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)

Delivery of the bifunctional alkylating agent, PTT.119 [p-F-L-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy-HCl], into tumor cells is significantly greater compared to L-phenylalanine mustard (L-PAM) as demonstrated by the 2-fold reduction in PTT.119 dosage required to reduce the viable L1210 cell fraction by 50% (TCD50). This increased uptake and consequent cytolytic efficacy observed in Dulbecco's phosphate buffer was more apparent in culture medium; under this physiologic condition the TCD50 concentration of PTT.119 was 5 times lower than L-PAM. PTT.119 entry into leukemia cells was examined using competition transport assays assessing the ability of the tripeptide to compete with various amino acids and nonmetabolizable substrates for carrier receptors of the L, A and ASC transport systems. A 1-min exposure to a 1- to 50-fold excess of PTT.119 prior to addition of radiolabeled substrates significantly reduced within 60 s both sodium-dependent and sodium-independent uptake of leucine, methionine, threonine and alpha-[1-14C]-aminoisobutyric acid (AIB), but not MeAIB. In complimentary studies, L1210 cells were protected from PTT.119 cytolysis by an 8,000-fold excess of AIB, whereas beta-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) only abrogated tripeptide cytotoxicity by 95-97% even at BCH:PTT.119 ratios of 200,000. Leucine and methionine protection were significantly less effective; the TCD50 of leucine and methionine were 3.23 and 2.4 microM, respectively, compared to 11.41 microM for AIB and 7.96 microM for BCH. In addition, MeAIB and phenylalanine were totally unable to protect L1210 cells from PTT.119-induced cytolysis. The data indicate that L121 cells actively transport PTT.119 primarily by the BCH-sensitive, AIB-sensitive, MeAIB-insensitive L carrier system. A second, BCH-insensitive, AIB-sensitive and MeAIB-insensitive carrier which is also involved in tripeptide uptake is probably the ASC system.
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PMID:Multiple transport pathways for L1210 cells: uptake of PTT.119, a bifunctional alkylator with carrier amino acids. 341 61

Deoxyspergualin, the 15-deoxy derivative of the antibiotic spergualin, is a novel guanidino analog structurally related to spermine. Deoxyspergualin has significant activity in selected experimental tumor models, and clinical trials have been initiated. Described here are in vivo evaluations of the therapeutic activity of deoxyspergualin against murine leukemia lines specifically resistant to eight clinically useful antitumor drugs. These were P388 lines resistant to doxorubicin, vincristine, L-phenylalanine mustard, cisplatin, ara-C, and methotrexate and L1210 lines resistant to 5-FU, L-phenylalanine mustard, and cyclophosphamide. Sensitivity to deoxyspergualin was evaluated in parallel comparisons of each resistant leukemia to the sensitive line from which it had been derived. All experiments were repeated at least once for confirmation of results. Responses were quantitated in terms of the change in tumor cell numbers from the beginning of treatment to the end of treatment as estimated from the median survival times of dying mice. The results indicated that P388 leukemia resistant to cisplatin (P388/DDPt) was cross-resistant to deoxyspergualin. No cross-resistance was observed in leukemias resistant to doxorubicin, vincristine, ara-C, methotrexate, or cyclophosphamide. L1210 resistant to 5-FU (L1210/5-FU) was collaterally sensitive to deoxyspergualin. Although cross-resistance was also observed in P388/L-PAM, L1210/L-PAM retained sensitivity to deoxyspergualin. Total glutathione concentrations in P388/L-PAM and L1210/L-PAM provided no apparent explanation for this unexpected result. It may be tentatively concluded that resistance to cisplatin, L-PAM, or other DNA alkylators or cross-linkers may increase the potential for cross-resistance to deoxyspergualin. This conclusion requires verification with additional alkylating agents, with drug-resistant human tumor cell lines, and with prospective clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cross-resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo. 343 39

Granulocytes from patients with chronic myelogenous leukaemia (CML) have been previously shown to have aberrant sialylation of membrane glycoproteins. We have examined the granulocytes from CML patients receiving intermittent chemotherapy to determine the relationship of the oligosaccharide changes to treatment. Compared to cells from non-leukaemic patients, granulocytes from untreated CML patients showed less adherence to nylon wool, decreased reactivity with peanut lectin, and decreased binding of the synthetic chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLP). Granulocytes from CML patients treated with chemotherapy showed nylon wool adherence, peanut lectin reactivity and FMLP binding comparable to non-leukaemic cells. Chemotherapeutic agents may interfere with oligosaccharide synthesis with a resulting change in the composition of cell surface glycoconjugates.
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PMID:Changes in the granulocyte membrane following chemotherapy for chronic myelogenous leukaemia. 345 89

During recent years N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been developed as targetable drug carriers. These soluble synthetic polymers are internalized by cells by pinocytosis and they can be tailor-made to include peptidyl side-chains degradable intracellularly by specific lysosomal enzymes. Thus they provide the opportunity fo achieve controlled intracellular delivery of anticancer agents. The anthracycline antibiotic daunomycin, and protein synthesis inhibitor puromycin, were bound to HPMA copolymers via several different peptide side-chains, including Gly-Gly, Gly-Phe-Leu-Gly and Gly-Phe-Phe-Leu. Incubation of polymer-drug conjugates with isolated lysosomal enzymes (either a mixture of rat liver lysosomal enzymes or purified thiol-dependent lysosomal proteinases, cathepsins L and B) showed that significant release of drug occurred over 20 h, more than 20% of daunomycin and more than 80% of puromycin being liberated. To test their pharmacological activity conjugates were incubated with either the mouse leukaemia L1210, or the human lymphoblastoid leukaemia CCRF in vitro. The conjugates tested were all less effective than free daunomycin, but they showed differential toxicity against L1210 depending on the aminoacid sequence of their drug-polymer linkage. Inclusion of fucosylamine-terminating side-chains into the HPMA copolymer structure increased the affinity of conjugates for the L1210 cell membrane and resulted in increased toxicity. In contrast HPMA-daunomycin conjugates with or without fucosylamine affected CCRF cells equally, but this cell line was more sensitive than the mouse leukaemia to both free and polymer-bound daunomycin. Incubation of L1210 cells in polymer-bound daunomycin for 72 h, followed by plating cells out in low density in drug-free medium, showed that a concentration of polymer-bound drug (184 micrograms ml-1) could be selected to achieve a cytotoxic effect.
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PMID:Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro. 346 94

Recently, a novel approach has been used in the treatment of leukemia: induction of the leukemic cells to undergo terminal differentiation. Based on its in vitro ability to induce differentiation in several myeloid leukemic cell lines, retinoic acid (RA) has been applied clinically in cases of myelodysplastic syndromes and acute myeloid and promyelocytic leukemia. In the present study we have determined in detail the ability of RA to induce expression of granulocytic functions in a human promyelocytic leukemia cell line (HL-60) and compared it with that of dimethylsulfoxide (DMSO). Several granulocytic characteristics (phagocytosis, surface adherence and generation of free radicals in response to phorbol-ester) were induced to the same degree by both agents. Other normal neutrophil functions, including lysozyme accumulation, spontaneous migration, chemotactic activity toward zymosan-activated serum (containing C5a), the peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and spontaneous motility in semi-solid medium were induced by DMSO, but they were absent or incompletely expressed in RA-induced cells. In contrast, only RA induced migration toward leukotriene B4 (LTB4). Simultaneous treatment with RA and DMSO proved synergistic with respect to morphological maturation and several functions (e.g. NBT reduction), but complementary stimulation of other activities (e.g. chemotaxis, lysozyme content) could not be demonstrated. Furthermore, characteristics induced by DMSO (i.e., expression of C5a and FMLP receptors and accumulation of lysozyme) were inhibited by the addition of RA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of granulocytic functions by leukemic promyelocytic HL-60 cells: differential induction by dimethylsulfoxide and retinoic acid. 347 6

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N''-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.
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PMID:Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy. 356 26

The fatty acid compositions of several tumors have been modified sufficiently to alter some of their properties and functions. These modifications were produced in culture by adding specific fatty acids to the growth medium or by feeding fat-supplemented diets to tumor-bearing mice. The phospholipid fatty acid composition of the plasma membrane was modified, but there were no changes in membrane phospholipid or cholesterol content or in phospholipid head group composition. Each of the most abundant membrane phosphoglyceride fractions exhibited some degree of fatty acid modification. Electron spin resonance measurements with nitroxystearate spin probes indicated that the fatty acid modifications were sufficient to alter the physical properties of the plasma membrane. The K'm for methotrexate uptake was reduced when the L1210 leukemia cells were enriched in linoleic acid. Even when the kinetics of uptake at 37 C were not altered, such as for melphalan and phenylalanine uptake, the temperature transition of transport was modified, indicating that these transport systems also are responsive to the membrane fatty acid modifications. Enrichment with highly polyunsaturated fatty acid did not affect either the growth rate or radiosensitivity of the L1210 leukemia. However, the sensitivity of the L1210 cells to the cytotoxic effects of Adriamycin and hyperthermia was increased. These findings suggest the possibility that fatty acid modification of tumors may be a useful adjunct to certain currently available therapeutic modalities.
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PMID:Membrane fatty acid modification in tumor cells: a potential therapeutic adjunct. 357 98

Sodium cyanate is a selective in vivo inhibitor of protein synthesis in a variety of mammalian tumor cells without a corresponding effect on the normal tissues of tumor-bearing animals. The in vivo decrease of protein synthesis observed 4 h post-NaOCN i.p. administration in the murine P388 leukemia cell cannot be explained by decreased amino acid pools in the mouse peritoneal cavity. In addition, the decrease in protein synthesis observed with NaOCN in isolated P388 cells was shown not to be secondary to (a) alterations in the kinetics of amino acid transport or (b) effects on total nucleotide pools. The incorporation of [14C]phenylalanine in P388 cell-free lysates from NaOCN-pretreated mice was significantly decreased to approximately 55% of control lysates in the presence of exogenous amino acids. The addition of exogenous calf liver tRNA to the lysates did not alter this result. However, no difference was observed in polyuridylic acid-directed [14C]phenylalanine incorporation into polypeptides in micrococcal nuclease-treated P388 lysates from NaOCN-pretreated or control mice. Quaternary initiation complex (48S) formation and mRNA synthesis were found to be significantly decreased by 35 and 38%, respectively, in P388 cells from NaOCN-pretreated mice. DNA synthesis was decreased by 66% of control at 1 h and 62% at 4 h post-NaOCN i.p. administration. No apparent effect with NaOCN was observed on total RNA synthesis in P388 cells. These results suggest that the decrease in P388 cell protein synthesis observed with NaOCN in vivo appears to be due to alterations manifested in the synthesis of cellular mRNA and protein synthesis initiation processes. NaOCN does not appear to affect the P388 cell ribosomal machinery, tRNA, or protein synthesis elongation processes.
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PMID:Mechanism of decrease of protein synthesis by sodium cyanate in murine P388 leukemia cells. 362 Nov 95

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

Metastatic migration of murine L1210 leukemia cells, sensitive and resistant to the antitumor agent L-phenylalanine mustard, from the peritoneal cavity of mice to the liver resulted in a 2-fold elevation in their GSH content. This increase in GSH was accompanied by a corresponding increase in their resistance to the drug. Cell surface binding studies with the non-penetrating disulfide, 6,6'-dithiodinicotinic acid, indicated that both tumors isolated from the liver had a greater than 5-fold elevation in surface sulfhydryls when compared to their ascitic counterparts. These results indicate a role for the hepatic microenvironment in the maintenance of tumor cell GSH, drug responsiveness, and surface sulfhydryls.
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PMID:Hepatic-mediated elevation and maintenance of metastatic tumor cell glutathione. 370


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