL of alkaloid fraction of Alstonia scholaris (ASERS) was evaluated in various neoplastic cell lines, namely: HeLa, HePG2, HL60, MCF-7, and KB exposed to 0, 0.5, 1, 2, 3, and 4 Gy of gamma-radiation. The irradiation of various cells caused a dose-dependent elevation in the cytotoxicity, and a maximum cytotoxic effect was observed at 4 Gy (the highest dose) in all the cell lines studied. The ASERS pretreatment increased the effect of radiation as evidenced by enhanced cell killing when compared with the concurrent phosphate-buffered saline (PBS) treated irradiation group. The greatest elevation in cell killing was observed for HeLa and KB cells, followed by HL60, MCF7, and HePG2 cells. The in vitro observations were confirmed by in vivo studies, where the Ehrlich ascites carcinoma (EAC) bearing mice were treated with 120 mg/kg body weight of ASERS before exposure to 0, 1, 2, 4, 6, and 8 Gy of hemibody (below the rib cage) gamma-radiation. Irradiation of EAC mice caused a dose-dependent tumor regression, as evidenced by increased life span of the animals. The pretreatment of tumor-bearing animals with 120 mg/kg ASERS resulted in a further remission in the tumor when compared with the concurrent nondrug-treated irradiated controls; as a result there was a radiation dose-dependent increase in the life span of tumor-bearing animals receiving 120 mg/kg ASERS, except for 8 Gy, where it was less than the concurrent control. The above findings corroborate with a time-dependent decrease in the glutathione (GSH) contents, accompanied by an increase in lipid peroxidation. Our study demonstrates that ASERS treatment enhances the effect of radiation and results in disease-free survival of the mice.

Evaluation of naphthal-NU, a 2-chloroethylnitrosourea derivative of naphthalimide, as a mixed-function anticancer agent.

Naphthal-NU, 2-[2-[3-(2-chloroethyl)-3-nitrosoureido]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new mixed-function anticancer agent from 1,8-naphthalic anhydride. Its chemical alkylating activity compared with CCNU as standard compound indicated that it possesses greater alkylating activity than the latter. Its antitumour efficacy was assessed in vivo in two murine ascites tumours namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. Three clinical drugs namely CCNU (lomustine), endoxan (cyclophosphamide) and 5-fluorouracil (5-FU) were used as positive controls for comparison. Compound 1 has displayed excellent and reproducible antitumoural activity having curative effects in these tumours comparable with CCNU and 5-FU. It has also significantly increased the life span of mice bearing highly advanced tumour for 10 days before the drug challenge. Its toxicity was also assessed in vivo in normal and in S-180 bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. The results indicated that the compound did not adversely affect hematopoiesis. Drug-induced hepatotoxicity and nephrotoxicity were also evaluated at its optimum dose on those days but no such toxicities were detected. It was further screened in vitro in 6 different human tumour cell lines but no significant activity was observed in those lines.

Anticarcinogenic effect of Commiphora molmol on solid tumors induced by Ehrlich carcinoma cells in mice.

The anticarcinogenic potential of Commiphora molmol (oleoresin) was studied in Ehrlich-solid-tumor-bearing mice. The antitumor activity of C. molmol was evaluated from the total count and viability of Ehrlich solid tumor cells and their nucleic acid, protein, malondialdehyde and glutathione levels at the end of 25 and 50 days of treatment. Furthermore, observations of animal survival rate and measurements of the tumor and body weight were made. The Ehrlich solid tumors were also evaluated for histopathological changes. Treatment with C. molmol (250 and 500 mg/kg/day) was found to be cytotoxic in Ehrlich solid tumors cells. The antitumor potential of C. molmol was comparable to the standard cytotoxic drug cyclophosphamide. This effect of C. molmol was less pronounced after 50 days of treatment. The present study confirmed the cytotoxic and anticarcinogenic potential of C. molmol. Further studies are warranted to explore its mode of action and safety for medicinal use in cancer therapy.

Study of interactions between Listeria monocytogenes and experimental tumors

OBJECTIVE--to verify the effects of Listeria monocytogenes (LM) inoculation in the survival of animals bearing Ehrlich's tumor. KIND OF STUDY--experimental. Animals-isogenic mice, Balb/c, female, 19-21 g. Tumor-Ascitic Ehrlich's tumor, dilution of 5 x 10(5) cells/0.1 ml. Bacteria-LM serotype 4a, solution with 7 x 10(3) bacteria (standard sub-lethal dose). Intervention-a) inoculation of LM in mice bearing Ehrlich tumor at the same time as ascitic cells transplantation. b) inoculation of LM seven days before and, again, seven and fourteen days after ascitic cells transplantation. c) to study the effect of using ampicillin 100 mg/kg, im, simultaneously with the inoculation of Ehrlich tumor and LM organisms and, again, 3, 5, 7, 14, 21 and 30 days after the ascitic cells transplantation. ANALYSIS--Chi-square test; p < 0.05 RESULTS AND CONCLUSION--LM increases significantly the survival of mice bearing Ehrlich tumor even when only one inoculum of viable LM was used, seven days before or seven days after the ascitic cells transplantation. The use of ampicillin after the inoculation of LM and tumor transplantation does not alter the survival of mice

Study of interactions between Listeria monocytogenes and experimental tumors.

OBJECTIVE: to verify the effects of Listeria monocytogenes (LM) inoculation in the survival of animals bearing Ehrlich's tumor. KIND OF STUDY: experimental. Animals-isogenic mice, Balb/c, female, 19-21 g. Tumor-Ascitic Ehrlich's tumor, dilution of 5 x 10(5) cells/0.1 ml. Bacteria-LM serotype 4a, solution with 7 x 10(3) bacteria (standard sub-lethal dose). Intervention-a) inoculation of LM in mice bearing Ehrlich tumor at the same time as ascitic cells transplantation. b) inoculation of LM seven days before and, again, seven and fourteen days after ascitic cells transplantation. c) to study the effect of using ampicillin 100 mg/kg, im, simultaneously with the inoculation of Ehrlich tumor and LM organisms and, again, 3, 5, 7, 14, 21 and 30 days after the ascitic cells transplantation. ANALYSIS: Chi-square test; p < 0.05 RESULTS AND CONCLUSION: LM increases significantly the survival of mice bearing Ehrlich tumor even when only one inoculum of viable LM was used, seven days before or seven days after the ascitic cells transplantation. The use of ampicillin after the inoculation of LM and tumor transplantation does not alter the survival of mice.

The effects of hyperthermia on the cell cycle of Ehrlich ascites cancer cells in vivo.

The effects of hyperthermia on the cell cycle of Ehrlich ascites cancer cells were studied, and these effects simultaneously evaluated in terms of prolonging the survival of test mice inoculated with tumor cells from heat-treated mice. DDY mice bearing Ehrlich ascites cancer cells were placed in a water bath at 37 degrees C, 39 degrees C, 41 degrees C, 42 degrees C. The heating of mice at 41 degrees C, 42 degrees C and 43 degrees C induced the accumulation of cancer cells at the G2M phase of the cell cycle with many cells exhibiting polyploidy (16 C). The extent of accumulation increased as the temperature of incubation was raised, however the interrupted cell cycle resumed 120 hours after heating. The retransplantation of cells from the heat-treated mice revealed that the mice which were inoculated with Ehrlich ascites cancer cells from mice heated at 43 degrees C survived longer, while the mice which were inoculated with Ehrlich ascites cancer cells from mice heated at 39 degrees C survived for only a slightly shorter time than those which were inoculated with cells from mice heated at 37 degrees C.

[Controlled prospective trial to evaluate Syosakiko-to in preventing hepatocellular carcinoma in patients with cirrhosis of the liver].

A controlled prospective study was conducted to evaluate the potential of Syo-saiko-to (Xiao-Chai-Hu-Tang) for the prevention of hepatocellular carcinoma (HCC). Pairs of patients were matched for age, sex, presence of HBs antigen and the scores of the severity of liver dysfunction from 260 cirrhotic subjects. We randomly assigned each patient to receive either a conventional medicine (control group), or 7.5 g/day of Syo-saiko-to (trial group). The patients were monitored during 34 months of treatment, and the incidence of HCC in the two groups were compared. Seventeen patients were found to have HCC in the control group, and nine were found to have HCC in the trial group. The incidence of HCC was significantly lower in the trial group. The results of this study suggested that Syo-saiko-to may prevent or delay the emergence of latent HCC in patients with cirrhosis of the liver.

Optimum schedule of selenium administration to reduce lethal and renal toxicities of cis-diamminedichloroplatinum in mice.

The optimum conditions of selenium administration to reduce the side effects of a single dose of cis-diamminedichloroplatinum (cis-DDP) in mice were examined. The best effects against lethal toxicity of cis-DDP was obtained when sodium selenite was administered subcutaneously (s.c.) to mice simultaneously with s.c. injected cis-DDP at a molar ratio of 1 to 3.5 (sodium selenite to cis-DDP) on the first day and the same amount of selenite was given daily for four subsequent days. This coadministration of selenite completely depressed not only lethal toxicity of cis-DDP but also its renal toxicity (indicated by increased blood urea nitrogen values) and intestinal toxicity (indicated by the incidence of diarrhea) which were usually observed in the mice treated with cis-DDP alone. Furthermore, coadministration of selenite did not compromise the antitumor activity of cis-DDP against several transplantable tumors in mice. Therefore, the administration schedule of selenite with cis-DDP described above may be useful for cancer chemotherapy.

Contribuiçäo ao estudo dos efeitos farmacológicos da Maytenus ilicifolia, Martius (espinheira santa) / Contribution to the study of the pharmacological effects of Maytenus ilicifolia, Martius (espinheira santa)

"Com a finalidade de contribuir ao estudo dos efeitos farmacológicos da "Espinheira Santa", realizamos os seguintes experimentos com seus respectivos resultados: Determinaçäo da DL em camundongos: näo foi menor que 80 mg/Kg. Açäo sobre o tumor de Erlich em camundongos: näo constatada. Dolorimetria em ratos: a droga possui efeito analgésico

Immunomodulation by a unicellular green algae (Chlorella pyrenoidosa) in tumor-bearing mice.

A unicellular algae, Chlorella pyrenoidosa, was used as a biological response modifier. In C57BL/6(B6), C3H/He and DDD/1 mice, both intraperitoneal or oral administrations of autoclaved Chlorella cells or heat-extracted substance were carried out every other day for 10 days before mouse mammary carcinoma (MM-2) or Ehrlich ascites cells were transplanted into the peritoneal cavity. In case of mouse leukemia cells (EL-4), subcutaneous transplantation was carried out. All control mice died within 20 days after each tumor cell transplantation, while 73.3-80% of the treated groups survived over 60 days in the combination of MM-2 vs. C3H/He and EL-4 vs. B6, respectively. The cytotoxic activities against tumor cells, that were abolished by treatment with anti-Thyl.2 monoclonal antibody plus complement, were evidenced in the experimental host. Since Chlorella cells and derivatives showed no indication of direct in vitro cytotoxicity to either tumor or mouse spleen cells, the antitumor effects documented may be mediated by host immune response.