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 amino- and carboxyl-terminal amino acid sequences of proteins (p10, p12, p15, and p30) coded by the gag gene of Rauscher and AKR murine leukemia viruses were determined. Among these proteins, p15 from both viruses appears to have a blocked amino end. Proline was found to be the common NH(2) terminus of both p30s and both p12s, and alanine of both p10s. The amino-terminal sequences of p30s are identical, as are those of p10s, while the p12 sequences are clearly distinctive but also show substantial homology. The carboxyl-terminal amino acids of both viral p30s and p12s are leucine and phenylalanine, respectively. Rauscher leukemia virus p15 has tyrosine as the carboxyl terminus while AKR virus p15 has phenylalanine in this position. The compositional and sequence data provide definite chemical criteria for the identification of analogous gag gene products and for the comparison of viral proteins isolated in different laboratories. On the basis of amino acid sequences and the previously proposed H-p15-p12-p30-p10-COOH peptide sequence in the precursor polyprotein, a model for cleavage sites involved in the post-translational processing of the precursor coded for by the gag gene is proposed.
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PMID:Amino- and carboxyl-terminal amino acid sequences of proteins coded by gag gene of murine leukemia virus. 20 97

The development of microbial enzymes for cancer therapy presents difficulties not commonly experienced with biological drugs. The development of the enzyme asparaginase from Escherichia coli in the USA and of the serologically different asparaginase from the plant pathogen Erwinia carotovora in this Establishment, has not only added to the choice of antileukaemia drugs but also provided a valuable guide to the selection and development of new therapeutic enzymes. Our own programme has led to the study of enzymes that degrade other amino acids (glutamine, arginine, phenylalanine and tyrosine) that appear to be important to certain leukaemia cells. Microbes with only remote associations with man were considered as a source of these to minimize initial immunological sensitivity. In the case of erwinia asparaginase the benefits of this have probably included a lower incidence of anaphylaxis compared with the escherichia enzyme. The selection of a stable, high-affinity enzyme that operates efficiently under physiological conditions ensures effective depletion of a circulating amino acid but the choice is very limited. It is also difficult to assess from laboratory tests the likely persistence, toxicity and efficacy of the enzyme in clinical use and to arrive at meaningful biological tests for the quality control of the finished product. Some of the difficulties will be described and proposals made for criteria of acceptance for this type of drug in experimental use.
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PMID:Amino acid degrading enzymes for cancer therapy. 41 22

The effect of the naturally occuring amino acids upon melphalan (L-phenylalanine mustard, L-PAM) toxicity to a host sensitive tissue, the granulocyte and macrophage precursor cells of murine bone marrow (CFU-C), was investigated. At physiological concentrations the L isomers of leucine and glutamine were found to be the most effective of the naturally occurring amino acids in reducing drug toxicity. Tyrosine, phenylalanine and methionine also protected murine CFU-C from melphalan toxicity although the amount of protection provided by these amino acids at physiological concentrations was less than that provided by leucine and glutamine. Little difference was observed in the pattern of amino acid protection of murine CFU-C and murine L1210 leukemia cells. Murine CFU-C however were more sensitive to melphalan both in the absence and presence of amino acids.
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PMID:Amino acid conferred protection against melphalan: comparison of amino acids which reduce melphalan toxicity to murine bone marrow precursor cells (CFU-C) and murine L1210 leukemia cells. 44 10

A set of 23 aniline mustards [X-C6H4N(CH2CH2Cl)2] have been tested for their activity against B-16 melanoma in mice. The following quantitative structure-activity relationship (QSAR) correlates the data well: log 1/C = -2.06 sigma - 0.15 pi - 0.13 pi2 + 4.13 (r = 0.936). When this equation is compared with those formulated for aniline mustards acting against leukemia, it is found that log P0 (ideal lipophilicity) is higher for solid tumors. The QSAR brings out the unique activity of phenylalanine aniline mustard.
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PMID:Structure-activity relationship of aniline mustards acting against B-16 melanoma in mice. 51 75

An antitoxic polytissular principle extracted from various tissues, improves the survival time of the AKR genetically leukemic mouse and protects it against the toxicity of an antimitotic, the para-di-(2-chlorethyl)-1-phenylalanine, used in leukemia and myelomae.
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PMID:[Action of the polytissular antitoxic principle (PATP) on the genitically leukemic AKR mouse treated by para-di(2-chloroethyl)-L-phenylalanine (PDCPA)]. 82 Apr 73

Formyl-methionine-containing peptides (e.g. fMet-Leu-Phe) stimulate a variety of neutrophil functions by interacting with specific cell surface receptors which are coupled via G-proteins to stimulation of phospholipase C. Two markedly distinct cDNAs coding for formyl peptide receptors have recently been isolated from a rabbit and a human cDNA library respectively. To examine the hitherto unknown signal transduction properties of the formyl peptide receptor encoded by the human cDNA, we have used the PCR to clone this cDNA from poly(A)+ RNA of myeloid differentiated human leukaemia (HL-60) cells, and have injected the cDNA-derived receptor cRNA into Xenopus laevis oocytes. Receptor activity was determined electrophysiologically by measuring the agonist-dependent opening of intracellular Ca2+ concentration ([Ca2+]i)-independent Cl- channels. Injection of pure formyl peptide receptor cRNA did not lead to peptide-dependent changes in membrane current. In contrast, marked alterations of membrane current were observed in response to formyl peptides when the receptor cRNA was supplemented with poly(A)+ RNA isolated from undifferentiated HL-60 cells. Injection of the latter RNA did not lead to formyl-peptide-dependent alterations of membrane current. Binding studies using a radioiodinated formyl peptide revealed that injection of formyl peptide receptor cRNA alone led to expression of the formyl peptide receptor on the oocyte surface, and that co-injection of poly(A)+ RNA from undifferentiated HL-60 cells did not alter the level of receptor expression. Size fractionation of poly(A)+ RNA from undifferentiated HL-60 cells showed that the mRNA required to complement formyl-peptide-dependent signal transduction in oocytes had a size of approx. 3-3.5 kb. These results strongly suggest that the human formyl peptide receptor requires a specific cofactor(s), which is lacking in Xenopus oocytes but is present in undifferentiated HL-60 cells, to activate the second messenger pathway in oocytes. Identification of this factor will provide important information about the molecular mechanisms by which G-protein-coupled granulocyte-activating receptors stimulate phospholipase C.
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PMID:Complementation of formyl peptide receptor-mediated signal transduction in Xenopus laevis oocytes. 131 22

Differentiated human leukemia (HL 60) cells contain high numbers of receptors for the chemotactic factors, N-formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe) and complement component 5a (C5a), both coupled to pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins (G proteins). Agonist activation of either receptor stimulated binding of the GTP analog, guanosine 5'-[gamma-thio]triphosphate (GTP[S]), to membrane G proteins and by a similar extent in a non-additive manner. The possible interaction of the two receptors was studied by measuring agonist binding to one receptor in the presence of the other receptor agonist. fMet-Leu-Phe and C5a had no effects on [125I]C5a and fMet-Leu-[3H]Phe receptor binding, respectively, when studied in the absence of regulatory ligands. Similarly, the inhibitory effects of NaCl and GDP on agonist receptor binding were not altered in the presence of the other receptor agonist. In contrast, in the presence of the GTP analogs, GTP[S] and guanosine 5'-[beta,gamma-imino] triphosphate, fMet-Leu-Phe and C5a reduced the binding of [125I]C5a and fMet-Leu-[3H]Phe, respectively, in a concentration-dependent manner. The potencies of the GTP analogs to inhibit binding of [125I]C5a and fMet-Leu-[3H]Phe was increased about 3-fold by fMet-Leu-Phe and C5a, respectively. The data presented suggest that fMet-Leu-Phe and C5a receptors share the same G protein pool in membranes of HL 60 cells and that activation of these G proteins by one of the two receptors decreases the availability of G proteins for the other receptor.
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PMID:G protein-mediated receptor-receptor interaction: studies with chemotactic receptors in membranes of human leukemia (HL 60) cells. 147 Feb 18

The effect of galactose-6-mustard (G-6-M) on cell growth and cell cycle kinetics was studied in murine P388 leukemia and Chinese hamster ovary (CHO) cells in vitro and compared with the effect of L-phenylalanine mustard (L-PAM). The IC50 values of G-6-M for the P388 and CHO cells were 10 and 100 microM, respectively. No difference of the IC50 value of L-PAM (2 microM) between the two cell lines was found. The effect of G-6-M and L-PAM on cell kinetics was similar for the two cell lines at IC50 doses. The relative cell outflow from the G2 stage was inhibited to a higher extent than the relative cell outflow from the S phase. The relative cell outflow from the G1 stage was only partly inhibited. These results are discussed in relation to growth conditions, differences in DNA repair capacity, and cellular uptake of G-6-M between P388 and CHO cells.
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PMID:Comparative studies of galactose-6-mustard and L-phenylalanine mustard on cell growth and cell cycle kinetics in vitro. 152 89

Retroviral infections are frequently associated with immunosuppression. Retroviral transmembrane envelope proteins (TM proteins) play an important role in this phenomenon. CKS-17, a synthetic heptadecapeptide, represents the immunosuppressive site of these retroviral TM proteins. Here we support on the further delineation of this immunosuppressive site using CKS-17-derived hexapeptides. The N-formyl-methionyl-leucyl-phenylalanine-induced monocyte polarization assay was used throughout this study because this monocyte function has been shown to be highly sensitive to TM protein p15E-related immunosuppression. We found that in addition to CKS-17 one CKS-17-derived hexapeptide, LDLLFL, reversibly inhibited monocyte polarization, with 50% inhibitory concentrations of 20 and 2 microM respectively. LDLLFL-mediated inhibition was sequence specific because the reverse peptide LFLLDL and scrambled peptides were not inhibitory. Hexapeptides corresponding to LDLLFL, but derived from various retroviruses other than murine leukemia virus, also inhibited monocyte polarization. Peptides most homologous to LDLLFL-LDILFL (feline leukemia virus) and LDLLFW (human T lymphotropic virus types I and II)--were the most potent inhibitors. Peptides homologous to primate and human endogenous proviruses were not suppressive. LDLLFL and some of its homologous also inhibited polarization of neutrophilic granulocytes. These findings lend further support to the view that conserved retroviral TM protein-related peptides can play an important role in suppression of inflammatory cell function as encountered in retrovirus-associated immunosuppression.
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PMID:Synthetic hexapeptides derived from the transmembrane envelope proteins of retroviruses suppress N-formylpeptide-induced monocyte polarization. 154 10

Membranes of myeloid differentiated human leukemia (HL 60) cells contain receptors for the chemotactic peptide, fMet-Leu-Phe (fMet, N-formylmethionine), interacting with pertussis-toxin-sensitive guanine-nucleotide-binding proteins (G proteins). Agonist activation of the receptors increases binding of the GTP analog, guanosine 5'-[gamma-thio]triphosphate (GTP[S]), to membrane G proteins, at 30 degrees C only in the presence of exogenous GDP. In contrast, at 0 degrees C fMet-Leu-Phe stimulated binding of GTP[S] to G proteins maximally without addition of GDP. Under conditions resulting in marked degradation of membrane-bound GDP, control binding of GTP[S] measured at 0 degrees C was significantly increased, whereas the extent of agonist-stimulated binding was reduced. Furthermore, there was a rapid spontaneous release of membrane-bound GDP at 30 degrees C, but not at 0 degrees C. The data suggest that in intact membranes of HL 60 cells G proteins are initially in a GDP-liganded form, which state allows the receptor-induced exchange of bound GDP for GTP[S] at low temperature. In contrast, at or near physiological temperature, bound GDP is rapidly released (and degraded), resulting in unligated G proteins to which GTP[S] will bind independently of agonist-activated receptors.
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PMID:Role of GDP in formyl-peptide-receptor-induced activation of guanine-nucleotide-binding proteins in membranes of HL 60 cells. 157 1


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