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

PTT.119 [p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met ethoxy HCl], a new synthetic tripeptide, was highly effective against the L-phenylalanine mustard (L-PAM) resistant (L1210/L-PAM and P388/L-PAM) tumor lines, as well as the sensitive L1210 leukemia. Cytolytic activity of PTT.119 against all three leukemias was significantly greater than equimolar doses of L-PAM. These in vitro results paralleled the significant increases in mean survival times of hosts and, in some cases, abrogations of tumor formation observed in the in vivo bioassays of PTT.119-treated L1210 and L1210/L-PAM cells. Dose-response studies failed to demonstrate cross-resistance to the tripeptide by L-PAM resistant cells. Doses of PTT.119 required to reduce the viable fraction by 50% (tissue culture dose 50, TCD50) or 100% (TCD100) were 1.3- to 3-fold lower for the L-PAM resistant cells than for the L1210 leukemia. In comparison, L-PAM was unable to completely eliminate cell survival; 0.2 to 3% of the cells in all three leukemias remained viable even at doses of 75 and 163 microM. In similar studies, L1210 leukemia cells made resistant to methotrexate (L1210 MTX) and cisplatin (L1210DDP) were also completely susceptible to PTT.119; TCD50 values of the two resistant lines were 1.94 microM for L1210 MTX and 0.525 microM for L1210DDP compared to 2.38 microM for the susceptible parent L1210S leukemia. Continuous low-dose PTT.119 treatment of MJY-alpha mammary tumor cells for 8 months and exposure of L1210 leukemia to escalating levels of tripeptide for over 100 passages failed to select or induce drug-resistant phenotypes in either cell line. PTT.119 appears to be a poor mutagen and is unlikely to readily increase the probability of drug-resistant mutants in the tumor cell populations.
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PMID:PTT.119, p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met ethoxy HCl, a new chemotherapeutic agent active against drug-resistant tumor cell lines. 404 Mar 66

Permeabilised, dimethyl sulphoxide-differentiated HL-60 human myelomonocytic leukemia cells accumulate 45Ca in an ATP-dependent manner. The 45Ca is taken up by a pool thought to be a component of the endoplasmic reticulum. Inositol trisphosphate induced a rapid release of Ca from this pool, suggesting that this molecule which is formed in these cells in response to f-Met-Leu-Phe may play a role in agonist-induced Ca metabolism.
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PMID:Inositol 1,4,5-trisphosphate may be a signal for f-Met-Leu-Phe-induced intracellular Ca mobilisation in human leucocytes (HL-60 cells). 633 56

A new synthetic tripeptide (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl), PTT.119, was demonstrated to have significant cancericidal activity against seven in vitro tumor cell lines of different origins and etiologies and against primary human AMML, ALL, and hairy cell leukemias. Viabilities of each murine tumor and rabbit, marmoset, and human leukemia and lymphoma line were significantly reduced by treatment with 1-50 micrograms PTT.119 in media containing serum. Continuous 24-h exposure or pulse treatment as short as 15 and 30 min with the tripeptide resulted in irreversible damage to the tumor cells. Under identical treatment conditions, freshly isolated human leukemic cells, particularly ALL lymphoblasts, were even more susceptible to PTT.119 than any of the tested tumor cell models. Examination of the parameters of PTT.119 activity revealed that reductions of tumor cell survival were dependent on the concentration of the tripeptide. Prolongation of PTT.119 exposure from 15 min to 24 h increased the rates of tumor cell death but did not proportionally reduce the numbers of surviving cells. Assessment of tumor cell viabilities for 5 consecutive days following pulse exposure to PTT.119 demonstrated increasing reductions in tumor cell survival, which were greatest 5 days after treatment of PTT.119 was compared with its three parental components either as individual agents or as a mixture. Both the alkylator moiety, m-sarcolysin (m.L.SL) alone or together with p-fluoro-phenylalanine and L-methionine ethoxy HCl, and L-PAM (L-phenylalanine and L-methionine ethoxy HCl, and L-PAM (L-phenylalanine mustard), the p-isomer of m.L.SL, were 1,5- to 3-fold less cytotoxic to L1210 leukemia and MJY-alpha mammary tumor cells than PTT.119. Covalent linkage of the amino acid residues to m.L.SL yielded a molecule with greatly augmented cancericidal activity capable of acting against a broad spectrum of tumor cells.
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PMID:Increased cancericidal activity of PTT.119, a new synthetic bis-(2-chloroethyl)amino-L-phenylalanine derivative with carrier amino acids. I. In vitro cytotoxicity. 642

The cancericidal efficacy of a new synthetic tripeptide was demonstrated using both in vitro cultures and in vivo tumorigenic assays. The antitumor agent PTT.119 (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl) was highly effective against three virulent murine tumor models: the L1210 leukemia, MJY-alpha mammary tumor and B16 melanoma. Treatment of tumor cells for periods as short as 15 min to 4 h with concentrations of 1-50 micrograms PTT.119/ml irreversibly reduced tumor cell viability, as evidenced by vital dye exclusion and abrogation of tumor formation and prolongation of host survival. Examination of the sensitivity of mice to PTT.119 revealed that the in vitro antitumor activity of the synthetic tripeptide was exerted at concentrations easily attainable and well tolerated in vivo.
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PMID:Increased cancericidal activity of PTT.119; a new synthetic bis-(2-chloroethyl)amino-L-phenylalanine derivative with carrier amino acids. II. In vivo bioassay. 669 28

Rat natural killer cell Met-ase-1 (RNK-Met-1) is a 30,000 M(r) serine protease (granzyme) found in the cytolytic granules of CD3- large granular lymphocytes (LGL) with natural killer (NK) activity. To characterize the genomic sequences responsible for the CD3- LGL-restricted expression of this gene, we screened a rat genomic library with RNK-Met-1 cDNA, and obtained bacteriophage clones that contained the RNK-Met-1 gene. The RNK-Met-1 gene comprises 5 exons and spans approximately 5.2 kilobases (kb), exhibiting a similar structural organization to a class of CTL-serine proteases with protease catalytic residues encoded near the borders of exons 2, 3, and 5. The 5'-flanking region of the RNK-Met-1 gene contains a number of putative promoter and enhancer regulatory elements and shares several regions of homology with the 5'-flanking region of the mouse perforin gene. We have prepared nested deletions from approximately 3.3 kb of the 5'-flanking region of the RNK-Met-1 gene, and inserted these upstream of the chloramphenicol acetyltransferase (CAT) reporter gene. These 5'-flanking RNK-Met-1-CAT constructs were transiently transfected into rat LGL leukemia, T-lymphoma, and basophilic leukemia cell lines. The transcriptional activity of the RNK-Met-1 5'-flanking region was strong, restricted to the RNK-16 LGL leukemia and controlled by several positive cis-acting regions spread over at least 3.3 kb. The longest and most active 5'-flanking region (-3341 to -33) was also used to drive specific expression of beta-galactosidase in RNK-16. These data are consistent with the NK cell-specific expression of RNK-Met-1 and suggest the potential utility of this gene promoter in the development of transgene models of NK cell biology in vivo.
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PMID:Cloning and characterization of a novel NK cell-specific serine protease gene and its functional 5'-flanking sequences. 760 1

C5a, a potent chemoattractant for monocytes, neutrophils, and other leukocytes, binds to a cell surface receptor of the seven-transmembrane superfamily. Here we report the effects of substituting Gln for Glu199 of the human C5a receptor (hC5aR) expressed in a model cell system for chemoattractant receptor signaling, the rat basophilic leukemia cell line RBL-2H3. Both the binding affinity for hC5a and the EC50 for subsequent cellular signals are reduced 5-10-fold by this substitution. A peptide mimic of the C terminus of C5a also binds to, and activates, hC5aR. The response to this peptide is reduced in cells bearing mutated hC5aR, indicating that the mutation affects interactions with the C terminus of hC5a. The C-terminal peptide contains only two basic residues, a Lys and an Arg (assumed to be analogous to Lys68 and Arg74 of hC5a), which could act as counter-ions for Glu199 of the receptor. If the counter-ion on hC5a was Arg74, then it would be expected that intact hC5a and hC5a des-Arg74 would have identical affinities and potencies when interacting with mutant hC5aR. It was found, however, that the binding affinity and potency (for receptor signaling events) of hC5a des-Arg74 was always lower than for intact hC5a. Furthermore, the equivalent C-terminal peptide to hC5a des-Arg74 (i.e. lacking the C-terminal Arg) could partially activate the wild type but not the mutant receptor, whereas the converse peptide, containing Arg but containing Met instead of Lys, had equal potencies for both wild type and mutant receptors. Taken together these data indicate that Glu199 of hC5aR is not involved in an interaction with Arg74 of hC5a, but may interact with Lys68 of hC5a. Mutation of Glu199 defines a second ligand binding site on hC5aR, distinct from the previously characterized site on the receptor N terminus. Unlike the N-terminal binding site, this second site is associated not just with the interaction with hC5a, but also with receptor activation.
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PMID:Mutation of glutamate 199 of the human C5a receptor defines a binding site for ligand distinct from the receptor N terminus. 762 71

AZT (7.5 or 15 mg/kg/dose) and the neuropeptide methionine enkephalin (Met-ENK, 1 or 3 mg/kg/dose) were used in a combined protocol for therapy of established murine retroviral infection. In both models used, Friend virus leukemia (FV) and BM5 complex (lymphadenopathy and immune deficiency), the drug combination was able to reduce mortality and splenomegaly. While increasing mean survival time of those animals that did not survive infection by FV, when compared to infected control mice or mice treated with AZT alone, Met-ENK used alone at 1 and 3 mg/kg/mouse had no effect in reducing morbidity or mortality due to either virus. This suggested that Met-ENK had no direct antiviral effect at the concentrations used. In fact, mice treated with either single drug therapy or the combination still yielded virus in their spleen, even when splenomegaly was absent. The data suggest that Met-ENK, which has been reported to be immunostimulatory, acts in combination to improve the efficacy of AZT in reducing progression of disease in murine retrovirus models for human AIDS.
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PMID:Methionine enkephalin combined with AZT therapy reduce murine retrovirus-induced disease. 786 96

One mechanism by which cytotoxic T lymphocytes and natural killer cells inflict target cell death depends upon secreting the contents of their specialized cytoplasmic granules, containing a pore-forming protein, perforin, and a family of homologous serine proteases ("granzymes") with various enzyme activities. We used a granzyme B-specific mouse anti-human monoclonal antibody 2C5 and Western blotting to demonstrate that nuclear extracts of human interleukin-2-stimulated peripheral blood mononuclear cells, the human NK leukemia cell line YT, and the rat NK leukemia cell line RNK-16 contain abundant granzyme B. In interleukin-2-activated peripheral blood mononuclear cells, more than 50% of the total cellular granzyme B was present in the nuclear lysate. Nuclear granzyme B had an apparent molecular mass of approximately 32 kDa in human cells and approximately 30 kDa in RNK-16 and was eluted from immobilized heparin at the same NaCl concentration as granzyme B from cytoplasmic granules. Granzyme B that was affinity-purified with 2C5 from the nuclei of YT or human LAK cells was capable of efficiently cleaving synthetic peptide thiobenzyl ester substrates with the same specificity (peptide cleavage after aspartic acid) as granule-localized granzyme B. By contrast perforin, which colocalizes with granzymes in cytotoxic granules, was not detectable in nuclear lysates. Granzyme B was also demonstrated to be present in the nucleus and cytoplasmic granules of YT by immunohistochemical staining with monospecific anti-granzyme B antisera. Other protease activities (tryptase and peptide cleavage after methionine) were also readily detectable in nuclear and cytoplasmic lysates of YT, RNK-16, and LAK cells, as determined by the cleavage of the synthetic substrates N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT) and Boc-Ala-Ala-Met-S-benzyl, except that BLT-esterase activity was absent from the nucleus of YT. The localization of serine proteases in the nucleus was restricted to lymphocytes with cytotoxic capacity, as non-cytotoxic cell lines expressed high levels of peptide cleavage after methionine and tryptase activities in their cytoplasm, but possessed no nuclear serine protease activity. Furthermore, non-cytotoxic monkey kidney COS-7 cells transfected with an SV40-driven expression plasmid incorporating full-length human granzyme B cDNA contained abundant cytoplasmic granzyme B, but demonstrated minimal nuclear granzyme B accumulation. We conclude that serine proteases of NK cells are not restricted to cytolytic granules and, further, that their capacity to access the nucleus may have implications for the role of these enzymes in eliciting target cell death.
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PMID:Granule serine proteases are normal nuclear constituents of natural killer cells. 803 81

Several tyrosine phosphorylation sites in the insulin receptor kinase substrate IRS-1 are predicted to be within Tyr-Met-X-Met (YMXM) motifs, and synthetic peptides corresponding to these sequences are excellent substrates for the insulin receptor kinase in vitro (Shoelson, S. E., Chatterjee, S., Chaudhuri, M., and White, M. F. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 2027-2031). In this study, YMXM-containing peptides are shown to act as substrates for two members of the nonreceptor subfamily of tyrosine kinases, v-Src and v-Abl (the transforming gene products of Rous sarcoma virus and Abelson murine leukemia virus, respectively). For v-Src, a baculovirus expression system was used which was capable of producing milligram quantities of pure 60-kDa v-Src in Spodoptera frugiperda (Sf9) cells. The source of v-Abl was an Escherichia coli expression vector that produces a fusion protein of glutathione S-transferase with the abl catalytic domain. The synthetic YMXM-containing peptides had among the highest apparent affinities described to date for either tyrosine kinase, with Km values as low as 97 microM for v-Src and v-Abl. Comparisons with the results obtained with the insulin receptor kinase revealed differences in substrate specificity among the enzymes. In particular, v-Src was more tolerant of substitutions at the Met+1 and Met+3 positions in the YMXM motif than either v-Abl or the insulin receptor kinase but was more dependent on the presence of a preceding acidic amino acid. For v-Abl, the presence of threonine at any position in the YMXM motif caused a reduction in catalytic efficiency. Phosphorylated YMXM motifs are recognition elements for binding to the src homology 2 domains of phosphatidylinositol 3'-kinase and additional proteins; hence, differences in specificity of tyrosine kinases toward YMXM-containing proteins may have relevance to downstream signaling events.
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PMID:Phosphorylation of synthetic peptides containing Tyr-Met-X-Met motifs by nonreceptor tyrosine kinases in vitro. 822 78

A cDNA clone encoding a human NK serine protease was obtained by screening a lambda-gt10 library from the Lopez NK leukemia with the rat natural killer Met-ase (RNK-Met-1) cDNA clone. In Northern blot analysis human Met-ase (Hu-Met-1) cDNA hybridized with a 0.9-kb mRNA in two human NK leukemia cell lines, unstimulated human PBMC, and untreated purified CD3-CD56+ large granular lymphocytes. Unlike other members of the granzyme family that are highly expressed in activated peripheral T cells, the Hu-Met-1 transcript was barely detected in a population of PMA and ionomycin or IL-2-treated high density T cells. Several in vitro cultured Burkitt lymphomas, chronic- and promyeloid leukemias, acute lymphoblastic leukemias, and colon and ovarian carcinomas and colon and ovarian carcinomas did not express Hu-Met-1 mRNA. Hu-Met-1 mRNA expression in a small number of human T cell tumor lines did not correlate with any particular phenotype or stage of development. The presence of Hu-Met-1 mRNA closely correlated with the Met-ase activity of cellular lysates prepared from these various human peripheral blood subsets and in vitro cultured cell lines. Met-ase activity detected in whole cell lysates of cytotoxic lymphocytes was associated with the cytoplasmic granules of these cells. The nucleotide sequence of the Hu-Met-1 cDNA clone encodes a predicted serine protease of 257 amino acids. The predicted protein is an active enzyme of 232 amino acids with a calculated unglycosylated m.w. of 27,100. Hu-Met-1 is 66% identical to RNK-Met-1 at the amino acid level. The human and rat mature protein sequences conserve the active site His, Asp, and Ser amino acids that form the catalytic triad of serine proteases, all 8 cysteine residues, and several amino acids critical in the formation of the substrate binding pocket. The gene for the Hu-Met-1 serine protease is located on chromosome 19, which distinguishes it from any other member of the human granzyme family.
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PMID:Met-ase: cloning and distinct chromosomal location of a serine protease preferentially expressed in human natural killer cells. 824 61


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