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)

Using four human tumor cell lines, MCF-7 and T47-D from breast tumors, MOLT-4 and K-562 from leukemia, flow cytometric DNA analysis of pure and mixed cell population was performed using monoclonal antibodies to cytokeratin to distinguish cytokeratin-containing carcinoma cells from leukemia cells which do not contain cytokeratins. Surprisingly, on pure or mixed K-562 cells, we found positive labeling with KL1, CK8, and CK18 antibodies (results confirmed by immunocytology). This preliminary study has allowed a DNA analysis on epithelial cells of human breast tumors.
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PMID:Cytokeratin analysis of breast and leukemia tumor cell lines by flow cytometry. 247 21

The Boon-Leigh procedure, involving condensation of a 6-chloro-5-nitropyrimidine (22) with an alpha-amino ketone (20 or 21) followed by reduction of the nitro group, cyclization, and L-glutamylation, led to the formation of 11-deazahomofolate (29) and its 10-methyl derivative (30). The corresponding (6R,S)-5,6,7,8-tetrahydro (4, 5) and 7,8-dihydro (31, 32) derivatives were prepared by catalytic hydrogenation. (6S)-11-Deazatetrahydrohomofolate was prepared from 29 by enzymatic reduction. Compounds 29 and 30 had little effect (IC50 greater than 2 x 10(-5) M) on Lactobacillus casei glycinamide ribonucleotide (GAR) formyltransferase but (6R,S)-11-deazatetrahydrohomofolate (4) is a potent inhibitor of this enzyme (IC50 = 5 x 10(-8) M). It is at least 100 times more inhibitory than 33, the 6S compound, indicating that the 6R component of the mixture having the unnatural configuration at C6 (34) is responsible for the potent inhibition. Compound 4 is a much weaker inhibitor of murine (L1210) and human (MOLT-4) leukemia cell GAR formyltransferases (IC50 greater than 1 x 10(-5) M). (6R,S)-11-Deaza-10-methyltetrahydrohomofolate (5) (IC50 = 1.1 x 10(-5) is 200 times weaker than 4 against L. casei GAR formyltransferase. However, 11-deaza-10-methyldihydrohomofolate (32) is more inhibitory (IC50 = 5.5 x 10(-7) M) than 5 or 30. None of the compounds showed inhibition of L. casei aminoimidazolecarboxamide ribonucleotide (AICAR) formyltransferase, dihydrofolate reductase, or thymidylate synthase. The dihydro derivatives 31 and 32 are 5% as active as dihydrofolate as substrates for L. casei dihydrofolate reductase. Compound 4 showed moderate inhibition of the growth of L. casei, Streptococcus faecium, MOLT-4 cells, and MCF-7 human breast adenocarcinoma cells.
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PMID:Folate analogues. 31. Synthesis of the reduced derivatives of 11-deazahomofolic acid, 10-methyl-11-deazahomofolic acid, and their evaluation as inhibitors of glycinamide ribonucleotide formyltransferase. 249 18

T lymphoma induction by the mink cell focus-inducing murine leukemia virus MCF 1233 in C57BL/10 and C57BL/6 mice is influenced by a strongly Th-dependent, H-2I-A-restricted antiviral immune response (25). We compared the MHC class I as well as viral env and gag antigenic cell surface profiles of frequent T lymphomas of H-2I-A nonresponder-type mice to that of rare T lymphomas of H-2I-A responder-type mice. Membrane immunofluorescence studies, with a panel of anti-env mAbs (reactive with the highly conserved gp70f epitope, the p15Ec epitope, and the gp70-p15E complex), a polyclonal anti-p30 serum, and anti-H-2 class I mAbs, showed that all 17 nonresponder tumors tested expressed high levels of both env and gag viral proteins, and 15 of these 17 nonresponder tumors expressed high levels of H-2 class I K and D antigens. In contrast, 10 of 11 responder lymphomas lacked env and/or gag determinants. The only responder lymphoma with both strong env and gag expression failed to express H-2K and -D antigens. Preferential loss of env or gag expression did not correlate with H-2 class I allelic specificities. Both responder and nonresponder T lymphoma DNA contained multiple, predominantly MCF-like, newly acquired proviral integrations. Differences in viral antigen cell surface expression were confirmed at cytoplasmic and RNA levels. The amounts of 8.2- and 3.2-kb viral RNA were greatly reduced in two responder lymphomas when compared with four nonresponder lymphomas. In both responder lymphomas, aberrantly sized viral RNA species were found. Upon in vivo passage of these responder lymphomas in either immunocompetent or T cell-deficient nu/nu mice, it was found that various molecular mechanisms may underlie the lack of viral antigen expression at the cell surface of these lymphomas. One lymphoma re-expressed viral antigens when transplanted with nu/nu mice, whereas the other remained stably gag negative. The combined findings indicate that an H-2I-A-regulated antiviral immune response not only strongly reduces T lymphoma incidence, but also forces T lymphomas that still arise to poorly express viral antigens, thus explaining their escape from immunosurveillance.
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PMID:Primary virus-induced lymphomas evade T cell immunity by failure to express viral antigens. 253 50

Inbred strains of mice contain in the genome 40-60 endogenous proviruses related to murine leukemia virus. To assess the genetic and pathogenic consequences of these to the host, we have developed a strategy to distinguish among the three different host-range subgroups--xenotropic, polytropic and modified polytropic--by using oligonucleotide probes specific for a polymorphic region in env. Each of these proteins detects a relatively small number of bands in a Southern blot, thus permitting us to enumerate all individual proviruses of this group. Using this approach, we have determined the distribution of different proviruses among inbred and recombinant inbred (RI) strains congenic or coisogenic for specific mutants. Using the RI results, we have been able to place over 100 proviruses on the mouse genetic map. A number of these are closely linked to well-characterized mutations, and we have been able to establish that at least one mutation, hr (hairless), was caused by a proviral insertion. If the other close linkages also prove to reflect causality, we estimate that up to 5% of recessive mutations in the mouse might be caused by insertion of proviruses of this group. Using a similar probe strategy, we have followed the evolution of murine leukemia viruses during spontaneous leukemogenesis in AKR mice. We have found that the final leukemogenic (MCF) virus is a recombinant of three different endogenous parents; an ecotropic virus, a polytropic virus that directs the gp70 region of env, and a xenotropic virus (identified as the inducible element Bxv-1) that directs the LTR. In addition to the recombinations, all such viruses also have a reduplication of the enhancer region of the LTR, compared to the endogenous parent. MCF viruses are created by these three genetic changes, which occur in a reproducible fashion and appear in the thymus between 10 and 14 weeks of age.
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PMID:Genetics of endogenous murine leukemia viruses. 255 92

Penclomedine, a synthetic alpha-picoline derivative, was identified as a potential antitumor agent in the P388 leukemia prescreen of the National Cancer Institute. Upon further evaluation in the National Cancer Institute in vivo tumor panel, the compound demonstrated good activity against two breast tumors. A single i.p. dose or five daily doses caused partial regressions of advanced-stage s.c. implanted mouse CD8F1 mammary adenocarcinomas. Also, penclomedine administered i.p. on Days 1,5, and 9 caused regression of the human MX-1 mammary carcinoma implanted under the renal capsule of athymic mice. In contrast, penclomedine demonstrated only marginal to moderate activity against the i.p. implanted L1210 leukemia and M5076 sarcoma and was inactive in three additional non-breast tumor models (i.p. B16 melanoma, i.v. Lewis lung carcinoma, and s.c. colon adenocarcinoma 38). Penclomedine administered p.o. and i.p. was equally effective against the subrenal capsule MX-1. Doses given p.o. every fourth day caused complete regression of 39 of 40 advanced-stage s.c. implanted MX-1 tumors but were much less effective against human H82 small cell lung carcinomas (13 of 80 complete regressions). Penclomedine p.o. also inhibited growth of the human MCF-7 and mouse 16/C breast adenocarcinomas. Further studies to support the development of penclomedine to clinical trial are in progress.
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PMID:Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors. 270 34

The bis-(n-butyl) quaternary salt of N,N'-bis-(6-quinolyl)terephthalamide (QBQ), a fluorescent antitumour compound in the phthalanilide series which is thought to bind to the minor groove of the DNA double helix, has been investigated with respect to its in vitro activity and subcellular localization. Cultured MCF-7 human breast carcinoma cells concentrated QBQ in mitochondria by a time-dependent process which was inhibited by the ionophore valinomycin, suggesting a possible mode of antitumour action of QBQ through mitochondrial poisoning. Growth of cultured P388 murine leukaemia cells was inhibited 50% in the presence of 0.52 microM QBQ and multidrug-resistant P388 sublines developed for resistance to actinomycin D, vincristine, Adriamycin and the phthalanilide NSC 38280 were cross-resistant to the drug. Cross-resistance was reduced in all lines by the presence of 11 microM verapamil, suggesting that a transport resistance mechanism operates on QBQ. The actinomycin D-resistant P388 cell line was found to be cross-resistant to the aromatic cations rhodamine 123, which binds to proteins, and ethidium and pyronin Y, which bind intercalatively to DNA. Thus mitochondrion-specific drugs with different macromolecular binding properties all appear to be excluded by multidrug-resistant cells.
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PMID:Localization of a nonintercalative DNA binding antitumour drug in mitochondria: relationship to multidrug resistance. 280 51

1,3-Butadiene (BD), a comonomer used in the production of synthetic rubber, is a rodent carcinogen. We have observed a marked increase in the incidence of thymic lymphoma in male B6C3F1 relative to NIH Swiss mice chronically exposed to BD in the absence of demonstrable differences in bone marrow (target organ) toxicity. Increased expression of murine leukemia virus (MuLV) antigens was also observed on lymphomas from BD-exposed B6C3F1 mice. Because NIH Swiss mice do not usually express endogenous retroviruses and their ecotropic proviral sequences are not intact, these findings provide presumptive evidence of a role for endogenous retrovirus sequences in BD-induced lymphoma in the B6C3F1 mouse. The present study was conducted to examine the expression and behavior of endogenous retroviruses in these strains during the preleukemic phase of BD exposure. Chronic exposure to BD (1250 ppm) 6 hr/day, 5 days/wk for 3 to 21 weeks increased markedly the quantity of ecotropic retrovirus recoverable from bone marrow, thymus, and spleen of B6C3F1 mice. However, expression of other endogenous retroviruses (xenotropic, MCF-ERV) was not enhanced. No viruses of any type were found in similarly treated NIH Swiss mice. The mechanism of this increase in ecotropic retrovirus in B6C3F1 mice is believed to be de novo activation in greater numbers of cells because changes in the Fv-1 tropism of the replicating viruses or changes in Fv-1 host restriction were not found. Endogenous retroviruses are thus implicated in BD-induced leukemogenesis in B6C3F1 mice. Further studies will examine the role of retrovirus in BD-induced leukemogenesis and the mechanisms of activation of ecotropic proviral sequences in murine cells.
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PMID:Selective activation of endogenous ecotropic retrovirus in hematopoietic tissues of B6C3F1 mice during the preleukemic phase of 1,3-butadiene exposure. 282 17

We isolated a novel infectious murine leukemia virus (HoMuLV) from the wild mouse Mus hortulanus. HoMuLV has an ecotropic virus host range, but the viral DNA fails to hybridize to viral envelope segments specific for the known inbred and wild mouse ecotropic as well as nonecotropic MuLVs. Despite this difference in its env gene, HoMuLV appears to use the same ecotropic cell-surface receptor since it infects only hamster and mouse somatic cell hybrids which contain the Rec-1 ecotropic virus receptor on chromosome 5. Furthermore, HoMuLV does not infect mice carrying the Fv-4r allele which is thought to prevent ecotropic virus infection through an interference mechanism. HoMuLV is NB-tropic and, unlike other infectious MuLVs, does not grow in cells derived from the wild mouse species. M. dunni. Five to ten months after neonatal inoculation with HoMuLV, 72% of female NIH Swiss mice (8/11) contracted lymphoma or erythroid leukemia, but 33% of the inoculated males (5/15) developed erythroid or myelogenous leukemia within 8-16 months. These data suggest that NIH Swiss males and females differ in their susceptibility to HoMuLV-induced disease. Furthermore, NIH Swiss mice were found to be more susceptible to HoMuLV-induced disease than NFS/N mice. Tumors contained infectious MCF virus, which is consistent with the hypothesis that MCF virus may mediate tumorigenesis by HoMuLV.
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PMID:HoMuLV: a novel pathogenic ecotropic virus isolated from the European mouse, Mus hortulanus. 284 96

We used 2-parameter flow cytometry (FCM) to investigate the relationship between the cell cycle phases and 3 proteins whose expression is known to increase in proliferating cells: the surface antigen transferrin receptor (Trf-r), the "cyclin" (a proliferating cell nuclear antigen, PCNA), and the nuclear antigen recognized by the monoclonal antibody (MoAb) Ki-67. FITC-labeled antibodies against Trf-r, PCNA, and the Ki-67-reactive antigen, as well as propidium iodide-DNA distribution, were simultaneously measured on human leukemia HL-60 and K562, and breast carcinoma MCF-7 cell lines and on fresh human leukemic and glioblastoma cells. The 70% ethanol fixation for Trf-r and PCNA and the 95% acetone fixation for Ki-67 plus permeabilization (with 0.1% and 1% Triton X100, respectively, for the surface and the nuclear antigens) produced cell suspensions with negligible cell clumping, high-quality DNA profiles, and bright specific immunofluorescent staining. The investigated proteins have different relationships with the proliferative state of the cell. Trf-r is expressed mainly at the transition from G0/G1 to S-phase. PCNA expression is prominent in late G1 and through S-phase and decreases in G2-M. The Ki-67-reactive antigen is widely distributed in G1, S, and G2-M phases. Knowledge regarding the relationships between proliferation-associated antigens and cell cycle phase in normal and neoplastic cells could improve our understanding of the mechanisms underlying growth regulation and neoplastic transformation. Bivariate FCM is an easy method for obtaining these data from large numbers of cells.
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PMID:Cell cycle-related proteins: a flow cytofluorometric study in human tumors. 290 62

The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (less than or equal to 50% colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10% VPD (v/v%) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50% but both i.p. and p.o. regimens achieved plasma levels greater than 1.0 micrograms/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.
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PMID:Antitumor activity and murine pharmacokinetics of parenteral acronycine. 291 Apr 53


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