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)

The selectivity of action of 1-beta-D-arabinofuranosylcytosine (ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of ara-C and of its mono-, di-, and triphosphate (ara-CTP) were measured in L1210 leukemic cells and in C57BL x DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of thymidine incorporation into DNA and with cytocidal effects as measured by loss of isotopically prelabeled DNA. ara-CTP levels, but not those of the mono- and diphosphates of ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues. DNA synthesis was equally inhibited by similar levels of ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of DNA synthesis was greater and more prolonged in leukemic cells. ara-C caused greater losses of prelabeled DNA in ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of ara-CTP and its duration are the determinants of chemotherapeutic efficacy of ara-C against L1210 leukemia. ara-C was the predominant nucleoside present in hydrolysates of ara-CTP fractions. By contrast, 1-beta-D-arabinofuranosyluracil predominated in hydrolysates of monophosphate nucleotide fractions from ascites cells, liver, small intestine, and blood. Monophosphate nucleotide was also present in ascites fluid and plasma.
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PMID:Metabolism and selective effects of 1-beta-D-arabinofuranosylcytosine in L1210 and Host tissues in vivo. 110 91

The pharmacological and therapeutic effects of the daunomycin (DNM):DNA complex were compared with those of free DNM in mice. A complex formation between dnm and DNA (1:11.7, w/w) resulted in a 79% decrease in DNM complex was dialyzable. The DNM fluorescence was completely recovered from the complex in 0.3 N HCl and 50% ethanol solution, and a short contact with biological tissues studied did not quench DNM fluorescence after extraction. The plasma fluorescence (DNM equivalent) 5 min after the i.v. injection of DNM:DNA complex at a dose of 20 mg/kg was 60-fold higher than that of an equivalent amount of free DNM. The complex was cleared for plasma with an initial half-life of 20 min. In spite of an initally higher blood generally similar except in liver and spleen, where DNM equivalent were significantly higher than those of free DNM. The uptake of DNM:DNA into L1210 cells in vitro was low and, at 1 hr, was about one-twentieth of that from DNM. Treatment of DBA/2 mice bearing i.p. L1210 leukemia transplant (initial cell number, 10-3) with DNM:DNA complex resulted in identical increases in life-span as occurred with free DNM. When routes of cell transplant and treatment were different, no therapeutic advantage of DNM:DNA over DNM was seen.
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PMID:Pharmacological and therapeutic efficacy of daunomycin:DNA complex in mice. 113 31

Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).
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PMID:Antineoplastic activity of cannabinoids. 115 36

Spleen cells from untreated young male and female C57BL/6 and C58 mice and of male C3H/He mice showed cytotoxic activity in vitro against BALB/c X-radiation-induced leukemia RL male 1 cells by 51Cr-releasing lymphocyte-mediated cytoxicity (LMC) tests, but old mice of these strains lacked LMC activity. In contrast, spleen cells from male and female AKR, BALB/c, and DBA/2 mice, and from female C3H/He mice had no appreciable LMC activity. The proportion of active cells in spleens from young (C57BL/6 times BALB/c)F1 or reciprocal hybrid mice was higher in females than in males. The specificity of the LMC reaction of RL male 1 cells, determined by LMC inhibition assays, was somewhat different from that of previously reported serologic X.1 tests. Thus the antigen detected by LMC has been tentatively designated X.1'. The main effector cells in this system were uncharacterized cells not adherent to glass surfaces or nylon-wool columns. These findings in RL male 1 leukemia extend the evidence for the presence of naturally occurring LMC. With the single unexplained exception of strain C3H/He, the LMC activity against RL male 1 cells, exhibited by untreated mice of various strains, corresponded with a previous classification of mouse strains immunologically as X.1 responders or as X.1 nonresponders according to their ability to reject X.1-positive leukemia cells.
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PMID:Natural occurrence of lymphocytes showing cytotoxic activity to BALB/c radiation-induced leukemia RL male 1 cells. 115 37

The conditions for generation of simultaneous and independent cytotoxic lymphocyte (CL) responses to each of two sets of alloantigens of limited cross-reactivity by mouse spleen cells in vitro have been investigated. Responder spleen cells were incubated with mitomycin C-treated C57BL/6 (H-2b) or DBA/2 (H-2d) stimulator spleen cells and day 5 CL responses were assayed with 51Cr-labeled EL-4 leukemia (H-2b) and P815 mastocytoma (H-2d) as target cells. Spleen cells from mice of the various H-2 haplotypes tested differed greatly in their ability to develop specific CL responses against alloantigens on the stimulator spleen cells and in the degree of cross-reactive cytotoxic activity against target cells bearing alloantigens not present on the stimulator spleen cells. In contrast to the other strains examined, DBA/1 (H-2q) spleen cells developed specific CL responses to either H-2b or H-2d alloantigens without exhibiting significant cross-reactive activity on the inappropriate target cell. The CL responses to H-2b and H-2d alloantigens by DBA/1 spleen cells were comparable in magnitude and had similar stimulator cell-dose requirements. Further, DBA/1 spleen cells developed CL responses of normal magnitude simultaneously against both target cells when incubated with both mitomycin C-treated C57BL/6 and DBA/2 stimulator cells.
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PMID:Cell-mediated immune responses in vitro. II. Simultaneous generation of cytotoxic lymphocyte responses to two sets of alloantigens of limited cross-reactivity. 118 65

Adult BDF1 and DBA/2J mice were inoculated i.p. with "L-1210" leukemia cells and then received i.p. control or immune sera raised in C27B1/6 and BALB/c mice. Undiluted sera were administered in single or multiple doses ranging from 0.2 to 0.4 ml/mouse on day 0., resp. 0., 2-4, and 7. In BDF1 hybrids permanent survivals (greater than 150 days) and distinct prolongation of the mean survival time (MST) after multiple injections were observed. However, normal serum derived from non-immunized C57B1/6 donors was also demonstrated to provide protection when injected three times. In DBA/2J recipients no permanent survivals were observed. In this mouse strain control sera proved ineffective. On the contrary, immune sera enabled the recipients to survive longer and this prolongation proved to be statistically significant (p less than 0.02). Partial natural immunity against "L-1210" leukemia in BDF1 hybrids must be, therefore, postulated. It is probably due to H-2-locus incompatibility versus "L-1210" cells, inherited from the C57B1/6 ancetor-line. Unknown factors which are present in normal serum seem to potientiate this natural resistance. In compatible DBA/2J mice normal serum constituents were ineffective, on the other hand, however, the effectiveness of specific immune factors directed against target cells of the tumor could be demonstrated in them
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PMID:Multiple immune serum injections in prevention of murine "L-1210" leukemia growth. 122 9

The immune response of BALB/c x DBA/2 F1 mice to a transplantable Moloney leukemia virus-induced tumor allograft (MBL-2) was studied to determine the mechanism of pyran copolymer-induced tumor enhancement. The relative levels of humoral, lymphocyte, and macrophage response were followed chronologically by in vitro cytotoxic microassays using 51Cr-labeled target cells. Although pyran increased the titer of humoral cytotoxic antibody, levels of humoral factors capable of abrogating lymphocytoxicity were not enhanced. Furthermore, splenic lymphocyte-mediated cytotoxicity, although slightly diminished in pyran-treated mice, was not significantly affected. Macrophages harvested from allograft-bearing animals exhibited marked tumoricidal activity, which was augmented by pyran treatment. This macrophage-associated activity was specific for MBL-2 cells and not attributable to cytotoxins elaborated into the culture medium. Pyran slightly activated macrophages from nonsensitized mice to become cytotoxic for MBL-2 cells; activation was not T-cell dependent. However, strikingly fewer macrophages infiltrated the allograft in pyran-treated animals as judged by both histopathology and direct measurement. The defect in the migration or deposit of macrophages at the allograft site may have contributed to tumor enhancement.
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PMID:Immune response of BALB/c X DBA/2F1 mice to a tumor allograft during pyran copolymer-induced tumor enhancement. 126 25

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily phenobarbital intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without phenobarbital pretreatment showed a constant 90% (1-log) reduction in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas enzyme induction had no effect on the toxicity of the drug to normal bone marrow colony-forming units. Parallel survival studies confirmed the 1-log diminution in the antileukemic activity of cyclophosphamide in phenobarbital-pretreated mice. This phenobarbital-induced change in the antitumor activity of cyclophosphamide appears explainable on a pharmacokinetic basis. The Friedman and Boger assay for plasma alkylating metabolites showed that the reduction in the area under the plasma metabolite curve caused by enzyme induction exactly predicted the observed reduction in cyclophosphamide antitumor effect.
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PMID:The effect of phenobarbital on cyclophosphamide antitumor activity. 127 88

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of allopurinol pretreatment on the antileukemic activity of cyclophosphamide and its bone marrow toxicity. Allopurinol drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily allopurinol intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without allopurinol pretreatment showed an almost constant 0.9-log increase in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas allopurinol had no effect on the toxicity of cyclophosphamide to normal bone marrow colony-forming units. Parallel survival studies revealed no difference in the antileukemic activity of cyclophosphamide as a result of allopurinol pretreatment. The allopurinol-induced change in the antitumor activity of cyclophosphamide as seen in the spleen colony assay was not explainable on the pharmacokinetic basis. Flow microfluorometric analysis of P388 leukemia tumor cell cycle parameters revealed no change in the blockading effects of cyclophosphamide as a result of allopurinol preexposure. Although we have failed to explain the underlying mechanism of this drug interaction, our data suggest that allopurinol may increase the antitumor activity of cyclophosphamide without increasing its bone marrow toxicity.
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PMID:The effect of allopurinol on cyclophosphamide antitumor activity. 127 89

We have isolated a cDNA (H52) of 2.8-kb-long encoding an 80-kDa mouse melanoma Ag that is defined by a syngeneic anti-B16 melanoma mAb with an ability to block anti-melanoma cytotoxic T cell responses. H52 transfectants were brightly stained with the antibody, and the 80-kDa molecule was immunoprecipitated from the transfectants. Northern blot analysis showed that this transcript was detected in mouse melanoma cells of C57BL/6 and DBA/2 origin, C1300 A/J neuroblastoma, L cell (C3H) and EL-4 T lymphoma (C57BL/6), faintly in BW5147 (AKR) T lymphoma, but not in other tumors, such as S913 fibrosarcoma (C57BL/10), NIH3T3, 70 Z/3 pre-B lymphoma, and P3U1 plasmacytoma (BALB/c). Since the transcripts were not found in normal C57BL/6 tissues of fetus, newborn, and adult origin, the H52 expression is associated with transforming phenotypes. However, no tissue- or cell type-specific expression was observed. Nucleotide sequence analysis has clearly demonstrated that H52 cDNA encodes the full length of the env gene and long terminal repeat region of endogenous ecotropic murine leukemia provirus of AKV-type, which is defective in C57BL/6. The H52 envelope protein has several amino acid changes compared to those of AKV, one of which is in the env 14 peptide region preferentially associated with MHC molecule, suggesting the possible reason for the difference of antibody reactivity even in H52-positive tumors. We also demonstrate that CTL against H52 transfectant kills B16 melanoma. Thus, the above results are direct evidence that even the endogenous self molecule, when constitutively expressed, does act as a tumor Ag.
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PMID:Molecular cloning and characterization of the gene encoding mouse melanoma antigen by cDNA library transfection. 138 36


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