Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phototoxicity of acridine orange and argon laser irradiation on Walker carcinosarcoma 256 stomach tumors was studied. Wistar strain rats bearing stomach tumors 4-6 mm in diameter 5-10 days after their implantation were injected intraperitoneally with 40 mg/kg of acridine orange 2 hr before irradiation. Then the forestomach was opened and the tumors were exposed to the argon laser at 488 nm at an intensity of 15 mW/cm2 for 20 min. Tumors in rats treated with acridine orange were brightly fluorescent during irradiation. No marked temperature rise was detected during irradiation. Argon irradiation significantly prolonged the survival of rats treated with acridine orange. Histologically, complete or partial tumor necrosis was observed, with sparing of surrounding mucosa, in rats treated by the combination therapy. Phase-contrast and electron microscopy showed that cytotoxicity was mediated by changes in the cell, nuclear and lysosomal membranes. Neither the dye nor laser alone had any effect.
 ...
PMID:Destruction of implanted gastric tumors in rats by acridine orange photoactivation with an argon laser. 653 6

The 4-(N-methylcarboxamido)-5-methyl derivative of amsacrine (NSC 249 992) has been synthesized as part of a program aimed at optimizing solid tumor activity in this series. Physicochemical studies of this analogue (N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide; NSC 343 499) indicate a slightly increased lipophilicity (estimated log p = 1.10), a decreased acridine base strength (pKa 6.40), and a 16-fold-higher association constant for double-stranded calf thymus DNA (Ka 2.1 X 10(6) M-1 at 0.01 ionic strength). Like amsacrine, the drug binds to DNA by intercalation. Inhibition of cell growth has been monitored by continuous drug exposure assays with a variety of rodent and human cell lines. The concentration for 50% inhibition varied from 6.7 nM (T-47D, a human breast carcinoma line) to 800 nM (P388/ADR, a murine cell line resistant to Adriamycin). N-5-Dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide was cytotoxic at growth-inhibitory concentrations and also induced cell cycle arrest in the G2 phase. It was active against P388 leukemia following administration by p.o., i.v., or i.p. routes, and it was superior to amsacrine, daunorubicin, and Adriamycin. It was curative towards i.v.-injected Lewis lung tumor in a proportion of animals when treatment was started on Day 1 or Day 5 after tumor inoculation. It also produced highly significant life extensions against advanced tumors (treatment starting Day 9 after i.v. inoculation or on Day 8 after s.c. inoculation) and was comparable to cyclophosphamide in its effectiveness. It is a candidate drug for clinical trial.
 ...
PMID:Synthesis, antitumor activity, and DNA binding properties of a new derivative of amsacrine, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide. 654 35

The acridine derivative amsacrine (m-AMSA) is used clinically for the treatment of acute leukemias. The mutagenic activity of this drug has been evaluated at the 6-thioguanine (6-TG) and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). m-AMSA was found to have weak but significant mutagenic activity at the 6-TG but not at the ouabain resistance locus, after either 1- or 45-hr exposures at concentrations causing up to 90% cell kill. Two other intercalating agents with antitumor activity, Adriamycin and actinomycin D, provided essentially identical results. All three drugs were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. For these intercalating agents, the yield of 6-TG-resistant mutants was approximately 100-fold lower than that for ethyl methanesulfonate after exposures causing equivalent toxicity or equivalent chromosome breakage. The acridine half-mustard ICR-191 resembled ethyl methanesulfonate rather than the other intercalating agents in providing a high yield of 6-TG-resistant mutants relative to its clastogenic activity. The tumor-inactive intercalator 9-aminoacridine demonstrated only low clastogenic activity with a lack of significant mutagenic activity at toxic concentrations. These results suggest that, for m-AMSA, Adriamycin, and actinomycin D, both cell killing and mutagenesis could be direct consequences of chromosome breakage, while 9-aminoacridine may kill cells by a different mechanism. In view of its mutagenic and clastogenic activity at clinically achievable exposures and the similarity of its genotoxic properties to Adriamycin, m-AMSA should be considered a potential carcinogen.
 ...
PMID:Comparison of the mutagenic and clastogenic activity of amsacrine and other DNA-intercalating drugs in cultured V79 Chinese hamster cells. 654 75

Replacement of the 1'-methanesulfonamide group of the 9-anilinoacridine class of antitumor agents with the 1'-(dimethyl phosphoramidate) group provides compounds that are generally more lipophilic and bind more tightly to DNA. On the average, the dimethyl phosphoramidates are twice as dose potent as the corresponding methanesulfonamide (AMSA) compounds against P388 leukemia in vivo, but also show about twice the acute toxicity and no resultant improvement in tumor cell selectivity (ILSmax values) is seen. A pairwise comparison of a range of acridine-substituted compounds shows that structure-activity relationships within each series are similar and dominated by the acridine substitution pattern.
 ...
PMID:Potential antitumor agents. 42. Structure-activity relationships for acridine-substituted dimethyl phosphoramidate derivatives of 9-anilinoacridine. 674 89

Bovine herpesvirus 5 antigens were detected by indirect immunofluorescence in the cytoplasm of tumor cells derived from bovine ocular squamous cell carcinomas. The number of tumor cells expressing bovine herpesvirus 5 antigens was increased following exposure to ultraviolet light or maintenance in pH 8.4 media. Infectious virus could not be detected in homogenates of tumors or by explantation of tumors. However, medium removed from the ocular tumor explants induced cytoplasmic vacuolization, inclusions and syncytia when inoculated onto bovine fetal spleen monolayers. Acridine orange staining revealed these cytoplasmic inclusions to contain double-stranded deoxyribonucleic acid. These results provide evidence that bovine herpesvirus 5 may be associated with bovine ocular squamous cell carcinoma.
 ...
PMID:Bovine herpesvirus-5 (DN599) antigens in cells derived from bovine ocular squamous cell carcinoma. 675 9

Benz[c]acridine (B[c]ACR) and 12 of its derivatives, including the 5 metabolically possible trans-dihydrodiols, the diastereomeric bay-region diol-epoxides, 2 non-bay-region diol-epoxides, and the K-region arene oxide, were tested for tumor-initiating activity on mouse skin. A single topical application of 0.4 to 2.5 mumol of compound was followed 12 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. B[c]ACR was a weak tumor initiator on mouse skin, producing a 37% tumor incidence and 1.33 tumors/mouse at the 2.5-mumol dose. Of the five metabolically possible trans-dihydrodiols of B[c]ACR, only trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR had significant tumor-initiating activity. This compound was at least 6-fold more active than was the parent compound at the three doses tested. The diastereomeric bay-region diol-epoxides, in which the epoxide oxygen is either cis(isomer 1) or trans (isomer 2) to the benzylic hydroxyl group, each had significant tumor-initiating activity, although isomer 2 was at least 5-fold more active than was isomer 1 and had activity equal to that of its potential metabolic precursor, trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR. Two non-bay-region diol-epoxides (isomer 2 of the 8,9-diol-10,11-epoxide and the 10,11-diol-8,9-epoxide) and the 5,6-arene oxide (K-region) were inactive at the doses tested. 3,4-Dihydro-B[c]ACR, the potential metabolic precursor of a bay-region tetrahydroepoxide, was the most potent tumor initiator analyzed in the present study. At an initiating dose of 0.4 mumol, this compound produced a 97% tumor incidence and 7.90 tumors/mouse after 15 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that B[c]ACR, the N-12 analogue of benz[a]anthracene, undergoes metabolic activation to an ultimate carcinogenic metabolite via formation of a bay-region diol-epoxide, as has already been demonstrated for benz[a]anthracene.
 ...
PMID:Tumor-initiating activity of benz[c]acridine and twelve of its derivatives on mouse skin. 688 19

Flow cytometry of cellular DNA content revealed ploidy abnormalities in 15% of 170 patients with various leukemias, in 50% of 26 patients with malignant lymphomas, and in 68% of 110 patients with multiple myeloma, for an overall incidence of DNA content abnormality of 37% in 306 patients with hematologic malignancies. Since the incidence of ploidy abnormality in over 100 solid tumors exceeded 90%. DNA flow cytometry is also ideally suited to screen for bone marrow metastases. Cell separation by centrifugal elutriation was shown to permit enrichment of aneuploid cells, including one example where cells with abnormal DNA content were not recognized in the unfractionated sample. Biparametric measurements of acridine orange-stained cells for DNA and RNA content analysis were suitable to enhance the discriminatory power of flow cytometric detection of lymphoma and myeloma tumor cells in heterogeneous cell populations of bone marrow and lymph nodes. DNA/RNA measurements in leukemia, (the disease category with the lowest incidence of abnormal DNA mode) revealed a markedly higher mean RNA content in acute myeloid leukemia compared with normal or acute lymphoblastic leukemia bone marrow. While these different RNA content patterns were found in whole marrow, cell separation by centrifugal elutriation of normal marrow disclosed cell subpopulations of myeloid precursor cells with a RNA content pattern similar to that of unseparated AML marrow. Hence, the described differences in RNA content between normal and AML marrow seem to be related to the greater heterogeneity of differentiated cells in normal marrow and per se do not appear to be a unique feature of the leukemia disease process.
 ...
PMID:Characterization of hematologic malignancies by flow cytometry. 700 71

The cytotoxic activity of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), a novel acridine derivative with clinical antitumor activity, has been examined in multicellular spheroids grown from Chinese hamster V79-171b cells. m-AMSA is much less effective against cells within these tumor-like structures than it is against exponential-phase V79-171b cells in monolayer cultures, the initial D0 of the survival curve for the latter being approximately 10-fold lower than for the former following a 60-min exposure to the drug. The resistance of spheroid cells to m-AMSA appears to be at least partially a result of the noncycling or slowly cycling state of the majority of these cells, although they are more sensitive than cells in plateau-phase monolayers. A further component of resistance in spheroids requires the presence of an intact spheroid structure and may be due to drug transport limitations. The use of sequential trypsinization techniques to recover cells at varying depths within spheroids demonstrates that a 60-min m-AMSA treatment preferentially kills cells nearest the spheroid surface, suggesting that tumor cells at a distance from the vasculature may limit the efficacy of m-AMSA in vivo.
 ...
PMID:Activity of 4'-(9-acridinylamino)methanesulfon-m-anisidide against Chinese hamster cells in multicellular spheroids. 701 70

A quiescent (nonproliferating) subpopulation was identified by flow cytometric analysis using two-step acridine orange staining in the EMT6/Rochester, N. Y. subline multicellular tumor spheroid, an in vitro culture system which provides a cellular microenvironment which mimics that of many of in vivo tumors. To isolate a viable quiescent cell subpopulation, centrifugal elutriation which allows for cell separation mainly on the basis of size was used. This technique provided single cells of relatively homogeneous cell volume which varied over a wide range (approximately 100 to 5000 cu microgram). Though the relatively small cell volume fractions were the most enriched (82%) in quiescent cells, such cells were also observed in significant numbers (congruent to 20%) even in the largest cell fractions. The cell clonogenicity of the various elutriation constant in fractions was also assessed and shown to be lowest (plating efficiency congruent to 20%) in the small spheroid cells but relatively constant in fractions containing intermediate and large cells (plating efficiency congruent to 50%). Continuous [3H]thymidine labeling indicated a slower rate of accumulation of labeled cells in the small spheroid cells, which may result from the transition of proliferating spheroid cells to the quiescent compartment during the course of labeling. These finding indicate the utility of centrifugal elutriation for quiescent cell characterization in in vitro tumor systems.
 ...
PMID:Isolation of quiescent cells from multicellular tumor spheroids using centrifugal elutriation. 703 95

Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency. The electronic properties of substituent groups proved important, but the most significant effects on drug potency were shown by the steric influence of groups placed at various positions on the 9-anilinoacridine skeleton. The results are entirely consistent with the physiologically important step in the action of these compounds being their binding to double-stranded DNA by intercalation of the acridine chromophore between the base pairs and positioning of the anilino group in the minor groove, as previously suggested. An equation was also derived for the acute toxicities of 643 derivatives of 9-anilinoacridine. This equation took a somewhat similar form to the one modeling antileukemia potency, emphasizing the usual fairly close relationship between potency and acute toxicity for antitumor agents in general. This study demonstrated the power of QSAR techniques to structure very large amounts of biological data and to allow the extraction of useful information from them bearing on the possible site of action of the compounds concerned.
 ...
PMID:Potential antitumor agents. 36. Quantitative relationships between experimental antitumor activity, toxicity, and structure for the general class of 9-anilinoacridine antitumor agents. 706 6


<< Previous 1 2 3 4 5 6 7 8 9 10