Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cephalosporins are a family of semisynthetic antibiotics, some of which have structural features associated with substrates for the multidrug transporter, P-glycoprotein. The activity of a series of six cephalosporins in reversing multidrug resistance (MDR) was examined in MDR variants (Dx5 cells) of the human sarcoma line MES-SA. Dx5 cells express high levels of the mdr1 gene product P-glycoprotein and are 25- to 30-fold resistant to doxorubicin (DOX), etoposide (VP-16), and vinblastine (VBL). Cytotoxicity was measured by the MTT assay. Cefoperazone (1.0 mM) was the most effective modulator of MDR, lowering the IC50 for VP-16 by 29-fold (29x), for VBL by 16x, and for DOX by 14x. Ceftriaxone at 1.0 mM produced 10x modulation of VP-16 cytotoxicity, 8x for DOX, and 2x for VBL. The reversal of resistance was concentration dependent, decreasing to 4x and 5x, respectively, for DOX with 0.25 mM cefoperazone and ceftriaxone. No modulation of cytotoxicity was observed in the parental MES-SA cells, which do not express mdr1. Cefazolin, cefotetan, cephradine, and ceftazidime were ineffective, producing less than 5x modulation of DOX at 1.0 mM. Among these cephalosporins, cefoperazone and ceftriaxone were the most highly protein bound in the media (30 and 52%), and the most lipid soluble, with octanol/water partitioning coefficients of -0.49 and -0.60. Varying the serum concentration in medium from 5 to 50% had less than a two-fold effect on the modulation of MDR by ceftriaxone. The ability to reverse MDR among these agents is associated with lipid solubility, high protein binding, a polycyclic planar geometry, and the presence of the piperazine group in cefoperazone. These data and the potential for achieving high tissue concentrations indicate that cefoperazone merits further study as a modulator of MDR.
Cancer Res 1989 Dec 15
PMID:Reversal by cefoperazone of resistance to etoposide, doxorubicin, and vinblastine in multidrug resistant human sarcoma cells. 258 32

Sensitivity of human transitional cancer cells to anticancer agents was evaluated utilizing cultured cell lines. T-24, MGH-U1 and KU-1. Simultaneously, chemosensitivity tests combined with 42 degrees C hyperthermia were performed. Cells inoculated in 96-well multiplates for 48 hours, were exposed to graded concentrations of doxorubicin (DOX), mitomycin C (MMC), bleomycin (BLM), peplomycin (PEP), cis-diamminedichloroplatinum (II) (CDDP) for 2 to 48 hours. After additional culture for 48 hours, viable cell numbers were estimated by the dye exclusion assay (DEA) and tetrazolium-based colorimetric assay (MTT-assay). In 2-hour exposure, most of anti-cancer agents did not significantly suppress the growth of the cell lines. Only DOX suppressed the cell growth. In 6-hour and 48-hour exposure, DOX, MMC and CDDP showed significant growth inhibitory effect on the transitional cancer cell lines. The effect of BLM and PEP was insufficient. The hyperthermia of 42 degrees C enhanced the growth inhibitory effect of MMC and CDDP, but did not influence the effect of DOX. In comparison of DEA and MTT-assay, viable cell numbers measured by DEA well correlated with the optical density in MTT-assay. Since MTT-assay is a semiautomated, rapid and inexpensive assay with good reproducibility, it can be a useful substitute for DEA in chemosensitivity testing of cancer cells.
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PMID:[Chemosensitivity testing on human bladder cancer cell lines, using MTT-assay]. 258 19

To investigate the possibility of increased activity of cytotoxic anticancer drugs combined with cytokines, we treated human melanoma cells with combinations of etoposide (VP-16) and human recombinant interleukin-1 alpha (rIL-1 alpha). We evaluated the combined cytotoxic effects of VP-16 and rIL-1 alpha using A375-C6 cells, which are sensitive to rIL-1 alpha, and A375-C5 cells, a clonal variant line resistant to rIL-1 alpha. We used the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium-bromid e) assay and the inhibition of [3H]thymidine incorporation into DNA. We analyzed data using the median effects principle of Chou and Talalay (Chou's analysis). The calculated combination index values, at a dose ratio of VP-16 to rIL-1 alpha of 12:1 in simultaneous exposure, indicated synergistic cytotoxicity toward both A375-C6 cells and A375-C5 cells. We observed more pronounced synergism with VP-16 and rIL-1 alpha toward the A375-C5 IL-1 alpha-resistant melanoma cells. These results suggest that rIL-1 alpha combined with cytotoxic antitumor drugs may provide increased benefit in the treatment of malignant melanoma.
J Natl Cancer Inst 1989 Dec 20
PMID:Synergistic antitumor activity of etoposide and human interleukin-1 alpha against human melanoma cells. 259 67

Valinomycin is a depsipeptide antibiotic that selectively translocates potassium ion across biologic membranes. This drug has been reported to display antitumor effects, but its use has been limited by its extreme toxicity. However, its incorporation into lipid vesicles (liposomes) has resulted in a reduction in toxicity and in the enhancement of the drug's therapeutic index. As a preliminary investigation of the mechanistic basis for this enhancement, the in vitro response of normal 3T3 and ras-transformed cells to free (VM) and liposomal valinomycin (VM-MLV) was examined. The incorporation of [3H]-leucine and [methyl-3H]-thymidine was used to assess macromolecular synthesis, and the MTT vital dye assay was used to measure cell survival and growth. Pretreatment of exponentially growing NIH/3T3 cells with 20 nM VM for 1 h decreased [3H]-leucine and [methyl-3H]-thymidine incorporation by 90% and 80%, respectively. However, Ha-ras 3T3 cells showed resistance to VM treatment with inhibitory doses in the range of 200 nM. At equimolar VM concentrations, VM-MLV was found to be less inhibitory than VM for protein and DNA synthesis. Specifically, marked protective activity was apparent with normal 3T3 cells. In this report we also demonstrate that VM selectively killed normal cells compared with ras-transformed cells grown in vitro. However, VM-MLV displayed a modest cytotoxic selectivity (3- to 4-fold) to ras-transformed cells. Our data suggests that first, there is good correlation between growth inhibition and inhibition of DNA and protein synthesis by VM, and second, VM-MLV exhibits a modest, selective toxicity to the ras-transformed 3T3 cell line as compared with nontransformed 3T3 cells, whereas free VM has the opposite selectivity.
Cancer Chemother Pharmacol 1989
PMID:In vitro effect of liposome-incorporated valinomycin on growth and macromolecular synthesis of normal and ras-transformed 3T3 cells. 264 10

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supra-additive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity. The demonstration of true supra-additive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supra-additive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supra-additive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.
Cancer Res 1989 May 01
PMID:Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II). 270 26

The tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), is reduced by live but not dead cells, and this reaction is used as the end point in a rapid drug-screening assay. It can also be used for accurate determinations of drug sensitivity but only if a quantitative relationship is established between cell number and MTT-formazan production. We have shown that reduction of MTT to MTT-formazan by cells is dependent on the amount of MTT in the incubation medium. The concentration required to give maximal MTT-formazan production differs widely between cell lines. The absorption spectrum of MTT-formazan varies with cell number and with pH. At a low cell density or a high pH, the absorption maximum is at a wavelength of 560 to 570 nm. However, at a high cell density or a low pH, there are two absorption maxima; one at 510 nm and a second at about 570 nm. Measurements of absorbance at 570 nm underestimate MTT-formazan production and, hence, cell number at high cell densities. This error can result in a 10-fold underestimation of chemosensitivity. Addition of a buffer at pH 10.5 to the solubilized MTT-formazan product can overcome the effects of both cell density and culture medium on the absorption spectrum. Provided that sufficient MTT is used and the pH of the MTT-formazan product is controlled, dye reduction can be used to estimate cell numbers in a simple chemosensitivity assay the results of which agree well with a commonly used clonogenic assay.
Cancer Res 1989 Aug 15
PMID:Effects of the pH dependence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay. 274 32

We describe the application of a simple, rapid, semi-automated assay to the sensitivity testing of cytotoxic drugs in 23 patients with acute myeloid leukaemia (AML). The survival of blast cells from the bone marrow was measured by the MTT assay after 48 h continuous exposure to drugs both singly and in combination. There was a linear relationship between the number of leukaemic cells and the optical density of the formazan produced. The assay demonstrated a variation in drug sensitivity between patients. The technique was reproducible and there was no significant difference in response between blast cells obtained from bone marrow or from peripheral blood. Preliminary results show a correlation between in vitro and in vivo data. The test can be repeated throughout the course of the disease to help identify any change in tumour sensitivity. This technique appears to give useful information to assist in the management of acute myeloid leukaemia.
Br J Cancer 1989 Aug
PMID:Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukaemia. 276 67

We have routinely used a [3H]-uridine microplate assay for assessing chemosensitivity. A colorimetric assay with the advantages of safety, cost and simplicity has previously been described and relies on the ability of living cells to reduce a soluble tetrazolium salt, 3-4,5-dimethylthiazol-2,5-diphenyl-tetrazolium bromide (MMT), into an insoluble formazan precipitate. We compared the chemosensitivity of 14 human tumour cell lines of colonic, lung and cervical carcinoma origin to doxorubicin, vindesine or vindesine immunoconjugates in both the [3H]-uridine assay and a modified MTT assay to evaluate whether we could change to the non-radiolabelled method. Correlation between the concentration of drug causing 50% inhibition of cell growth (IC50) for these agents between the two assays was very poor. However, taking account of recent reports in the literature, we modified the MTT assay by removing serum-containing medium and using dimethyl sulphoxide to solubilise the formazan precipitate. This considerably improved the correlation between the assays for doxorubicin (r = 0.871; P = 0.001) and vindesine (r = 0.981; P less than 0.001). Our data indicates that the MTT assay can be used to replace the [3H]-uridine assay for chemosensitivity screening, but further modifications are necessary to improve the sensitivity and decrease the problem of cell loss after washing, which was noted with some adherent cell lines.
Cancer Chemother Pharmacol 1989
PMID:Comparison of tetrazolium colorimetric and [3H]-uridine assays for in vitro chemosensitivity testing. 278 39

Thirty human lung cancer cell lines were tested for chemosensitivity using the semi-automated, non-clonogenic MTT assay. The tumour cell lines came from three major categories of patients: untreated small cell lung cancer (SCLC); SCLC relapsing on chemotherapy; and non-SCLC predominantly from untreated patients. From these data IC50 values were derived for each drug in each cell line. While some inter-experimental variability was observed, the rank order of chemosensitivity of each cell line within this panel was significantly correlated between experiments. These results show that tumour cell lines derived from untreated small cell lung cancer patients were the most chemosensitive for adriamycin, melphalan, vincristine and VP16 compared to the other cell types. In addition, untreated SCLC was more sensitive than non-SCLC to BCNU and cis-platin, while vincristine was the only drug to which treated SCLC was more sensitive compared to the non-SCLC lines. In contrast, no significant differences between the lung cancer types were observed for vinblastine. Thus, this panel of lung cancer cells exhibited a drug sensitivity profile paralleling that observed in clinical practice. These results suggest that this lung cancer cell line panel in combination with a relatively simple but reproducible chemosensitivity assay, such as the MTT assay, has potential for the testing of drug combinations and evaluating new anti-cancer agents in vitro.
Br J Cancer 1988 Jun
PMID:Chemosensitivity testing of human lung cancer cell lines using the MTT assay. 284 61

Seven small- (SCLC) and four non-small-cell (NSCLC) lung cancer cell lines were used to examine the in vitro cytotoxicity of cytotoxic drugs such as (1aS-(1a alpha,8 beta,8a alpha,8b alpha]-8-[aminocarbonyl)oxy)methyl)-4,8a- dimethoxy-1,1a,2,8,8a,8b-hexahydro-7-hydroxy-5-methyl-6- nitrosoazirino(2',3':3,4)-pyrrolo-(1,2-a)indole (RM-49) and 11-acetyl-8-carboxymethyl-4-formyl-14oxa-1,11-diaze- tetracyclo(7.4.1.0(2,7),0(10,12]tetradeca-2-4-6-trien-6,9-++ +diyl-diacetate (FK973). In vitro cytotoxicities of RM-49 and FK973 were compared with those of mitomycin C (MMC), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP16), adriamycin (ADM) and vindesin (VDS). Drug sensitivity was determined using a tetrazolium (MTT)-based assay. Average IC50 values of these two drugs were not statistically different compared with that of MMC, although FK973 showed strong antitumor activity against SCLC cell lines such as LT3, N857, and H69 at the same concentration. The predicted peak plasma concentration (predicted PPC) calculated by the formula proposed by Scheithauer, log (predicted PPC) = -0.788 + (0.755 x log(LD50], and relative antitumor activity, RAA (PPC/IC50), of RM-49 were higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05), and those of FK973 were also higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05). Based on these promising in vitro studies, the clinical trials of RM-49 and FK973 were warranted.
Cancer Chemother Pharmacol 1988
PMID:In vitro antitumor activity of mitomycin C derivative (RM-49) and new anticancer antibiotics (FK973) against lung cancer cell lines determined by tetrazolium dye (MTT) assay. 284 80


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