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)

Methotrexate (MTX) analogues 27a-c bearing 2, omega-diaminoalkanoic acids (ornithine and its two lower homologues) in place of glutamic acid were synthesized by routes proceeding through N2-[4-(methylamino)benzoyl]-N omega-[(1,1-dimethylethoxy)carbonyl]-2, omega-diaminoalkanoic acid ethyl esters and N2-[4-(methylamino)benzoyl]-N5-[(1,1-dimethylethoxy)carbonyl]-2, 5-diaminopentanoic acid followed by alkylation with 6-(bromomethyl)-2, 4-pteridinediamine hydrobromide. Reactions at the terminal amino group of 27-type analogues or of appropriate precursors led to other MTX derivatives whose side chains terminate in ureido, methylureido, N-methyl-N-nitrosoureido, N-(2-chloroethyl)-N-nitrosoureido, and 4-chlorobenzamido groups. Also prepared were unsymmetrically disubstituted ureido types resulting from addition of ethyl isocyanatoacetate and diethyl 2-isocyanatoglutarate to the ethyl esters of 27a,b. Of these ureido adducts (32a,b and 33a,b, respectively), only 33a was successfully hydrolyzed to the corresponding pure acid, in this instance the tricarboxylic acid 34, a pseudo-peptide analogue of the MTX metabolite MTX-gamma-Glu. Biological evaluations of the prepared compounds affirmed previous findings that the gamma-carboxyl is not required for tight binding to dihydrofolate reductase (DHFR) but is operative in the carrier-mediated transport of classical antifolates through cell membranes. High tolerance levels observed in studies against L1210 leukemia in mice suggest the reduced potency may be due not only to lower transport efficacy but also to loss of the function of intracellular gamma-polyglutamylation. The N-nitrosoureas 30 and 31 showed appreciable activity in vivo vs. L1210, but the activity did not appear to be due to antifolate action as evidenced by their poor inhibition of both L1210 DHFR and cell growth in vitro.
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PMID:Syntheses and evaluation as antifolates of MTX analogues derived from 2, omega-diaminoalkanoic acids. 402 Aug 24

Elevated levels of polyamines and gamma-Glutamyl Transpeptidase were seen in the liver of P388 leukemia bearing mice. There was also increase in specific activity of beta-Hexosaminidase and the B/A isoenzyme ratio. Administration of a 2% solution of alpha-Difluoromethylornithine (DFMO) immediately after inoculation of tumor cells prevented increases in polyamines in liver, but did not have any effect on gamma-Glutamyl Transpeptidase. Almost normal ratio of beta-Hexosaminidase B to A was maintained during treatment. Endogenous ornithine level was not altered both in treated and untreated mice. However, proline level was elevated in liver of untreated mice and DFMO prevented this increase. Glutathione levels were altered both by leukemia and DFMO in the host liver. The effect of drug was more prominent in the early stages rather than during terminal stages of leukemic growth.
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PMID:Host liver changes in leukemic mice: effect of alpha-difluoromethyl ornithine, an inhibitor of polyamine synthesis. 615 40

Sequential administration of alpha-difluoromethyl ornithine and methylglyoxal bis(guanylhydrazone), two differently acting inhibitors of the biosynthesis of natural polyamines, produced a rapid and distinct therapeutic response in four children with advanced lymphoblastic and in one with myeloblastic leukemia. The synergism between the action of the two compounds was based upon a unique drug interaction; a preceding treatment with difluoromethyl ornithine greatly increased the uptake of subsequently administered methylglyoxal bis(guanylhydrazone) as verified by the actual determinations of the latter drug in the circulating leukemia cells. The side-effects associated with the combined drug regiment were either absent or mild.
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PMID:Synergistic action of two polyamine antimetabolites leads to a rapid therapeutic response in childhood leukemia. 679 28

Plasma membranes prepared from rat livers inhibited the in vitro growth of various mammalian cells including hepatoma cells in a concentration-dependent manner, showing almost complete arrest of cell growth at 0.1 mg protein/ml. Some of these cells tested, i.e., leukemia (L1210 and P388) and myeloma (P3-NS-1/1-Ag4-1) cells, were labile in the presence of plasma membranes (losing the viability), and CHO (Chinese hamster ovary) cells became round without detaching from the substratum. The culture medium preincubated with liver plasma membranes no longer supported the growth of hepatoma cells (AHI3 and AH66F). However, the 'conditioned' medium supplemented with L-arginine, supported the growth of the cells. Moreover, the addition of L-ornithine to the cultures containing plasma membranes markedly reduced the inhibitory effect of plasma membranes. The plasma membrane preparations were found to possess considerable arginase activity. There results seem to indicate the possible involvement of arginase in the inhibition of cell growth by liver plasma membranes.
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PMID:Arginase as an inhibitory principle in liver plasma membranes arresting the growth of various mammalian cells in vitro. 720 Aug 4

Over thirty amino acid and peptide derivatives of the antitumor drug daunorubicin (DM) were tested for their potency to inhibit EL4 leukemia cell growth in mice. The therapeutic effect of the basic amino acids lysine, arginine, ornithine, and 2,4-diaminobutyric acid coupled to the amino group of the DM moiety proved superior to that of the parent drug. The derivatized amino acids and their di- or tripeptides are significantly less toxic than DM, which enabled their administration at much higher doses. Seventy percent to 80% of tumor-bearing C57BL/6 mice were cured by multidose treatment with diaminobutyryl-DM, which was found to be the most efficient derivative.
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PMID:Improved antitumor activity of basic amino acid and dipeptide derivatives of daunorubicin on EL4 leukemia cells in mice. 723 50

The mechanistic effectiveness of various polyamine analogs and enzyme inhibitors is typically determined by their ability to deplete intracellular polyamine pools. In this study, we describe an assay that may prove useful in augmenting this relatively static assessment of drug action. The assay relies upon the substitution of 4-fluoro-L-ornithine (Fl-Orn) for ornithine as a polyamine precursor to provide a means to measure metabolic flux through polyamine pools. At concentrations up to 500 microM, the analog did not inhibit the growth of L1210 murine leukemia cells during incubations of up to 72 hr. Using HPLC, the analog was processed metabolically over time to what was deduced to be 2-fluoroputrescine, 6-fluorospermidine and 6-fluorospermine. The relative proportion of fluorinated polyamine analog to the natural polyamine increased with time and Fl-Orn concentration. The sum of the two was found to be nearly identical to the respective polyamine pool of control cells exposed instead to 500 microM ornithine. This indicates that Fl-Orn was recognized and utilized as a precursor at a rate very similar to that of ornithine itself. Using L1210 cells at different stages of cell growth, it was determined that the metabolic flux through the pools, as indicated by the rate of appearance of individual fluorinated polyamine species, reflected the proliferation status of the cells--non-growing cells failed to incorporate the analog. Likewise, in cell types with varying polyamine pool profiles, such as polyamine enzyme overproducers or those with constitutively different spermidine of spermine ratios, the incorporation of the fluorinated analogs into pools was found to be proportional to the size to the natural polyamine pool. In cells treated with inhibitors of S-adenosylmethionine decarboxylase, Fl-Orn incorporation indicated a total blockade of polyamine synthesis at that enzyme site. Overall, the Fl-Orn assay has demonstrated that polyamine pool profiles generally reflect the rate of flux through the pathway in proliferating cells, suggesting that most intracellular polyamines are freely exchangeable with those undergoing metabolic flux.
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PMID:Use of 4-fluoro-L-ornithine to monitor metabolic flux through the polyamine biosynthetic pathway. 750 94

Gyrate atrophy (GA) of the choroid and retina is an autosomal recessive chorioretinal degeneration, caused by deficiency of the mitochondrial matrix enzyme ornithine-delta-aminotransferase (OAT). This deficiency results in the accumulation of ornithine in the body fluids and leads to hyperornithinemia. Although the clinical phenotype is largely confined to the eye, OAT deficiency is a systemic disorder. With the final goal of applying gene therapy to this human genetic disease, we have established an in vitro model to test the correction of OAT enzymatic deficiency in mammalian cells, using OAT recombinant retroviruses. We report the construction of several Moloney murine leukemia virus (MoMLV)-based recombinant retrovirus vectors, in which the human OAT cDNA was placed under the transcriptional control of the mouse phosphoglycerate kinase (PGK) promoter or under the enhancer-promoter regulatory element derived from the MoMLV long terminal repeat (LTR). The retrovirus constructs were packaged in the PG13-GALV cell line and used to transduce C9, an OAT deficient cell line derived from Chinese hamster ovary cells (CHO-K1). We show that the recombinant retrovirus transfers the human OAT (hOAT) gene into C9. Expression of the hOAT gene in the transduced C9 deficient cell line exceeded the OAT mRNA level and enzymatic activity of endogenous human fibroblasts.
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PMID:Correction of ornithine-delta-aminotransferase deficiency in a Chinese hamster ovary cell line mediated by retrovirus gene transfer. 771 30

Ornithine delta aminotransferase (OAT) is a nuclear-encoded mitochondrial matrix enzyme that catalyzes the reversible transamination of ornithine to glutamate semialdehyde. In humans, genetic deficiency of OAT results in gyrate atrophy of the choroid and retina, a blinding chorioretinal degeneration usually beginning in late childhood. This disorder has been shown to be autosomal recessive, and is often caused by missense, nonsense, and/or frameshift mutations in the OAT gene. With the view of applying gene therapy, a Moloney murine leukemia virus (MoMLV)-based recombinant retrovirus vector has been constructed. The human OAT cDNA was placed under the control of the enhancer-promoter regulatory elements derived from the MoMLV long terminal repeat (LTR). The construct was transfected into the retroviral packaging cell lines GP + E - 86 and psi CRIP to produce virus particles. Supernatant from these OAT retrovirus producer cell lines were used to transduce mouse C57B1/6 embryonal fibroblasts. We showed that the recombinant retrovirus transfers the OAT gene to the recipient cells, which produce an OAT RNA transcript when analyzed by Northern blot. Western blot analysis and enzymatic assays confirmed the presence of an OAT polypeptide that has a high enzymatic activity in the transduced cell lines, even after a long period of time in vitro.
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PMID:Retrovirus-mediated gene transfer and expression of human ornithine delta-aminotransferase into embryonic fibroblasts. 794 32

CCRF-CEM human leukemia sublines resistant to short-term methotrexate (MTX) exposure as a result of decreased folylpolyglutamate synthetase (FPGS) activity were examined for their response to other cytotoxic agents. The R3/7 and R30dm sublines display 25 and 1%, respectively, of the FPGS activity of CCRF-CEM cells as measured with MTX in vitro. Response to agents in outgrowth experiments was examined under both continuous exposure (120 h, where MTX resistance is not observed) and short-term (6-14.5 h) exposure. During continuous exposure to various classes of agents, cross-resistance of R3/7 and R30dm that correlated with FPGS level was not observed, although some minor (< or = 3-fold) stochastic variations in sensitivity were noted. These agents included actinomycin D, Adriamycin, etoposide, vincristine, cisplatin, cytosine arabinoside, 5-fluorouracil, and some other antifolates. Cross-resistance during continuous exposure that did correlate with FPGS level was noted, however, to glutamate-containing thymidylate synthase inhibitors (including ICI D1694) and, to a minor extent, to 6-mercaptopurine and 5-fluorodeoxyuridine. Slight collateral sensitivity during continuous exposure that apparently correlated with FPGS level was noted to the lipid-soluble antifolate trimetrexate and to 5,8-dideazapteroyl-L-ornithine, an FPGS-specific inhibitor. In short-term exposures (where MTX resistance of the sublines is observed), the resistant sublines displayed sensitivity or cross-resistance to each agent that was qualitatively similar to that observed for the same agent in continuous exposure. Because of the requirement for reduced folates in the anti-DNA mechanism of action of fluoropyrimidines and the current clinical use of leucovorin (LV) to enhance their effects, the interaction of LV and fluoropyrimidines was examined. The results suggest that even highly FPGS-deficient cells are as sensitive to the effects of LV modulation as are wild-type cells even at fluoropyrimidine exposure times as short as 4 h.
Leukemia 1993 Dec
PMID:Cross-resistance studies of folylpolyglutamate synthetase-deficient, methotrexate-resistant CCRF-CEM human leukemia sublines. 825 99

A number of RA-VII derivatives having various amino acids including proline (6), pipecolic acid (11), norvaline (12), ornithine (14), aspartic acid (15) and methionine (20) in place of Ala2 have been synthesized from RA-X methyl ester (3) and evaluated for cytotoxicity to P388 leukemia and KB cells in vitro. Comparison of the cytotoxicity of these compounds suggests that the polarity and the length of the 2nd amino acid residue affect the activity. An NMR study revealed that, in solution, 6 and 11 are locked in one conformational state, corresponding to conformer A of RA-VII.
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PMID:Studies on RA derivatives. V. Synthesis and antitumor activity of Ala2-modified RA-VII derivatives. 840 89


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