Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of the lethal growth of 10(1) L1210 murine leukemia cells in mice was higher in intraperitoneal (i.p.) (97%) than in intradermal (i.d.) (17%) inoculation, and survival time of mice was shorter in i.p. than i.d. inoculation. It was supposed that resident peritoneal cells (PC) enhanced tumor progression. I.d. inoculation of 10(1) L1210 cells mixed with 10(6) PC induced a lethal tumor growth at higher incidence than that of 10(1) L1210 cells alone or the mixture of 10(1) L1210 cells and 10(4) peripheral blood mononuclear cells (PBM) did. Furthermore, co-inoculation of a tumorigenic number of L1210 cells (10(3] with 10(6) PC resulted in marked shortening of median survival time of mice. Similar growth enhancing effect of PC was observed in Meth 1 fibrosarcoma. Meth A fibrosarcoma and colon carcinoma 26 (C26). Further study showed that PC, intact or X-rayed, helped the in vitro tumor growth under the conditions in which L1210 alone did not grow at all, whereas PBM had no enhancing effect to L1210 growth. We characterized the cells involved in tumor growth enhancement by the in vivo and in vitro tests. Plastic dish adherent cells of PC which were Mac-1 positive, large in size and resistant to X-ray, enhanced L1210 growth, whereas non-adherent cells which were Mac-1 negative and small in size, did not. These data suggest that the cells responsible for enhancing activity of tumor progression in the peritoneal cavity were macrophages (M phi).
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PMID:Environmental conditions favorable for tumor progression in peritoneal cavity induced by peritoneal cells without tumor selectivity. 268 89

A method using murine P-388 leukemia or human HT-29 colon carcinoma cells was developed for the bioautography of potential antitumor agents. Of 18 cancer chemotherapeutic drugs and natural products tested, all were detected by toxicity at 0.01 or 1.0 micrograms with P-388 cells, and 11 of the 18 were detected at 10 micrograms or less with HT-29 cells. Bioautography of a crude extract of Pseudoplexaura wagenaari and subsequent purification yielded the known compound crassin acetate. With modification, the assay detected specifically toxic DNA-binding agents.
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PMID:A mammalian cell agar-diffusion assay for the detection of toxic compounds. 277 49

The human T-cell- or lymphocyte-specific gene, lck, encodes a tyrosine kinase and is a member of the src family. In this report we demonstrate that there are two classes of human lck transcripts (types I and II), containing different 5'-untranslated regions, which are expressed from two distinct promoters. No apparent sequence similarity was observed between the 5'-flanking regions of the two promoters. The expression of lck in human T-cell leukemia and carcinoma cell lines and in human peripheral blood T lymphocytes was examined by S1 nuclease and primer extension mapping and by Northern (RNA) blot analysis of total cellular RNA. The following results were obtained. (i) Two RNA start sites in the downstream promoter were used to generate type I transcripts. (ii) The major human type I start site has not been described for the mouse. (iii) At least five RNA start sites in the upstream promoter were used to generate type II transcripts. (iv) In T cells and in two colon carcinoma cell lines, type II transcripts were present in higher amounts than type I transcripts. (v) In T cells treated with phytohemagglutinin, tetradecanoylphorbol acetate, and cyclosporin A, the modulation of lck expression was associated primarily with changes in levels of type II transcripts. The above results suggest that the two human lck promoters are utilized differentially and may be regulated independently during certain physiological states.
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PMID:Structure of the two promoters of the human lck gene: differential accumulation of two classes of lck transcripts in T cells. 278 74

Spirogermanium is a germanium containing azaspirane which has been shown to have activity in experimental models of cancer and immune dysfunction. A series of analogs of the parent compound were synthesized and evaluated in a number of in vitro and in vivo biological assays to define the structure-activity relationships of this class of compounds relative to their potential therapeutic activities. In a colony-forming assay using HT-29 human colon carcinoma cells various analogs in which carbon replaced germanium (e.g. carbon) retained the potent cytotoxic activity in vitro seen with spirogermanium. Increased cytotoxic potency within the group of carbon containing analogs was directly related to increase in the length of the alkyl group(s) attached to the carbon atom opposite the azaspirane ring structure. DNA and protein synthesis by HT-29 cells was inhibited by these compounds. However, inhibition occurred only at supralethal concentrations or after long exposure times with the drug. None of the azaspiranes demonstrated in vivo anti-tumor activity against P388 leukemia or ADJ-PC6 plasmacytoma. The effect of these compounds on macrophage cell function was evaluated in vitro by their ability to modulate superoxide (O2-) production by macrophages. Spirogermanium inhibited the production of O2- by activated macrophages with an IC50 of 5 microM. Although macrophage viability did not appear to be decreased at the respective IC50 concentrations, the rank order potency for the analogs in the O2- production assay was directly proportional to that measured for their cytotoxic potency in the HT-29 colony formation assay. The results demonstrate that, within this class of compounds, (1) potent biological activity does not require the presence of germanium in the structure; (2) in vitro cytotoxic activity does not appear to be a direct result of the inhibition of macromolecular synthesis, and (3) macrophage function can be modulated in vitro at non-cytotoxic concentrations. These results are discussed in context with the reported anti-tumor activity of spirogermanium and the potential anti-arthritic and immunomodulatory activity of this class of compounds.
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PMID:Pharmacological activities of spirogermanium and other structurally related azaspiranes: effects on tumor cell and macrophage functions. 293 Jun 25

Twenty-five samples of fresh malignant cells of patients with acute leukemia (16 with acute myeloblastic leukemia, five with acute lymphoblastic leukemia, and four with chronic myelocytic leukemia in blast crisis) and of two patients with colon carcinoma were exposed for 1 hr to different concentrations of methotrexate (MTX) or trimetrexate (TMQ). In all samples, TMQ was at least one log more potent than MTX in inhibiting [3H]deoxyuridine incorporation into DNA. Cells relatively resistant in vitro to MTX also displayed decreased sensitivity to TMQ, although TMQ "resistance" was usually much less pronounced. In eight of the 25 leukemia samples, intracellular drug levels after exposure in vitro could also be measured. The intracellular levels of TMQ were 6 to 64 times higher than those of MTX, indicating that the difference in potency of these drugs may be related to the difference in intracellular accumulation. The intracellular levels of both agents varied widely and were not directly related to the degree of DNA synthesis inhibition. There was, however, a clear positive correlation between the intracellular ratio [TMQ]/[MTX] and the deoxyuridine incorporation after exposure to MTX. This observation suggests that 1) intracellular TMQ levels may be used as an internal standard to correct steady state intracellular MTX levels for variations such as cell size, and 2) in analogy to tissue-culture models, decreased intracellular accumulation of MTX may contribute to clinically encountered drug resistance.
Leukemia 1987 Feb
PMID:Effects of methotrexate and of the "nonclassical" folate antagonist trimetrexate on human leukemia cells. 295 24

Mouse leukemia cells (p388D1) were grown in medium containing various amounts of mitomycin C for 4 h. Cellular localization of protein B23 was detected using an immunofluorescence technique. Translocation of protein B23 from nucleoli to the nucleoplasm was observed with increasing dose of mitomycin C. To study the correlation of B23 translocation and drug resistance, three human colon carcinoma cell lines, HCT116, HCT116b (a line that is natively or intrinsically resistant to mitomycin C), and HCT116-44 (a line with an acquired resistance to mitomycin C), were employed. These cells were incubated with 1--150 micrograms/ml of mitomycin C. The drug concentration that caused 50% of the cells to have complete translocation (IC50) was determined for each cell line. The IC50 values of HCT116, HCT116b and HCT116-44 were 6, 10 and 50 micrograms/ml, respectively. These IC50 values correlate well with the mitomycin C resistant phenotype of these tumor cells as determined by other in vivo and in vitro assays (Willson, et al. (1985) Cancer Res., 45, 5281-5286). These results identify an inverse relationship between the ease of protein B23 translocation and the degree of mitomycin C resistance in human colon carcinoma cells. This relationship applies to cells that have either acquired mitomycin C resistance or intrinsic resistance to the drug.
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PMID:Assessment of tumor cell sensitivity to mitomycin C by "B23 translocation" assay. 313 7

In an attempt to find how much the low therapeutic effectiveness of antitumor drugs against so-called chemotherapy-refractory tumors such as colon carcinoma depends on drug sensitivity at the cellular level, sensitivity of five carcinoma cell lines (three colorectal, one pancreatic, and one renal) to nine typical anticancer agents was compared in vitro with that of four generally chemotherapy-susceptible leukemia cell lines. Sensitivity was assessed in terms of the percentage cell growth in control cultures, which was determined by exposing exponentially growing cells for 48 h to the following antitumor drugs: 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), adriamycin (ADM), bleomycin (BLM), cisplatin (DDP), etoposide (VP-16), 5-fluorouracil (5FU), mitomycin C (MMC), methotrexate (MTX), and vinblastine (VLB). As expected, 10-fold or greater differences in sensitivity were scarcely ever observed between the two kinds of cell lines. Thus, we recorded a result of more (or less) sensitivity when there was a difference of 3-fold or more; and compared the drug sensitivity in every pair of carcinoma and leukemia cell lines (20 pairs for each drug). We found that carcinoma cell lines were less sensitive to VP-16, ADM, DDP, and MTX than leukemia cell lines in 18, 15, 12, and 10 of 20 pairs, respectively; only one opposite case was observed, with DDP. On the other hand, no such tendency between the two groups was observed with BLM, 5FU, or MMC. Overall, significantly different sensitivities were observed between them in 91 out of 180 pairs (i.e., 9 antitumor drugs x 5 carcinomas x 4 leukemias), and carcinoma cell lines were less sensitive than leukemia cell lines in 79 of these 91 pairs. These results suggest that the refractoriness of colon carcinoma, etc. to chemotherapy is, at least in part, due to low drug sensitivity of the tumor cell itself.
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PMID:Comparison of cellular basis of drug sensitivity of human colon, pancreatic, and renal carcinoma cell lines with that of leukemia cell lines. 316 59

Sparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.
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PMID:In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models. 322 41

Antitumor activity against the Lewis lung carcinoma in mice is reported for the series of 36 acridine-substituted derivatives of the antileukemia agent amsacrine. This series is the one from which the analogue N,5-dimethyl-9-[(2-methoxysulfonylamino)phenylamino]-4-acridinecarboxamide (CI-921), presently in clinical trial, was chosen. The analogues also were tested in vitro by comparing growth inhibition data [IC50 values (concentration required to reduce growth of cultured cells to 50% of that of untreated cultures)], using L1210 murine leukemia cells and HCT-8 human colon carcinoma cells. Determined IC50 values were highly dependent on the culture medium used, and it was found that the presence of ascorbate in the medium had a major effect on the stability of compounds to oxidation. A survey of 115 analogues of amsacrine indicates that a low ratio of IC50 values (HCT-8/L1210) is necessary but not sufficient for good antitumor activity against the solid tumor. DNA binding constants did not in themselves predict activity, although they were related to dose potency. Other factors, such as drug lipophilicity, acridine base strength, and drug solubility, also are involved, probably in providing effective drug distribution. It is concluded that in vitro assay data provide information useful for drug design but that other factors also are important for in vivo activity.
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PMID:Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma. 334 11

A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross-resistance as measured by the ratio of IC50 values varied from 2-fold and 272-fold. A high degree of resistance was found to be associated with the presence of amino or substituted amino groups on the acridine ring system. Logarithmic IC50 values were determined for other cell lines (L1210 leukaemia, Lewis lung carcinoma and HCT-8 human colon carcinoma) and were compared with those for the P388 lines to determine the degree of linear correlation. HCT-8 values were strongly correlated with P/ADR values (r = 0.84) while L1210 values correlated strongly with those of the sensitive P388 line (r = 0.98). Values for Lewis lung cells showed an intermediate pattern and correlated with a linear combination of values for both P388 lines (r = 0.88). Examination of available IC50 values for a number of rodent and human cell lines indicates that their sensitivity patterns are either P388-like or else intermediate between P388 and P/ADR. The series of amsacrine derivatives may be useful in characterizing the nature and degree of multidrug-resistance in cultured cell lines.
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PMID:Relationship between the structure of analogues of amsacrine and their degree of cross-resistance to adriamycin-resistant P388 leukaemia cells. 335 8


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