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 important advances made in recent years in the therapy of adult ALL have been reviewed. The definition of bad-prognosis patients has been improved and includes those with T-ALL, ABLL, and Ph1+ALL, in addition to those presenting with evidence of extensive disease. In contrast to childhood ALL, induction chemotherapy should include another drug (or drugs) in addition to VCR and prednisolone, and one of the anthracycline drugs (ADR or DNR) has been employed most frequently in this context. Such therapy should result in a CR rate of 70 to 75%. Similar to the experience in childhood ALL, the improvement in haematological response rate has led to an apparent increase in CNS leukaemia, and the need for adequate CNS prophylaxis is stressed. Despite these improvements, the outlook for adults with ALL is not yet as good as it is for childhood ALL. Controlled studies involving large numbers of patients are urgently needed to provide answers to a number of questions. In induction therapy, the use of higher drug dosage, the use of more and other drugs, and the use of an individual patient's risk factors to determine drug dosage, must be assessed. The benefits of consolidation therapy and the optimal duration and intensity of maintenance therapy have yet to be established. Methods of CNS prophylaxis other than cranial irradiation and IT MTX must be carefully studied. These important questions require that adult patients with ALL should be concentrated in centres capable of providing optimal overall care and, at the same time, able to conduct the necessary clinical trials.
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PMID:The management of adult acute lymphoblastic leukaemia. 36 95

The effects of emetine on protein and DNA synthesis in vitro and in vivo were compared in P388 leukemia cells (P388/S) and in an adriamycin-resistant subline of P388 leukemia (P388/ADR), which was completely cross-resistant in vivo to emetine. In P388/ADR cells in vitro no apparent resistance to emetine was found; no difference in cytotoxicity was evident in P388/S or P388/ADR cells exposed to emetine in vitro for 1 or 6 hours. Protein and DNA synthesis was inhibited to a similar extent in P388/S and P388/ADR cells at equivalent concentrations of the drug. However, inhibition of protein synthesis by emetine in P388/ADR cells was more reversible than in P388/S cells when the cells were exposed to emetine and subsequently incubated in drug-free medium for 1 hour prior to addition of labeled L-leucine. Differences between P388/S and P388/ADR cells were evident in vivo. The duration of inhibition (greater than 90%) of protein and DNA synthesis in P388/ADR cells was about 8 hours compared to 24 hours in P388/S cells following administration of a therapeutic dose of 25 mg emetine/kg to tumor-bearing mice. The level of radioactivity in the P388/ADR cells 24 hours after in vivo administration of the emetine analog, (+/-)-[3'-14C]2,3-dehydroemetine, was only 26% of that in P388/S cells. This evidence suggests that the resistance of P388/ADR to emetine is due to decreased retention of the drug.
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PMID:Biochemical parameters of resistance of an adriamycin-resistant subline of P388 leukemia to emetine, an inhibitor of protein synthesis. 64 26

A subline of P388 leukemia resistant to adriamycin (P388/ADR) was developed by exposure to the drug in vivo. Resistance to adriamycin proved to be a stable characteristic of P388/ADR. There was no significant inhibition of nucleic acid synthesis in P388/ADR cells in vivo following a dose of 10 mg/kg of adriamycin in contrast to a prolonged and complete inhibition, particularly of DNA synthesis, observed in parental sensitive P388 leukemia cells. P388/ADR proved to be completely cross-resistant to a spectrum of anthracycline derivatives. Cross-resistance was observed to nonanthracycline DNA intercalating agents (with the exception of anthramycin), to agents which interfere with mitotic spindle function, and to antineoplastic inhibitors of protein biosynthesis (with the exception of bruceantin). P388/ADR was sensitive to antimetabolites and alkylating agents. Cross-resistance was also observed to several agents (ICRF-159, a terephthalanilide, taxol, lymphosarcin, bouvardin, and a crude extract of Ervatamia hyneana) whose mechanisms of action have not yet been clearly defined. This observation has proved useful in providing a lead for determination of mechanism of action of some of these drugs. The pattern of cross-resistance of a subline of P388 leukemia resistant to daunorubicin, though not studied extensively, appears to be similar to that of P388/ADR.
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PMID:In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia. 70 55

Spleen cells from 2- to 3-month-old normal mice of some strains having a low incidence of spontaneous leukemia were found to lyse cells of the spontaneous AKR leukemia K36 in the 51Cr release assay. Incubation of 51Cr-labeled ADR K36 cells with spleen cells from normal C57BL/6, C57L, C57BL/10, and RF mice resulted in the release of significantly more 51Cr than that released in the presence of medium alone. In contrast, 51Cr released from AKR K36 cells after incubation with spleen cells from mice of the high leukemic strains AKR and C58 was less than that released spontaneously. The results of competitive inhibition tests when C57BL/6 spleen cells were incubated simultaneously with 51Cr-labeled AKR K36 target cells and varying numbers of nonlabeled cells demonstrated that the cytotoxic activity of normal C57BL/6 spleen cells was directed against an antigen(s) associated with several leukemias, but that was undetectable on normal thymocytes. Pretreatment of C57BL/6 spleen cells with carbonyl iron and a magnet, which removed phagocytic macrophages, did not decrease the cytotoxic acitivity for AKR K36 cells.
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PMID:Lysis of leukemia cells by spleen cells of normal mice. 105 93

A new nitroxyl labeled tetracycline is synthesized. Proton NMR experiments of tetracycline, spin-labeled tetracycline, and the diamagnetic reduced form in DMSO-d6 are reported. The signals observed in the NMR spectra are all assigned. The NMR data revealed that the spin label is attached to the C-2 amide group on ring A of tetracycline. The spin-labeled tetracycline is also tested in vitro for antitumor activity and is found to be active against leukemia P338/ADR cell line and in melanoma LOX cell line.
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PMID:Spectroscopic and biological studies of spin-labeled tetracycline. 131 98

Inhibitors of protein phosphatases 1/2A (okadaic acid and calyculin A) exhibited differential cytotoxicity toward three human leukemia cell lines, in an increasing order of resistance, HL60 less than HL60/ADR less than K562 cells. Cytotoxicity of the toxins was associated with marked mitotic arrest of the cells, characterized by chromatid scattering/overcondensation and abnormal mitotic spindles. In all cases, calyculin A was more potent than okadaic acid. Protein phosphorylation experiments in intact cells revealed that HL60/ADR, the adriamycin-resistant variant, showed a higher overall phosphorylation of nuclear proteins than the drug-sensitive parental HL60, and that phorbol ester (protein kinase C activator) and calyculin A appeared to more specifically stimulate phosphorylation of p66 and p60, respectively. It was suggested that the toxins might be useful in delineating mechanisms underlying certain properties of cancer cells (such as multidrug resistance, mitosis and differentiation) related to protein phosphorylation/dephosphorylation reactions.
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PMID:Comparative effects of protein phosphatase inhibitors (okadaic acid and calyculin A) on human leukemia HL60, HL60/ADR and K562 cells. 132 92

The impact of the novel chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)benzenesulfonyl))indolizine (SR33557) on the intracellular distribution of doxorubicin (DOX) within the multidrug-resistant murine P388/ADR leukemia cell line was studied by fluorescence microscopy. We found that under conditions which modulated multidrug-resistant (30 microM SR33557 for 1 h), P388/ADR cells presented an original sequestration of DOX in large intracellular vesicles, where SR33557 is itself sequestered, as seen by colocalization studies. Colocalization experiments with lysosomal and mitochondrial probes suggest that these vesicles are neither mitochondrial in nature nor functional lysosomes. To investigate the biochemical basis for this effect, we studied the impact of SR33557 on the sphingolipid metabolism of P388/ADR cells. We observed that although P388/ADR cells normally catabolized exogenous [3H]sphingomyelin, when pretreated with SR33557 they showed almost complete inhibition of sphingomyelin breakdown. Finally, in order to demonstrate that the inability of P388/ADR cells to degrade sphingomyelin in the presence of SR33557 (which is a potent inhibitor of acid lysosomal sphingomyelinase) leads to phospholipid accumulation, we performed electron microscopy where we observed laminated inclusions. These morphological modifications are similar to those observed in Niemann-Pick disease lymphoblastoid cell lines which are inherently deficient in acid sphingomyelinase activity. The observation that, in the absence of SR33557, these Niemann-Pick disease cell lines presented similar DOX sequestration to that of SR33557-treated P388/ADR cells strongly suggests that DOX accumulates in SR33557-induced myeloid bodies. The redistribution of DOX within these vesicles, perhaps by preventing its expulsion by P-glycoprotein, may be a key in discovering the mechanism of action of SR33557.
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PMID:Modulation of subcellular distribution of doxorubicin in multidrug-resistant P388/ADR mouse leukemia cells by the chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)-benzenesulfonyl))indolizine. 142 91

Cyclosporin (CsA) is a potent modulator of multidrug resistance (MDR) and has been combined with etoposide (VP-16) to purge MDR leukemic cells from human bone marrow (BM) in vitro. We studied the feasibility of this approach in an in vivo model for autologous BM transplantation using the murine leukemia cell line P388 and its MDR variant P388/ADR. Colony-forming assays with 2-h drug exposure revealed a tumor selectivity of VP-16 for P388 cells compared to normal murine marrow granulocyte-macrophage colony-forming units (CFU-GM), whereas P388/ADR cells were resistant to VP-16. Simultaneous incubation with CsA restored sensitivity in these cells. Almost 4 logs of cell kill were achieved by treating P388/ADR cells with 60 microM VP-16 plus 2.5 microM CsA (combination A) or 40 microM VP-16 plus 10 microM CsA (combination B), whereas there was a 2.5-log reduction of CFU-GM at these doses. Even though the myelotoxicity of VP-16 was increased by the addition of CsA, this effect was nonspecific as shown by a similar chemosensitization in sensitive P388 as well as in P388/VP 2.5 cells, an atypical MDR variant lacking P-glycoprotein. In vivo experiments addressed the ability of BM treated with VP-16 and CsA to rescue lethally irradiated mice and to purge leukemic cells. In total, 1/14 lethally irradiated mice died due to sepsis within 10 days after receiving 15 x 10(6) BM cells treated ex vivo with combination A in contrast to 1/4 for combination B. All 16 surviving animals demonstrated long-term engraftment. When simulated remission marrow contaminated with 0.1% P388/ADR was purged with VP-16 (60 microM) or CsA (2.5 microM) alone, all mice died from leukemia before day 16 after transplantation (median 14.3 and 12.2 days). In contrast, nine of ten animals receiving similar marrow purged with combination A survived > 60 days without any evidence of disease (p < 0.01). We conclude that combining VP-16 and CsA was effective in purging MDR leukemia cells from transplanted BM in this murine model.
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PMID:Use of etoposide in combination with cyclosporin for purging multidrug-resistant leukemic cells from bone marrow in a mouse model. 146 39

The antitumor effects of mitoxantrone (MITO) and the various mechanisms involved therein were investigated in the adriamycin sensitive (P388/S) and resistant (P388/ADR) P388 leukemia cells. Utilizing the MTT (3-[4,5/dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, MITO concentration less than 100 ng elicited 50% inhibition of P388/S tumor cell survival, while a 10 times greater dose of MITO was required to inhibit the P388/ADR cell survival by 50%. A MITO dose dependent inhibition of DNA, RNA and protein biosynthesis was observed in the sensitive cells, while MITO elucidated a negligible effect on the macromolecular biosynthesis in the resistant tumor cells. Induction of DNA strand scission was observed in P388/S cells exposed to 0.1 and 1 microgram/ml MITO, while a minimal formation of DNA lesions was evident in the P388/ADR cells treated with 5 micrograms/ml MITO. These strand breaks were found to be not associated with proteins in either P388/S or P388/ADR cells. Generation of free radicals due to MITO and formation of alkylating metabolites of MITO were found to be not involved in the cytotoxic response of MITO against P388/S and P388/ADR cells. MITO did not affect the glutathione based detoxification mechanism of the sensitive and resistant tumor cells. Results indicate that in spite of reduced intracellular drug retention and induction of DNA strand breaks in P388/ADR cells other hitherto unknown mechanisms besides DNA binding might be involved in the antitumorigenic potential of MITO.
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PMID:Antineoplastic activity of mitoxantrone and its biological interactions in parental and multidrug resistant subline of P388 murine leukemia cells. 152 4

The P388 murine leukemia and P388/ADR, a subline expressing the multi-drug resistance (MDR) phenotype, were examined with regard to the role of MDR as a determinant of responsiveness to photodynamic therapy in vitro. Mesoporphyrin was used as a model substrate. We found no differences in porphyrin accumulation nor transport alterations associated with exposure of P388/ADR cells to the verapamil analog DMDP. There was a significant correlation between photodamage to mitochondria vs loss of cell viability in both cell lines, and LD50 sensitizer levels were not significantly different in P388 vs P388/ADR. P388/ADR cells were partly resistant to porphyrin-catalyzed photodamage to amino acid transport, but this result was not associated with differences in sensitizer localization, as indicated by fluorescence studies. Moreover, photodamage to membrane transport was not associated with loss of viability. These studies suggest that cells which express the MDR phenotype are unlikely to be cross-resistant to photodynamic therapy.
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PMID:Porphyrin photosensitization of multi-drug resistant cell types. 156 Dec 37


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