Antitumor activity of Nitronaphthal-NU, a novel mixed-function agent

Nitronaphthal-NU (Compound 1) was synthesized as a mixed-function antitumor agent based on the structures of the clinical drug CCNU and experimental compound Mitonafide. In vitro screening in four human tumor cell lines namely SNB-78 CNS, HOP-62 Lung, T47D Breast and SiHa - cervix revealed significant cytotoxicity in the former two cell lines much greater than CCNU and comparable to Mitonafide used as standards. In vivo antitumoral potency assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice, revealed highly significant (p<0.001) tumor regression effects greater than standards. Life span of mice bearing advanced tumor for 10 days before the drug challenge was also considerably increased. Its toxicity was assessed in vivo in normal and S-180 bearing mice by measuring drug-induced changes in haematological parameters, femoral bone marrow and splenic cellularities as well as hepatotoxicity and nephrotoxicity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. Results indicate that it did not adversely affect haematopoiesis. The other parameters were within normal limit. The compound comparable to standards inhibited the synthesis of DNA and RNA in S-1 80 tumor cells.     

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.     

Evaluation of naphthalmustine, a nitrogen mustard derivative of naphthalimide as a rationally-designed anticancer agent

Naphthalmustine, 2-[2-[bis-(2-chloroethyl)amino]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new anticancer agent from N-(2-bromoethyl)naphthalimide. Its chemical alkylating activity exceeded that of nor-HN2 used as standard compound for comparison. 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. The clinical drug cyclophosphamide and the experimental compound mitonafide were used as positive controls for comparison. Compound 1 has displayed substantial and reproducible antitumoural activity in these tumours since very high remission times of treated animals were observed. Significant increase in the life span of mice bearing highly advanced tumour for 10 days before the drug challenge was also noted after its treatment. Its LD50 value was 200 mg/Kg by single i.p. injection. 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 12 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 on those days but no such toxicities were detected. Naphthalmustine inhibits the synthesis of DNA and RNA in S-180 tumour cells. It was further screened in vitro in 4 different human tumour cell lines but no significant activity was observed in those lines.     

Evaluation of toxicity of beta-tethymustine, a new anticancer compound, in mice.

The toxicity of beta-tethymustine, a potential anticancer compound 1 ((Cancer Lett., 119 (1997) 7-12) was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton' s Lymphoma (DL) tumour-bearing Swiss male mice by measuring drug-induced changes in haematological parameters, femoral bone marrow cellularity and splenic cellularity on days 9, 15 and 21 following drug treatment at the optimum dose of 8.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12 and 18, respectively. The results indicate that the compound did not adversely affect haematopoiesis as it was observed that no significant decrease in haematological parameters and femoral marrow cellularity occurred in treated groups. Initial hyposplenic activity was, however, noted in EAC and normal treated groups on day 9 which soon reached normal count within 7-10 days after termination of drug therapy. Drug-induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and tumour-bearing mice on days 9, 15 and 21 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in host mice at this optimum dose.     

Antitumor property of the active principle of jawaharene

The active principle of Jawaharene (JF1), a mixture of fatty acids, was studied for antitumor properties against Ehrlich Ascites Carcinoma (EAC) and Sarcoma-180 (S-180). Using a Warburg respirometer, respiratory O2-uptake by EAC and S-180 cells was completely inhibited by JF1 at the dose of 100 micrograms ml-1. The in vitro cytotoxicity assay revealed that 100% of JF1-treated tumor cells were killed within 60 min incubation. In vivo, EAC and S-180 ascites tumor development was completely inhibited by JF1 at the dose of 5 mg mouse-1 day-1 X 8.     

Evaluation of beta-tethymustine, a new anticancer compound, in murine tumour models

beta-Tethymustine, 1-[2- {bis(2'-chloroethyl)amino}ethyl]spiro[imidazolidine-4,2'-(1'H),3',4'-dihydronaphthalene]-2,5-dione, has been synthesised and LD50 value determined in Swiss male mice, which was found to be 100.00 mg/kg by single i.p. injection. The following three criteria, namely ascites cell count, ascites fluid measurement and increase in median survival times (MST) of drug-treated (T) over untreated control (C) mice, were studied for evaluation of its antitumour efficacy in vivo in three murine ascites tumours, namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). At the optimum dose range of 8.0 mg/kg (higher) to 4.0 mg/kg (lower) for 1-7 days treatment following tumour transplantation on day 0, it exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and displayed excellent ILS(max) value of 80 in EAC, 224 in S-180 and 240 in DL, respectively, showing 'curative' effect (2-3/6 mice having 90 days survival rate). It also demonstrated a high ILS value of 150 with one cure/six mice bearing S-180 for 6 days prior to drug therapy. Screening results were compared with two clinical drugs, cyclophosphamide and 5-fluorouracil, serving as positive controls. Its chemical alkylating activity was compared with nor-HN2 (NSC 10873) and spiromustine (NSC 172112). The results indicate that it possesses greater alkylating activity than nor-HN2 and comparable activity with spiromustine.     

Antitumour activity of saffron (Crocus sativus)

Antitumor activity of saffron (Crocus sativus) extract a commonly used spice in India was studied against intraperitoneally transplanted sarcoma-180 (S-180), Ehrlich ascites Carcinoma (EAC) and Dalton's lymphoma ascites (DLA) tumours in mice. Oral administration of 200 mg/kg body weight of the extract increased the life span of S-180, EAC, DLA tumour bearing mice to 111.0%, 83.5% and 112.5%, respectively. The same extract was found to be cytotoxic to P38B, S-180, EAC and DLA tumour cells in vitro. Thymidine uptake studies indicated the mechanism of action of the extract at the site of DNA synthesis. Toxicity studies showed that the hematological and biochemical parameters were within normal range. These results indicate the potential use of saffron as an anticancer agent.     

Antitumour principles from Nigella sativa seeds.

The active principle of Nigella sativa seeds containing certain fatty acids was studied for antitumour activities against Ehrlich ascites carcinoma (EAC), Dalton's lymphonia ascites (DLA) and Sarcoma-180 (S-180) cells. In vitro cytotoxic studies showed 50% cytotoxicity to Ehrlich ascites carcinoma, Dalton's lymphoma ascites and Sarcoma-180 cells at a concentration of 1.5 micrograms, 3 micrograms and 1.5 micrograms respectively with little activity against lymphocytes. The cell growth of KB cells in culture was inhibited by the active principle while K-562 cells resumed near control values on day 2 and day 3. Tritiated thymidine incorporation studies indicated the possible action of an active principle at DNA level. In vivo EAC tumour development was completely inhibited by the active principle at the dose of 2 mg/mouse per day x 10.     

Poly-L-Lysine Inhibits Tumor Angiogenesis and Induces Apoptosis in Ehrlich Ascites Carcinoma and in Sarcoma S-180 Tumor

Background: This study focuses on the role of Poly-L-lysine (PLL), an essential amino acid, on molecular changes of tumor angiogenesis suppression, pro-apoptotic and anti-apoptotic gene expression after treatment on Ehrlich ascites carcinoma (EAC) and solid sarcoma-180 tumor cells bearing mice. Materials and Methods: The cell viability was carried out using MTT assay. The antitumor activity was evaluated by treatment with PLL at 20 and 40mg/kg/b.w doses for 14 days in EAC ascites tumor and 21 days for Sarcoma-180 solid tumor model. Several tumor evaluation studies, haematological and biochemical parameters were estimated. Importantly, the tumor cell apoptosis was assessed using microscopic observations, DNA fragmentation assay, Flow cytometric analysis, cell-cycle and electron-microscopic study, following which, the expression of several signal proteins related to pro-apoptosis, anti-apoptosis and tumor angiogenesis were quantified using western blotting and immunohistochemistry study. Results: Precisely, PLL had cytotoxic effect on K562; A549; U937 and B16F10 cancer cells. Significant decreases in liquid and solid tumors and increased life span of treated mice were observed (P<0.05). Typical morphological changes, apoptosis bleb phenomenon and sub-G1 cell cycle arrests revealed that PLL promoted apoptotic cell death. Western blot and immunohistochemistry confirms, PLL activated apoptotic signalling cascades through down regulation of Bcl-2 and CD31 protein and up-regulation of Bax and p53 proteins. The anti-angiogenic effects were also accompanied with decreased VEGF expression and reduced peritoneal-angiogenesis and microvessel density. Conclusions: The antitumor and antitumor-angiogenic activity of PLL was confirmed from all the results via up and down regulation of relevant signal proteins reported in this publication.     

The triterpenoid fraction from Trichosanthes dioica root exhibits antiproliferative activity against Ehrlich ascites carcinoma in albino mice: involvement of possible antioxidant role

The present study assessed the triterpenoid fraction from T dioica root (CETD) for antiproliferative effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Twenty-four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, CETD was administered at 2 and 4 mg/ kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, haematological, and hepatic antioxidative parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase(SOD)and catalase (CAT); the rest were kept alive for assessment of survival parameters. The antiproliferative effect of CETD was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, mean survival time and percentage increase in life span of EAC-bearing mice. CETD exhibited dose dependent and significant (p < 0.001) decreases in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC-bearing mice. Hematological profiles were significantly (p < 0.001) normalized in CETD treated mice as compared to EAC control. CETD treatment significantly (p < 0.001) modulated the aforementioned hepatic antioxidative parameters as compared to EAC control. The present study demonstrated that CETD possessed promising antiproliferative efficacy against EAC in mice, plausibly mediated by alleviation of oxidative stress by multiple mechanisms.     

左旋一二脱水伊地醇双甲磺酸酯抗肿瘤作用及毒性

左旋一二脱水伊地醇双甲磺酸酯对大鼠吉田肉瘤腹水型(YAS)及实体型(YSS),大鼠W_(256)有显著抗肿瘤作用,对小鼠淋巴细胞白血病L_(1210)及P_(388)有较好疗效,对黑色素瘤B_(16)、小鼠S_(180)(实体型及腹水型),艾氏腹水癌(EAC)以及小鼠肝癌腹水型(HepA)也有抗瘤活性。对L_(1210)细胞有较强杀灭作用。小鼠一次给药,腹腔注射LD 50为628mg/kg;灌胃给药LD 50为572mg/kg。对狗的毒性主要表现为白细胞及血小板减少,对大鼠的白细胞影响较轻。     

Anticancer potential of cleistanthin A isolated from the tropical plant Cleistanthus collinus

A diphyllin glycoside called cleistanthin A was isolated from the tropical plant Cleistanthus collinus and its anticancer potential was assessed. This compound showed preferential cytotoxicity in several tumor cell lines. The GI50 values for normal cell lines were between 10(-6) and 10(-7) M while for tumor cells the values ranged from 10(-7) to 10(-9) M. When the cytotoxicity of this compound was compared with five anticancer drugs, cleistanthin A was found to be most effective for the oral carcinoma cell line KB and the cervical carcinoma cell line SiHa. The efficacy of cleistanthin A in arresting tumor growth was assessed in mice harboring Dalton's ascites lymphoma and a solid tumor S-180 sarcoma. In both cases, the tumor volume was drastically reduced upon treatment with cleistanthin A. This compound also increased the life span of mice with S-180 sarcoma to a similar extent as that done by cisplatin (CDDP: cis-diamminedichloroplatinum) and etoposide. However, cleistanthin A was less toxic than these drugs because it did not affect the body weight and lymphocyte count in treated animals. Although the molecular mechanisms of action of cleistanthin A in arresting cell growth are yet to be explored in various perspectives, our present results indicate that this compound arrests growth by inhibiting DNA synthesis and cell division and by driving cells to apoptosis. Time-lapse video microscopic recordings of cleistanthin A-treated cells showed vigorous membrane blebbing, characteristic of apoptosis.     

榄香烯乳注射液抗癌作用的研究

目的探讨榄香烯乳注射液对小鼠移植性肿瘤及肿瘤细胞株的抗癌作用.方法体内抑瘤试验:选肝癌H22、肉瘤S-180、艾氏腹水癌等瘤株.腹腔注射给药,观察记录对腹水癌的生命延长作用及对实体瘤的抑制作用.体外细胞毒试验:选用K562白血病、Hela宫颈癌细胞株,采用MTT法,计算对肿瘤细胞株平均细胞生长抑制率.结果榄香烯乳注射液能明显延长腹水型荷瘤小鼠的生存时间.对K562白血病、Hela宫颈癌细胞株有一定的抑制作用.结论榄香烯乳注射液对肿瘤细胞体内抑瘤试验、体外细胞毒试验均有明显的抑制作用.     

A case of gastric cancer with multiple bone metastasis that responded to S-1 with low-dose cis-platinum

We report a patient with multiple bone metastasis who was treated successfully using S-1 and low-dose cis-platinum (CDDP). Metastasis was diagnosed 4 years after distal gastrectomy for early gastric cancer in a woman now 68 years old. Surgery was performed on February 9, 1999. The primary tumor was located in the midportion of the gastric body, and had invaded the submucosa with metastasis to lymph nodes in the area of the lesser curvature. She was discharged from our hospital 24 days after surgery. About 4 years after surgery, she experienced a backache and her CEA and CA19-9 levels had risen to 15.30 ng/mL and 996.5 U/mL, respectively. The results of an imaging examination were suggestive of multiple bone metastasis. Treatment with S-1+CDDP was started with the following regimen: daily oral administration of 100 mg/body/day S-1 for 14 days, followed by a 7-days rest and CDDP 20 mg/body infusion on day 1 and 8. Three months after initiation of therapy, the CEA and CA19-9 levels decreased 2.80 ng/mL and 36.8 U/mL, respectively. No severe adverse effects were observed with this therapy. The combination of S-1 and CDDP can be a good tool for the management of gastric cancer with bone metastasis.     

Evaluation of Antitumor and Antioxidant Activity of Sargassum tenerrimum against Ehrlich Ascites Carcinoma in Mice

Context: In the last half century, discovering, developing and introducing of clinical agents from marinesources have seen great successes, with examples including the anti-cancer compound trabectedin. However,with increasing need for new anticancer drugs, further exploration for novel compounds from marine organismsources is strongly justified. Objective: The major aim of this study was to evaluate the antitumor and antioxidantpotential of Sargassum tenerrimum J.Agardh (Sargassaceae) on Ehrlich ascites carcinoma (EAC) in Swissalbino mice. Materials and Methods: An ethanol extract of S. tenerrimum (EEST) from whole algae was used toevaluate cytotoxicity followed by in vivo assessment of toxicity, using biochemical parameters including hepaticand non-hepatic enzymes. Antioxidant properties were examined in animals bearing EAC treated with dailyoral administration of 100-300 mg/kg extract suspension. Results: Antitumor effects of EEST in EAC bearingmice was observed with LD50 1815 mg/kg. Parameters like body weight, tumor volume, packed cell volume,tumor cell count, mean survival time and increase in life span in animals in the EAC bearing animals treatedwith EEST 300 mg/kg was comparable with control group. Significant differences were also seen with changesin total protein content, hepatic enzymes contents, MDA level, and free radical scavenging enzymes in untreatedvs. EEST treated group animals. Conclusions: Evaluation of antioxidant enzymes and hepatic enzymes in theEAC animal model treated with EEST exhibited similar effects as the positive control drug 5-flurouracil. S.tenerrimum extracts contain effective antioxidants with significant antitumor activity.     

Dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 may be effective against peritoneal dissemination in gastric cancer

The effects of a novel oral fluoropyrimidine derivative S-1 on peritoneal metastasis from gastric cancer were investigated. OCUM-2MD3 cells, a highly peritoneal-metastatic cell line, were injected intraperitoneally in nude mice. These mice were allocated to the following three groups (each group, n=10): the S-1 group, to which 10 mg/kg body weight of S-1 was administered per os daily; the FT group, to which 100 mg/kg body weight of tegafur (FT) was administered per os daily; the control group, to which no anticancer drug was administered. Drug administration was starting the day after inoculation. The median survival time of the S-1 group was found to be significantly longer than that of the FT group (30 days vs. 23 days; P<0.005) and the control group (vs. 24 days; P<0.005). The mean values of 5-fluorouracil (5-FU) concentrations in ascites of the S-1 group at 1-4 h were 414-580 ng/ml (n=5), and those of FT group were 70-87 ng/ml (n=5), with significant differences between the two groups at each observation time. The high CDHP concentrations in ascites of the S-1 group were observed at 1-6 h after drug administration. DPD was expressed strongly in fibrous tissue around peritoneal metastasis and weakly in tumor cells of peritoneal metastasis themselves. The high concentrations and long duration of 5-FU in the peritoneal cavity after S-1 administration suggest that S-1 may be effective against peritoneal dissemination. High concentrations of CDHP may prevent 5-FU degradation in peritoneal dissemination and its surrounding fibrous tissue.     

山仙颗粒对S-180荷瘤小鼠T细胞活性及瘤组织中Caspase-9影响的实验研究

目的:通过建立昆明小鼠S-180荷瘤模型,观察山仙颗粒(SXG)对S-180荷瘤小鼠T细胞活性及肿瘤组织中Caspase-9表达的影响,探讨其抗肿瘤的分子机制.方法:构建S-180荷瘤小鼠模型,并随机分为5组,即空白对照组、模型组、SXG低、中、高剂量组,早晚灌胃给药,连续30天.颈椎脱臼处死小鼠,游离脾脏,剥离肿瘤组织.应用MTT比色法及免疫组织化学法分别检测荷瘤小鼠脾脏T细胞活性与S-180实体瘤组织中Caspase-9的表达.结果:SXG用药各组小鼠T细胞对于S-180细胞的抑制率均高于模型组,与模型组比较均有显著差异(P<0.01);SXG用药各组,S-180肿瘤组织中Caspase-9的表达明显上调,与模型组相比较具有显著差异(P<0.01).结论:SXG有抑制肿瘤的作用,其机制与促进Caspase-9介导的肿瘤细胞凋亡密切相关.     

Cytotoxic and antitumour principles from Ixora coccinea flowers

The antitumour activity of Ixora coccinea L. (Rubiaceae) flowers was studied in comparison to intraperitoneally transplanted Dalton's lymphoma (ascitic and solid tumours) and Ehrlich ascites carcinoma (EAC) tumours in mice. Intraperitoneal administration of 200 mg/kg of the active fraction (AF) of the I. coccinea flower increased the life-span of DLA and EAC ascitic tumour-bearing mice by 113 and 68%, respectively. The AF showed less activity against solid tumours (DLA) as compared to ascitic tumours. The same active fraction showed 50% cytotoxicity to DLA, EAC and Sarcoma-180 (S-180) cells in vitro at concentrations of 18, 60 and 25 μg/ml, respectively. It was not toxic to normal lymphocytes, whereas it was toxic to transformed lymphocytes from leukaemic patients, acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML) and K-562 suspension cell cultures. The AF inhibited tritiated thymidine incorporation in cellular DNA.     

A case of advanced gastric cancer successfully treated by surgery after chemotherapy with S-1/CDDP

A-46-year-old male with advanced-stage IV multicentric gastric cancer was treated with S-1/CDDP as neoadjuvant chemotherapy. S-1(initially 100 mg/day, up to 120 mg/day)was orally administered for 3 weeks(day 1-21)followed by 1 drug-free week as a course, and CDDP(initially 60 mg/day, up to 100 mg/day)was administered by intravenous drip on day 8. After the fourth course, a significant tumor reduction was obtained and curative surgery was performed. Thereafter, S-1 therapy was continued. There has not been any recurrence for 19 months postoperatively.     

Novel Mononuclear Ruthenium(II) Compounds in Cancer therapy

The present study was conducted to evaluate in vivo anticancer activity of two novel mononuclear ruthenium(II)compounds, namely Ru(1,10-phenanthroline)2(2-nitro phenyl thiosemicarbazone)Cl2 (Compound R1) andRu (1,10-phenanthroline)2(2-hydroxy phenyl thiosemicarbazone)Cl2 (Compound R2) against Ehrlich ascitescarcinoma (EAC) mice and in vitro cytotoxic activity against IEC-6 (small intestine) cell lines and Artemiasalina nauplii using MTT [(3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide)] and BLT [brineshrimp lethality] assays respectively. The tested ruthenium compounds at the doses 2 and 4 mg/kg body weightshowed promising biological activity especially in decreasing the tumor volume, viable ascites cell counts andbody weights. These compounds prolonged the life span (% ILS), mean survival time (MST) of mice bearing-EAC tumor. The results for in vitro cytotoxicity against IEC-6 cells showed the ruthenium compound R2 to havesignificant cytotoxic activity with a IC50 value of 20.0 μg/mL than R1 (IC50=78.8μg/mL) in the MTT assay and theLC50 values of R1 and R2 compounds were found to be 38.3 and 43.8 μg/mL respectively in the BLT assay. Thebiochemical and histopathological results revealed that there was no significant hepatotoxicity and nephrotoxicityassociated with the ruthenium administration to mice.