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)

A variety of analogs of 1,25-(OH)2D3 with less calcemic activity and lower receptor binding affinity than 1,25-(OH)2D3 have been developed. However, these compounds have equal or greater ability to differentiate leukemia cells and psoriatic fibroblasts and to suppress PTH synthesis and secretion. The mechanism for this selectivity has not been elucidated. Because the lower potency of ergocalciferol compared to cholecalciferol in preventing or curing rickets in chicks was associated with a lower affinity of the avian vitamin D binding protein (DBP) for vitamin D2, we tested five analogs with low calcemic activity including 22-oxa-1,25-(OH)2D3 (OCT), MC903, 1,25-(OH)2-16 ene-23-yne D3, 1,25-(OH)2-26,27 dihomo-22-ene-D3, and 1,25-(OH)2-24-trihomo-22-ene-D3 for their affinity for rat serum DBP. All analogs had a low affinity for DBP, ranging from 50-3000 times less than that of 1,25-(OH)2D3. OCT also bound with low affinity to dog and human serum DBP. We tested with OCT the possible consequences of its low affinity for serum DBP. One of the functions of DBP is to prolong the lifetime of 1,25-(OH)2D3 in circulation. Quantification of the metabolic clearance rate (MCR) of OCT in 8 normal dogs using a single bolus injection technique showed that OCT was cleared at a rate of 48.2 +/- 7.5 ml/min, approximately 6-7 times more rapidly than 1,25-(OH)2D3 (6.8 +/- 0.4 ml/min). The estimated half-life of OCT in the circulation was 2.5 +/- 0.3 h compared to 7.0 +/- 0.6; n = 7 for 1,25-(OH)2D3. As our primary interest is the potential of OCT in treating the secondary hyperparathyroidism of CRF, we also measured the MCR of OCT in 5/6 nephrectomized dogs. Uremia does not affect the rate of clearance of OCT from the circulation (MCR: 56.8 +/- 4.5; t1/2 = 2.1 +/- 0.2 n = 4). Despite its shorter half-life, OCT suppressed PTH secretion in vivo in uremic dogs. The effects of low binding to DBP on the percentage uremic dogs. The effects of low binding to DBP on the percentage of free sterol were determined using an ultrafiltration procedure. We compared the proportion of free (unbound) OCT and 1,25-(OH)2D3 in 0.1% BSA-PBS with concentrations of human serum ranging from 0-25%. The proportion of OCT in the free form was significantly higher than that of 1,25-(OH)2D3 for every serum concentration tested. The physiological relevance of a higher percentage of free OCT was tested in normal human macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:On the mechanisms for the selective action of vitamin D analogs. 200 95

Retrovirus virions carry a diploid genome associated with a large number of small viral finger protein molecules which are required for encapsidation. Our present results show that finger protein p12 of Rous sarcoma virus (RSV) and p10 of murine leukaemia virus (MuLV) positions replication primer tRNA on the replication initiation site (PBS) at the 5' end of the RNA genome. An RSV mutant with a Val-Pro insertion in the finger motif of p12 is able to partially encapsidate genomic RNA but is not infectious because mutated p12 is incapable of positioning the replication primer, tRNATrp. Since all known replication competent retroviruses, and the plant virus CaMV, code for finger proteins analogous to RSV p12 or MuLV p10, the initial stage of reverse transcription in avian, mammalian and human retroviruses and in CaMV is probably controlled in an analogous way.
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PMID:Small finger protein of avian and murine retroviruses has nucleic acid annealing activity and positions the replication primer tRNA onto genomic RNA. 245 20

The antileukemic effects of lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) therapy were assessed in mice with Friend virus (FV)-induced erythroleukemia. LAK cells were generated by incubating normal spleen cells for 72 hr in the presence of rIL-2 (1000 units/ml). At the time of injection, the LAK cells were cytotoxic in vitro against FV-infected fibroblasts and NK-sensitive and -resistant tumor targets but not normal controls. To determine in vivo activity, fully leukemic mice (spleen weight greater than 0.75 g) were injected with either PBS or LAK cells (10(8) cells/mouse IV at 14 and 17 days post virus) and rIL-2 (10,000 units/mouse IP every 8 hr on days 14 through 18 post virus). More than 70% of the progressively leukemic mice experienced permanent leukemia regressions (disease-free for greater than 100 days) following LAK cell plus rIL-2 therapy. Regressions were characterized by return of spleen and liver weights to normal and elimination of virus-infected erythroid (CFU-E) and macrophage (CFU-C) progenitor cells from spleen and marrow. Leukemic animals treated with either LAK cells alone or IL-2 alone experienced only transient leukemia regressions. These results demonstrate that LAK cell plus rIL-2 treatment can induce permanent regressions in progressively leukemic mice and provide a responsive and manipulable model system to elucidate the mechanisms involved in this form of immunotherapy.
Leukemia 1989 Feb
PMID:Lymphokine-activated killer cell plus recombinant interleukin-2 therapy of erythroleukemia in mice. 278 72

The antitumor effect on Meth-A fibrosarcoma in BALB/c mice of a synthetic cord factor, 6,6'-di-O-decanoyl-alpha,alpha-trehalose (designated as SS554), was examined. Only intratumoral injection had a curative effect; subcutaneous, per oral, or intravenous routes had no such effect. The co-presence of an oily vehicle has been shown to be necessary for antitumor activity of a natural cord factor. When SS554 was examined in suspensions of sesame oil, squalane, squalene or sesame oil and water emulsion, a 60% cure rate was achieved. However, no such effect was obtained with a suspension in Tween-PBS or a solution. It should also be noted that sequential but independent administrations of SS554 and oil were found to be as effective as the simultaneous administration of oil and SS554 in emulsion form. In the case of the emulsion, the amount of sesame oil necessary was over 10%, or 0.01 ml in absolute terms. Cures were obtained in a dose-dependent manner by injection of SS554 in amounts in excess of 1 mg. The effect of the time of administration was also examined; the best result was obtained when intratumoral injection was done on day 3 after tumor implantation. Mice cured by SS554 exhibited growth inhibition and rejection of rechallenged Meth-A cells. However, this immunity was specific; it did not extend to a rechallenge with RLmale-1 leukemia cells.
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PMID:Antitumor effect of a synthetic cord factor, 6,6'-di-O-decanoyl-alpha,alpha-trehalose (SS554), in mice. 308 95

The antitumor effect of a synthetic cord factor (6, 6'-Di-O-decanoyl-alpha, alpha-trehalose) (SS 554) on the growth of Meth-A fibrosarcoma in BALB/c mice was examined. With regard to administration routes, only intratumoral (i.t.) injection showed a curative effect; subcutaneous (s.c.), per oral (p.o.) or intravenous (i.v.) routes has no such effect. To show the antitumor effect of known natural and synthetic cord factors, the co-presence of oily vehicles has been shown to be necessary. Accordingly, compound SS 554 examined in suspensions of sesame oil, squalane (SQA), squalene (SQE) or sesame oil and water emulsion had a curative effect with a 60% survival rate. However, no such effect was obtained with a suspension in PBS or in HCO-60 solution. In this regard, it should be noted that sequential but independent administration of SS 554 and oil was found to be equally as effective as simultaneous administration of oil with SS 554. Thus the effect of the oil should be reconsidered through an examination of the sequential appearance of effector cells. In the case of sesame oil, the amount of oil necessary was over 10%, or 0.01 mg absolutely. When the dose effect of SS 554 was examined in the presence of 10% sesame oil, doses over 1 mg exhibited a dose dependent curative effect. In tumor-bearing mice, the effect of the time of administration was also examined; the best result was obtained when intratumor injection was performed on day 3 after tumor implantation. Mice that recovered after SS 554 treatment exhibited growth inhibition and rejection of rechallenged Meth-A cells. However, this immunity was specific as it did not extend to a rechallenge with RL male-1 leukemia cells.
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PMID:[Antitumor effect of a synthetic cord factor, 6,6'-di-O-decanoyl-alpha, alpha-trehalose (SS 554) in mice]. 375 12

A SCID mouse model of human T-ALL has been used to determine the in vivo therapeutic efficacy of two anti-CD7-saporin immunotoxins constructed with either a hindered (HB2-SMPT-Sap) or non-hindered (HB2-SPDP-Sap) disulphide bond between antibody and saporin. Groups of 10 SCID mice were injected intravenously (i.v.) with 2 x 10(6) human T-ALL HSB-2 cells followed seven days later by i.v. injection with either a single dose or with 3 doses of HB2-SPDP-Sap or HB2-SMPT-Sap given on alternate days. Control groups received equivalent sham injections of PBS or molar equivalent amounts of unconjugated HB2 antibody+saporin. Animals receiving a single dose of HB2-SMPT-Sap showed better survival than animals receiving a single dose of HB2-SPDP-Sap but the difference was not shown to be significant by log-rank analysis. When given as a triple dose both immunotoxins performed similarly. Comparison of single-dose with triple-dose IT therapy revealed that the therapeutic effect of a triple dose of HB2-SPDP-Sap was significantly better than that of single dose, but this was not the case with HB2-SMPT-Sap. Pharmacokinetic studies of HB2-SPDP-Sap and HB2-SMPT-Sap in normal and HSB-2 leukaemia bearing SCID mice failed to reveal any difference in clearance rates for these two IT's. We conclude from these studies that there is no therapeutic advantage to be gained from constructing the HB2-Sap IT with a hindered disulphide bond in this particular model of human T-ALL.
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PMID:Therapy of human T-cell acute lymphoblastic leukaemia in severe combined immunodeficient mice with two different anti-CD7-saporin immunotoxins containing hindered or non-hindered disulphide cross-linkers. 751 86

Reverse transcription of a retroviral RNA genome requires two template jumps to generate the linear double-stranded DNA required for integration. The RNase H activity of reverse transcriptase has several roles during this process. We have examined RNase H cleavages that define the maximal 3' and 5' ends of Moloney murine leukemia virus minus strand DNA prior to the second template jump. In both the endogenous reaction and on model substrates in vitro, RNase H cleaves the genomic RNA template between the second and third ribonucleotides 5' of the U5/PBS junction, but other minor cleavages between 1 and 10 nucleotides 5' of this junction are also observed. Similar experiments examining the specificity of RNase H for tRNA primer removal revealed that cleavage generally leaves a ribo A residue at the 5' end of minus strand DNA. These observations suggest that three bases are typically duplicated on the ends of the minus strands, leading to an intermediate following the second jump which contains unpaired nucleotides. Model substrates mimicking the structure of this intermediate demonstrate that reverse transcriptase has little difficulty in utilizing such a branched structure for the initiation of displacement synthesis.
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PMID:Cleavage specificities of Moloney murine leukemia virus RNase H implicated in the second strand transfer during reverse transcription. 759 16

Mice with severe combined immunodeficiency (SCID) were injected with 1 x 10(7) MOLT-3 human T-lineage acute lymphoblastic leukemia cells to provide a model for the evaluation of anti-CD7-pokeweed antiviral protein (PAP) immunotoxin directed against the human CD7 antigen. Of control SCID mice (treated with phosphate-buffered saline, PBS) challenged intravenously with 1 x 10(7) MOLT-3 cells, 5/5 died at 29 to 35 days after inoculation, with a median event-free survival of 33 days. Similarly, 6/6 anti-CD19-PAP treated control SCID mice died of MOLT-3 leukemia at a median of 36 days. In contrast, treatment with anti-CD7-PAP (15 micrograms total dose in 5 micrograms intraperitoneal injections on days 1-3) significantly improved event-free survival of SCID mice challenged with 1 x 10(7) MOLT-3 cells. Of nine SCID mice treated with anti-CD7-PAP, four died at 54-149 days and five remained alive for > 172 days without clinical evidence of leukemia (median event-free survival > 172 days). When long-term survivors among the anti-CD7-PAP treated SCID mice were electively killed at 173 days to assess their leukemia burden, histopathologic examination and polymerase chain reaction provided evidence of disseminated leukemia in some of these mice. Intriguingly, marked differences in morphology, tissue distribution, and histologic pattern of organ invasion existed between leukemic blasts killing 100% of PBS-treated control mice at a median of 33 days and 'therapy-refractory' leukemic blasts detected in anti-CD7-PAP-treated long-term survivors. This novel SCID mouse model of disseminated human T-lineage ALL provides a unique in vivo system to investigate the therapeutic potential of new treatment strategies and to study possible mechanisms of in vivo immunotoxin resistance.
Leukemia 1993 Feb
PMID:In vivo anti-leukemic efficacy of anti-CD7-pokeweed antiviral protein immunotoxin against human T-lineage acute lymphoblastic leukemia/lymphoma in mice with severe combined immunodeficiency. 767 82

AKR/J mice, highly susceptible to spontaneous T cell leukemogenesis, were protected from developing the disease by H-2-compatible allogenic bone marrow transplantation (BMT) and intermittent treatment with interleukin-2(IL-2). Allogeneic BMT from C3H/HeJ mice and treatment with PBS yielded T cell leukemia in chimeras after the same latent period as that observed in normal AKR/J mice. In contrast, IL-2-treated chimeras caused an incidence of only 40% T cell leukemia. The preventing effect of IL-2 on leukemia development was not observed in one-year-treated chimeras, probably due to a lack of continuous antileukemic effects over the long term. Both LAK and NK activities in spleen cells were significantly increased in IL-2-treated chimeras. The cytotoxicity against T cell lymphoma cell line derived from AKR/J also increased in the IL-2-treated chimeras. Similarly, LPS-, PWM-, and IL-2-induced responses were increased in the IL-2-treated chimeras. TNF-alpha secretion from spleen cells also rose after IL-2-administration. IL-1 beta, IFN-gamma, and TNF-alpha mRNA became detectable in spleen cells using the PCR technique. The characteristics of leukemia cells in chimeras with overt leukemia were not directly affected by IL-2 administration. It is suggested that partial inhibition of spontaneous T cell leukemia development in AKR/J mice by allogeneic BMT and IL-2 may be due to the enhancement of graft-versus-leukemia effects. Further study may provide insights into the mechanisms involved in preventing leukemia development after allogenic BMT and IL-2 in AKR/J mice.
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PMID:Antileukemic effect of interleukin-2 on spontaneous development of leukemia after H-2-compatible allogenic bone marrow transplantation in AKR/J mice. 792 84

CD72 is a broadly expressed B-lineage specific surface antigen. We used J3-109(anti-CD72) monoclonal antibody to examine primary neoplastic cells from patients with acute leukemia for CD72 expression. CD72 was present at high levels in 70 of 100 B-lineage acute lymphoblastic leukemias (ALL), but it was not expressed on cells from 23 T-lineage ALL patients or 9 acute myeloblastic leukemia patients. We have prepared an anti-CD72 immunotoxin by conjugating J3-109 monoclonal antibody to the ribosome-inactivating protein, PAP.J3-109-PAP effectively killed > 99.9% of clonogenic blasts from a CD72+ B-lineage ALL cell line. We used a SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo anti-leukemic efficacy of the J3-109-PAP immunotoxin. An intravenous challenge with 1 x 10(6) NALM-6-UM-1(pre-B ALL) cells caused 100% of SCID mice to die of disseminated leukemia within 41 days. Importantly, a three-day treatment with non-toxic doses of J3-109-PAP significantly improved event-free survival of SCID mice. The Kaplan-Meier estimate (+/- standard error) of the probability of event-free survival at 2 months after inoculation of NALM-6-UM-1 cells was 40 +/- 16% for SCID mice treated with a total of 15 micrograms J3-109-PAP (median survival = 58 days) as compared to 0 +/- 0% for PBS treated mice (median survival = 34 days). At 6 months after the inoculation of NALM-6-UM-1 cells, 10 +/- 9% of the J3-109-PAP treated SCID mice were still alive with no evidence of leukemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An anti-CD72 immunotoxin against therapy-refractory B-lineage acute lymphoblastic leukemia. 858 Aug 13


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