Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro cytotoxicity testing is used increasingly during the development of clinical treatment protocols. These tests are influenced by many variables, not all of which have been assessed systematically yet. We analyzed the influence of the recovery time between the end of treatments and measurements on the detection of cellular resistance. The development of resistance to cisplatin and radiation was chosen as a model since the schedule of these treatments is the objective of several ongoing clinical trials. C6 rat glioma, T98G, 86HG-39, A172 human glioma and TE671 human rhabdomyo-sarcoma cells were pretreated with radiation or cisplatin. The cellular resistance was then compared in pretreated and wild-type cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. In all cell lines, apparent drug concentrations killing 50% of the cells were dependent on the recovery time. In A172 cells this concentration was 10.3+/-02.1 microM after 48 h but decreased to 3.56+/-0.44 microM after 120 h recovery time (P < 0.001). After recovery times of more than 168 h, 53% of all pretreated cell lines were resistant to cisplatin or radiation, 25% were unchanged and 22% were more sensitive. However, only half the resistant cells could be identified when the MTT test was done with only 48 h recovery time. The sensitivity of detection increased from 0.46 to 0.83 when the recovery time of the test system was extended from 48 h to 168 h. The specificity was not dependent on the recovery time. Experiments showing resistance after short recovery times are reliable, but lack of resistance can only be shown in experiments with long recovery times. Cisplatin treatment can result in resistance to radiation in glioma cells.
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PMID:Long recovery times improve the detection of cellular resistance in vitro. 975 16

L-Canavanine (L-CAV) is a naturally occurring L-arginine analog that induces the formation of non-functional proteins in a variety of organisms. Previous studies have shown that L-CAV is cytotoxic for several human tumor cell lines. In this study, we have evaluated the cytotoxicity of L-CAV for both parental and multi-drug resistant (MDR) human tumor cells. We have also determined the effect of L-CAV exposure on cellular expression and activity of the MDR P-glycoprotein (P-gp) membrane efflux pump, and the effect of L-CAV on cellular accumulation of P-gp substrates. The effect of pre-treatment with non-cytotoxic doses of L-CAV on cellular sensitivity to ten standard antineoplastic agents was also evaluated, in order to assess the chemosensitization potential of L-CAV. 3-(4,5-Dimethylthiazol-)2,5-diphenyl tetrazolium bromide (MTT) cytotoxicity assays revealed that the MDR variants of human uterine sarcoma and leukemic cells were equally sensitive to L-CAV as compared with their respective parental controls. Although the presence of free L-CAV in the uptake media did not influence cellular accumulation of P-gp substrates, cells cultured for 72 h in 250 microM L-CAV accumulated from 16 to 23% less P-gp substrate than untreated controls. Although L-CAV-cultured sarcoma cells accumulated 17% less doxorubicin (DOX) than untreated controls, they were three times more sensitive to its cytotoxic effects. L-CAV-treated cells were also significantly more sensitive to cisplatin, 5-fluorouracil, mitoxantrone and bleomycin than were untreated controls. Indirect immunofluorescence revealed that 72-h exposure to as much as 1000 microM L-CAV did not alter cellular expression of P-gp. These studies suggest that L-CAV may be equally cytotoxic for both parental and MDR tumor cells, and that L-CAV neither induces the expression of, nor is a substrate for, P-gp. The observation that L-CAV pre-treatment reduces cellular accumulation of DOX, yet sensitizes tumor cells to DOX and other DNA-targeting antineoplastic drugs, suggests a role for L-CAV as a chemosensitizer for the chemotherapy of cancer.
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PMID:L-Canavanine modulates cellular growth, chemosensitivity and P-glycoprotein substrate accumulation in cultured human tumor cell lines. 1039 78

IL-2 kinetics was assessed in mice vaccinated with irradiated syngeneic tumour vaccines carrying an inserted IL-2 gene and producing constitutively IL-2. For comparison, the kinetics of i.v. administered recombinant IL-2 was also examined. During regular time intervals after the vaccination or administration of recombinant IL-2, samples of serum and peritoneal fluid were collected and examined, using CTLL bioassay or its MTT modification. After i.p. administration of irradiated IL-2-producing plasmacytoma (X63-m-IL-2) vaccine, the levels of IL-2 were substantially higher in the peritoneal fluid than in the serum. Both in the peritoneal fluid and in the serum, the IL-2 level was increasing up to 60 min after administration and then it gradually decreased. The last time point when IL-2 was still detectable both in the peritoneal fluid and in the serum was 30 h. Almost identical results were obtained when the IL-2 levels were detected by the conventional CTLL assay, in which DNA synthesis was monitored by 3H-thymidine labeling, and by the isotope-free MTT modification of the CTLL assay, in which the DNA synthesis was monitored by staining. The MTT modification has the advantage of an isotope-free method. Comparison of two different IL-2-producing vaccines, a murine plasmacytoma X63-m-IL-2, with high IL-2 production, and murine sarcoma MC12-IL-2, with low IL-2 production, revealed that whereas after i.p. administration of the high producers, the peak of IL-2 was reached both in the peritoneal fluid and in the serum after 1 h, the administration of low producers gave the peak level of IL-2 later, 5 h after i.p. administration. Comparison of IL-2 levels obtained after i.p. administration of live and irradiated X63-m-IL-2 vaccine revealed that the irradiated vaccine produced both in vitro and in vivo higher amounts of IL-2. As compared to i.p. administration, the kinetics after i.v. administration of the X63-m-IL-2 vaccine was different. The maximum level of recombinant IL-2 was reached 10 min after administration and IL-2 was undetectable after 5 h. When the injections of recombinant IL-2 were repeated, the elimination of IL-2 from the circulation was substantially faster.
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PMID:IL-2 gene-modified tumour vaccines: monitoring of IL-2 levels in serum and peritoneal cavity of vaccinated mice. 1073 12

Human epithelioid sarcoma (ES) is an extremely aggressive soft tissue tumour of unknown histogenesis. Although growth factor-dependent signalling cascades significantly affect the biological behaviour of malignant tumours, little is known so far about their role in human ES. The present investigation, therefore, analyses the coexpression and function of different growth factors and their receptors in the human ES cell line GRU-1 and its clonal subpopulations (GRU-1A, GRU-1B and GRU-1C). As shown by Northern blot, flow cytometry, immunocytochemistry and MTT assay, all ES cell lines expressed transforming growth factor (TGF)-alpha and the epidermal growth factor receptor (EGF-R). Although no response to exogenous TGF-alpha was observed, antagonistic anti-EGF-R antibodies (at 20 microg/ml) induced significant (P<0.05) growth inhibition in all cell lines. All cell lines showed coexpression of platelet-derived growth factor (PDGF)-A and the corresponding receptors. Neutralisation of ES-derived PDGF by anti-hPDGF antibodies resulted in significant (P<0.05) growth inhibition of all clonal subpopulations. Although all cell lines expressed TGF-beta(1) as well as TGF-beta type I and type II receptors (TGF-BI-R and TGF-BII-R), growth inhibition (P<0.05) by exogenous TGF-beta(1) was achieved in the clonal subpopulations only and not in the parental cell line. No ES cell line expressed acidic fibroblast growth factor (FGF) but stimulation of FGF type 3 and type 4 receptors (FGF-3R and FGF-4R) by exogenous acidic FGF (aFGF) resulted in a marked (P<0.05) acceleration of proliferation in all cell lines. In conclusion, our investigation suggests an intricate network of autocrine, juxtacrine and paracrine signalling between ES tumour cells and adjacent non-neoplastic stromal cells.
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PMID:Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines. clues To the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma. 1085 51

Microparticles will probably play a promising role in the future of chemotherapy. These polymeric delivery systems are capable of maximizing the therapeutic activity while reducing side effects of anti-cancer agents. Usnic acid (UA) is a secondary metabolite produced by lichens, which exhibits an anti-tumour activity. In this study, PLGA-microspheres containing usnic acid from Cladonia substellata were prepared by the double emulsion method, with or without PEG as stabilizer. The morphology of the microspheres was examined by optical and scanning electron microscopy. The in vitro kinetic profile of usnic acid loaded-microspheres was carried out by dissolution testing. The usnic acid content was analysed by HPLC. The cytotoxicity of free and encapsulated usnic acid was evaluated against HEp-2 cells using the MTT method. The anti-tumour assay was performed in mice against Sarcoma-180 tumour (UA 15 mg kg(-1) weight body/day) during 7 days. Animals were then sacrificed and tumour and organs were excised for histopathological analysis. Microspheres presented a smooth spherical surface with a mean diameter of 7.02 +/- 2.72 microm. The usnic acid encapsulation efficiency was approximately 100% (UA 10 mg 460 mg(-1) microspheres). A maximum release of 92% was achieved at the fifth day. The IC50 values for free and encapsulated usnic acid were 12 and 14 microg ml(-1), respectively. The encapsulation of usnic acid into microspheres promoted an increase of 21% in the tumour inhibition as compared with the free usnic acid treatment. In summary, usnic acid was efficiently encapsulated into PLGA-microspheres and the microencapsulation improved its anti-tumour activity.
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PMID:In vitro and in vivo properties of usnic acid encapsulated into PLGA-microspheres. 1551 45

Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21(CIP1/WAF1) and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.
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PMID:Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin. 1561 70

Multidrug resistance (MDR) is a major obstacle to successful clinical cancer chemotherapy. A novel doxorubicin anti-resistant Stealth liposomes (DARSLs), prepared by co-encapsulating doxorubicin (DOX) and verapamil (VER) into stealth liposomes, has been developed. The average particle size of DARSLs was 118.1+/-22.3 nm. Encapsulation efficiencies of DOX and VER in DARSLs were greater than 95% and 70%, respectively. The IC(50) of DARSLs as measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in multidrug resistant rat prostate cancer Mat-LyLu-B2 (MLLB2) cells was 0.079+/-0.017 microM, 13 fold less than that for liposomal DOX with free VER (LDFV 0.96+/-0.46 microM) but only about 2 times less than FDFV. The IC(50) cytotoxicity on MLLB2 cells of the various formulations was as follows: DARSLs approximately LDLV<FDFV<FDLV<LDFV<LD<FD, (LD: liposomal DOX; LV: liposomal VER; FD: free DOX; FV: free VER). Similar cytotoxicities were shown between DARSLs and FDFV in DOX-resistant human uterus sarcoma MES-SA/DX5 cells, reversing DOX-resistance to that shown by FD on DOX-sensitive MES-SA cells. For MLLB2 cells, DARSLs was the most cytotoxic, but its intracellular concentration of DOX, measured as mean cellular fluorescence with flow cytometry was lower (p<0.01) than that observed with the FDFV formulation. In conclusion, DARSLs was an effective DOX formulation which could overcome drug resistance in DOX-resistant tumor cells, but its mechanisms of action may be complex.
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PMID:In vitro cytotoxicity of Stealth liposomes co-encapsulating doxorubicin and verapamil on doxorubicin-resistant tumor cells. 1586 86

Immunization of adult animals with the Ehrlich ascytic cancer cells homogenate three months prior to an experiment, did not affect either tumor transplantation or the progress of cancerogenesis induced by injection of 20-methylcholanthrene oil solution into the femoral muscle. All consequences of adult animal vaccination disappeared in 30-40 days following antigen administration. Quite different consequences were observed after immunization of the newborn mice. The same antigen (Ehrlich cancer cells homogenate) injected to newborn mice on days 1 and 3 after birth in a dose that failed to develop tolerance not only significantly increased the ascytic tumor transplantation threshold (by nearly 200 times for sarcoma 37 cells and by nearly 400 times for Ehrlich cancer cells) in adult animals but also led to almost 50% inhibition of cancerogenesis (induced by injection of 20-methylcholanthrene oil solution in the femoral muscle of mature mouse) after three and even after 12 months following immunization. The MTT-analysis did not reveal any noticeable differences in the number and activity of the cytotoxic lymphocytes in populations of splenocytes obtained from the intact mice (control) and from the adult animals which had been exposed to postnatal immunization (experiment).However, after a new vaccination such differences were found. In the populations of splenocytes obtained from control animals, the cytotoxic activity measured on day 10 after vaccination had increased 2.86-fold mainly at the expense of an increased number of effector cells. In the populations of splenocytes obtained from the experimental group of animals the activation was much greater (25.8-fold), being accomplished not only at the expense of an increased number of the effector cells, as observed in the control group, but also at the expense of their higher activity. The kinetic analysis of a mechanism of effector cells/target cells interaction has led to derive equations for estimation of the limiting rates of such interaction and of the equilibrium constants for interacting cells. Analysis of a generally accepted mechanism of the cytotoxic lymphocytes formation, with an account of the kinetic analysis data, has shown that a major reason of low antitumor resistance of animal organism is the negligible population of resting cells--the precursors of antitumor cytotoxic lymphocytes. Newborn mice vaccination does not produce any increase in the number of resting cells of the necessary type. This circumstance explains both, increase of the ascytic tumor transplantation threshold and increase of the resistance to 20-methylcholanthrene action in adulthood. Adult animal immunization does not possess such action. Analysis of the problem leads to the conclusion that the system of organism's antitumor resistance becomes effective only in those cases when, owing to antigen activation of resting cells, the concentration of cytotoxic lymphocytes rises to such an extent that the rate of tumor cell destruction becomes greater than the rate of target cells reproduction.
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PMID:Antitumor resistance activation in mice: can the immunological memory cells enhance resistance? 1647 21

The anticancer effects of wogonin on murine sarcoma S180 both in vitro and in vivo were investigated, and its pro-apoptotic molecular mechanism was further studied. Wogonin treatment resulted in significant inhibition of S180 cells in a concentration-dependent manner detected by MTT assay. The IC50 value for 48 h was (7.37+/-1.53) x 10(-5) M. Typical morphological changes and apoptosis bleb phenomenon in S180 cells exposed to wogonin were distinctly observed by the inverted light microscope and the fluorescence microscope, respectively. According to protocols of transplanted tumor research, mice were transplanted with tumor cells S180. The weight of tumor and the peripheral leucocyte count were observed after the treatment of wogonin. The significant suppression of tumor growth was observed, and the peripheral leucocyte count of S180-bearing mice remained no significant changes compared with control group. After the treatment of 40 mg/kg wogonin, the inhibitory rate of tumor weight was 53.01%. Additional DNA fragmentation assay showed that wogonin induced apoptosis on murine sarcoma S180 tissue. RT-PCR results indicated that the increasing mRNA levels of bax and p53 and the decreasing mRNA level of bcl-2 were induced by wogonin. Western-blot assay showed that the increasing protein level of bax and the decreasing protein level of bcl-2 were induced by wogonin. Collectively, wogonin could induce apoptosis in murine sarcoma S180 thereby inhibiting the tumor growth both in vitro and in vivo. The pro-apoptotic effects might be related to the improvement of mRNA level of p53, the improvement of mRNA and protein levels of bax, and the reduction of mRNA and protein levels of bcl-2.
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PMID:The anticancer activities of wogonin in murine sarcoma S180 both in vitro and in vivo. 1675 5

We previously reported that wogonin, a flavonoid compound, was a potent apoptosis inducer of human hepatoma SMMC-7721 cells and murine sarcoma S180 cells. In the present study, the effect of oroxylin A, one wogonin structurally related flavonoid isolated from Scutellariae radix, on human hepatocellular carcinoma cell line HepG2 was examined and molecular mechanisms were also investigated. Oroxylin A inhibited HepG2 cell proliferation in a concentration- and time-dependent manner measured by MTT-assay. Treatment with an apoptosis-inducing concentration of oroxylin A caused typical morphological changes and apoptotic blebbing in HepG2 cells. DNA fragmentation assay was used to examine later apoptosis induced by oroxylin A. FACScan analysis revealed a dramatic increase in the number of apoptotic and G(2)/M phase arrest cells after oroxylin A treatment. The pro-apoptotic activity of oroxylin A was attributed to its ability to modulate the concerted expression of Bcl-2, Bax, and pro-caspase-3 proteins. The expression of Bcl-2 protein and pro-caspase-3 protein was dramatically decreased after treatment with oroxylin A. These results demonstrated that oroxylin A could effectively induce programmed cell death and suggested that it could be a promising antitumor drug.
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PMID:Oroxylin A induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity. 1706 58


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