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)

Enhanced DNA repair activity is important for the development of cellular resistance to alkylating agents. Here, we quantitated the kinetics of DNA excision repairs initiated by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in human leukemia CCRF-CEM cells. CEM cells that had been established resistant to BCNU (CEM-R) were evaluated in comparison with parental CEM cells (CEM-S). The excision repair kinetics were quantitated as the amount of DNA single strand breaks, which were generated from the incision/excision of the damaged DNA and were diminished by the rejoining of renewed DNA, using the single cell gel electrophoresis (Comet) assay. CEM-R cells were 10-fold more resistant to BCNU than CEM-S cells, and also showed cross-resistance to melphalan and cisplatin. In response to the treatment with BCNU, both CEM-S and CEM-R cells initiated an incision/excision reaction at the end of the incubation period, and completed the rejoining process within 4 hr. While CEM-S cells could not repair the damage induced by the high concentration of BCNU, CEM-R cells completed the repair process regardless of BCNU concentrations, suggesting enhanced excision repairs in CEM-R cells. The excision repair activity of CEM-R cells was increased with regard to the incision reaction and to the rate of the repair. Similar results were obtained using ultraviolet C, suggesting enhanced nucleotide excision repair in CEM-R cells. Thus, the enhanced DNA excision repairs were successfully quantitated in the resistant leukemic cell line using the Comet assay. The evaluation of the repair activity may predict the sensitivity of cancer cells to chemotherapy and provide a clue to overcome the resistance.
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PMID:Enhanced DNA excision repair in CCRF-CEM cells resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, quantitated using the single cell gel electrophoresis (Comet) assay. 1296 80

The human O(6)-methylguanine-DNA methyltransferase (MGMT) gene and its mutants have been used for in vivo selection of transduced hematopoietic stem cells with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) alone or in combination with O(6)-benzylguanine (BG). To allow similar in vivo selection in dogs, without the risk of inducing an immune response, we have cloned the canine MGMT drug resistance gene. Comparison of canine and human MGMT-coding regions indicates that there is about 62% amino acid identity and 78% similarity between the two MGMTs. The canine MGMT is also longer, by nine amino acids. Proline at position 140 and the surrounding amino acids of the human MGMT are highly conserved in the canine sequence. To determine whether mutation of the proline residue at position 144 to lysine in the canine MGMT would provide a similar advantage for selection of transduced cells as the human mutant, Moloney murine leukemia virus and human immunodeficiency type 1 vectors encoding the corresponding mutant MGMT were created and used to express separately canine and human MGMTs in cultured cells. Drug resistance assays using BCNU alone or BCNU with BG demonstrated that the wild-type and mutant canine MGMTs provided resistance to the selection agents that was comparable to the human MGMT counterparts.
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PMID:Cloning and expression of canine O6-methylguanine-DNA methyltransferase in target cells, using gammaretroviral and lentiviral vectors. 1505 63

Nitrogen mustards (NMs) are useful chemotherapeutic agents in the treatment of lymphoma, leukemia, multiple myeloma, and ovarian carcinoma. The antitumor activity of NMs has been attributed to their ability to cross-link the twin strands of DNA. The resulting bifunctional lesions, if not repaired, can inhibit DNA replication and transcription, eventually leading to cell cycle arrest, apoptosis, and the inhibition of tumor growth. The predominant bifunctional DNA lesions of NM have been reported to involve the distal guanine bases in the opposite strands of 5'-GNC sequences. In the present work, the formation of guanine-adenine and adenine-adenine adducts of N,N-bis(2-chloroethyl)methylamine (mechlorethamine) in double-stranded DNA is demonstrated. Guanine-adenine cross-links of mechlorethamine were identified as N-(2-[N3-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine (N3A-N7G-EMA), N-(2-[N1-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine, and N-(2-[N(6)-adenyl]ethyl)-N-(2-[N7-guanyl]ethyl)methylamine. All three adducts were produced interstrand, while N3A-N7G-EMA was the dominant intrastrand G-A cross-link. The prevalent adenine-adenine mechlorethamine lesions have the structure of N,N-bis(2-[N3-adenyl]ethyl)methylamine (bis-N3A-EMA). DNA-derived lesions have the same HPLC retention times, UV spectra, and MS/MS fragmentation patterns as the authentic standards prepared independently. bis-N3A-EMA lesions were produced in a concentration-dependent manner in calf thymus DNA treated with increasing amounts of mechlorethamine. Furthermore, HPLC-ESI-MS/MS analysis was used to demonstrate the formation of analogous N3-N3 adenine lesions in DNA treated with aromatic nitrogen mustards, N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid and L-phenylalanine mustard. The presence of cross-linked adenine-adenine lesions may explain the enhanced cytotoxicity and mutagenicity of NMs in cells deficient in N3-alkyladenine glycosylase.
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PMID:Adenine-containing DNA-DNA cross-links of antitumor nitrogen mustards. 1525 21

Cloretazine (VNP40101M; 101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine) is a sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species on activation. To explore the molecular mechanisms underlying the broad anticancer activity observed in preclinical studies, cloretazine and chloroethylating-only [i.e., 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine] and carbamoylating-only (i.e., 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine) analogues were evaluated in five murine hematopoietic cell lines. These cell lines were separable into two groups by virtue of their sensitivity to 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine; the sensitive group included L1210, P388, and F-MEL leukemias (IC50s, 6-8 micromol/L) and the resistant group consisted of Ba/F3 bone marrow and WEHI-3B leukemia cells (IC50s, 50-70 micromol/L). Resistant cells expressed O6-alkylguanine-DNA alkyltransferase (AGT), whereas sensitive cells did not. A correlation existed between AGT expression and the functional status of p53; AGT- cells possessed defective p53, whereas AGT+ cells contained wild-type p53. Based on recent findings on regulation of AGT gene expression by others, we suspect that silencing of the AGT gene by promoter hypermethylation frequently occurs during tumor progression involving p53 inactivation. O6-Chloroethylguanine is the initial DNA lesion that progresses to lethal interstrand DNA cross-links. Cloretazine exhibited a much higher preference toward the O6-chloroethylation of guanine, as measured by the difference in IC50s to wild-type and AGT-transfected L1210 cells, than 1,3-bis(2-chloroethyl)-1-nitrosourea, which targets the same site in DNA. Preferential toxicity of cloretazine against AGT- tumor cells coupled with decreased toxicity to AGT+ cells in host tissues constitute the therapeutic basis for cloretazine.
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PMID:Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine. 1627 97

In this study, we have investigated the genotoxic, cytostatic, antineoplastic and apoptotic effects of three newly synthesized modified steroidal esters, having as alkylating agent p-N,N-bis(2-chloroethyl) aminophenyl butyrate (CHL) or p-N,N-bis(2-chloroethyl) aminophenyl acetate (PHE) esterified with the steroidal nucleus modified in the B- and D-ring. The genotoxic and cytotoxic effects of the compounds were investigated both in vitro, in lymphocyte cultures obtained from blood samples of healthy donors and in vivo, in ascites cells of P388 leukemia obtained from the peritoneal cavity of DBA/2 mice. Preparations were scored for sister-chromatid exchange (SCE) and proliferation-rate indices (PRI). The newly synthesized compounds were also studied for antineoplastic activity against lymphocytic P388 and lymphoid L1210 leukemias in mice, by calculating the mean of the median survival of the drug-treated animals (T) versus the untreated control (C) (T/C%). The activity of caspase-2 and caspase-3, indicators of apoptosis, was assessed biochemically in primary cultures of human lymphocytes. Our results show that the newly synthesized compounds caused severe genotoxic effects by significantly increasing the frequency of SCE and decreasing the PRI values in cultures of peripheral lymphocytes in vitro and in ascites cells of lymphocytic P388 leukemia in vivo. A significant correlation was also observed in both the in vitro and in vivo experiments: the higher the SCE frequency the lower the PRI value (r=-0.65, P<0.001 and r=-0.99, P<0.01, respectively). The measured antileukemic potency was statistically increased by all test compounds in both types of tumours, while the activity of caspase-2 and caspase-3 showed a statistically significant increase after two periods of exposure. The genotoxic (increase of SCE), cytostatic/cytotoxic (decrease of PRI) and antileukemic effects (increase of T/C%) in combination with the induction of apoptosis (activation of caspase-2 and caspase-3) caused by the newly synthesized compounds, lead us to propose them as agents with potentially antineoplastic properties.
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PMID:Genotoxic, cytostatic, antineoplastic and apoptotic effects of newly synthesized antitumour steroidal esters. 1938 48

Effects of polymethoxyflavonoids tangeretin and nobiletin and the related polyphenolic compounds baicalein, wogonin, quercetin, and epigallocatechin gallate on the cell growth, P-glycoprotein function, apoptosis, and cell cycle of human T lymphoblastoid leukemia MOLT-4 and its daunorubicin-resistant cells were investigated. The IC50 values of these compounds on the cell growth were 7.1-32.2 micromol/L, and the inhibitory effects were observed to be almost equal to the parent MOLT-4 and the daunorubicin-resistant cells. Tangeretin and nobiletin showed the strongest effects with the IC50 values of 7.1-14.0 micromol/L. These polymethoxyflavonoids inhibited the P-glycoprotein function and significantly influenced the cell cycle (p<.05), whereas they did not induce apoptosis.
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PMID:Effects of naturally occurring polymethyoxyflavonoids on cell growth, p-glycoprotein function, cell cycle, and apoptosis of daunorubicin-resistant T lymphoblastoid leukemia cells. 1986 51

New compounds with potential antitumour activity were synthesised by combining nitrogen mustard with the steroidal skeleton, in an effort to improve specificity and at the same time reduce systemic toxicity. The steroidal part is aimed to serve as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties. The purpose of the present investigation was to evaluate these compounds for anti-neoplastic activity. The compounds tested have as alkylators either para-NN-bis(2-chloroethyl)-aminophenyl-butyrate (CHL) or para-N,N-bis(2-chloroethyl)-aminophenyl-acetate (PHE) esterified with a differently modified steroidal nucleus. The eight newly synthesised compounds were compared on a molar basis with respect to their ability to induce sister chromatid exchanges (SCEs) and to modify proliferation rate indices (PRI) in lymphocytic leukaemia P388 cells in mice in vivo. The life span of BDF1 mice inoculated with P388 leukaemia cells was also estimated (anti-leukaemic activity). The compounds that were effective in inducing cytogenetic effects in lymphocytic leukaemia cells in vivo were also effective in inducing antineoplastic effects in BDF1 mice inoculated with P388 leukaemia cells. These results suggest that the in vivo cytogenetic effects in conjunction with the antineoplastic activity of modified steroidal alkylators depend on the configuration of the whole molecule and on the appropriate combination of the alkylator with the steroidal molecule: a pronounced cytogenetic and anti-neoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with either a steroidal nucleus that carries a cholesten group in the 17 position of the D-ring, or with a steroidal nucleus having an exocyclic NHCO-group in the D-ring. In contrast, a ketone group or an NHCO-group in the D-ring inserted endocyclically in the steroidal nucleus esterified with either CHL or PHE failed to induce cytogenetic or anti-neoplastic effects.
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PMID:Cytogenetic and antineoplastic effects by newly synthesised steroidal alkylators in lymphocytic leukaemia P388 cells in vivo. 2246 85

On the basis of the results of in-silico predictions and in an effort to extend our structure-activity relationship studies, the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl) amino-phenyl]butanoic acid (2-PHE-BU) was synthesized and conjugated with various steroidal alcohols. The resulting steroidal esters were evaluated for their in-vivo toxicity and antileukemic activity in P388-leukemia-bearing mice. The new derivatives showed significantly reduced toxicity and marginally improved antileukemic activity compared with free 2-PHE-BU. Nevertheless, they did not prove to be superior either to the template steroidal ester used for in-silico predictions or to previously synthesized steroidal esters of aromatic nitrogen mustards. The results obtained indicate that in-silico design predictions may guide the design and synthesis of new bioactive steroidal esters, but further parameters should be considered aiming at the discovery of compounds with optimum activity.
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PMID:Steroidal esters of the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl)amino-phenyl]butanoic acid (2-PHE-BU): synthesis and in-vivo biological evaluation. 2318 13

Polymethoxylated flavones (PMFs) are found in the peel tissues of some citrus species. Here, we report that PMFs, such as nobiletin, potentiate the cytolytic activity of KHYG-1 natural killer (NK) leukemia cells. Nobiletin markedly enhanced the expression of granzyme B, a serine protease that plays critical roles in the cytolytic activity of NK cells. The potentiated cytolytic activity induced by nobiletin was canceled by the granzyme B inhibitor Z-AAD-CMK. Nobiletin also increased the levels of phosphorylated CREB, ERK1/2, and p38 MAPK in KHYG-1 cells, which are known to participate in NK cell function. Inhibition of an upstream kinase of ERK1/2 failed to reduce the granzyme B expression and KHYG-1 cytolytic activity. Meanwhile, inhibition of p38 MAPK attenuated both granzyme B expression and KHYG-1 cytolytic activity. These results suggest that the primary role of nobiletin in KHYG-1 cytolytic activity lies in upregulation of granzyme B expression, at least in part, mediated through p38 MAPK function.
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PMID:Polymethoxylated flavones potentiate the cytolytic activity of NK leukemia cell line KHYG-1 via enhanced expression of granzyme B. 2551 3

Tangeretin, a major phytochemicals in tangerine peels--an important Chinese herb, has been found to have anti-carcinogenic properties. To improve bioavailability and increase potency of tangeretin, its derivative, 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF), has been synthesized and shown potent inhibition of proliferation activity against human breast and leukemia cancer cell lines. In this study, we have further investigated the anticancer effects of 5-AcTMF on CL1-5 non-small cell lung cancer cells (NSCLC) both in vitro and in vivo and demonstrated that 5-AcTMF effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with cdc2 and CDC25c and increased in the apoptotic cells associated with caspase activation, down regulation of Bcl-2, XIAP and Survivn, inducing release of cytochrome c into the cytosol and disruption of mitochondrial membrane potential. We also found that 5-AcTMF treatment of CL1-5 activated autophagy, indicated by triggered autophagosome formation and increased LC3-II levels and formation of LC3 puncta. Moreover, we also found that 5-AcTMF lowered phophoatidylinositol 3-kinase/AKT/mTOR signaling pathway. Over-expression of AKT by AKT cDNA transfection decreased 5-AcTMF mediated apoptosis and autophagy, supporting the induction of apoptosis and autophagy by inhibition of AKT pathway. In an animal study, 5-AcTMF effectively delayed tumor growth in a nude mouse model of CL1-5 xenografts without observed adverse effect. Immunohistochemistry Analysis indicated that 5-AcTMF induced CL1-5 cell apoptosis and autophagy in vivo. Taken together, these data demonstrate that 5-AcTMF is a novel small molecule agent that can inhibit NSCLC cell proliferation, and induce G(2)/M phase arrest and via the mitochondrial apoptotic pathway and autophagy.
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PMID:Tangeretin derivative, 5-acetyloxy-6,7,8,4'-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. 2656 90


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