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)

Exponentially growing cells of human cancer lines have been utilized to investigate the cytotoxic activity of antineoplastic agents. Different cancer cell lines differ greatly in their responsiveness to both clinical and experimental cytotoxic drugs. For example, sensitivities to 5-fluorouracil and cytosine arabinoside ranged over 15- and 30-fold respectively. Cell lines derived from carcinomas were more sensitive to 5-fluorouracil and less sensitive to cytosine arabinoside than was a leukaemic cell line. In general, colon carcinoma lines were most resistant to DNA-intercalating drugs, and a breast carcinoma and leukaemia line most sensitive. In a congeneric series of amsacrine analogues, in vitro patterns of activity against different lines were shown to correlate with activity against the Lewis lung mouse carcinoma in vivo. Results suggest that established cell lines manifest responsiveness to anticancer drugs consistent with that expected from their tumours of origin. This assay is economical, reproducible and convenient, and could be used to complement the human tumour stem cell assay in drug development studies.
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PMID:The use of human cancer cell lines as a primary screening system for antineoplastic compounds. 654 Jan 94

Indicine-N-oxide, a pyrrolizidine derivative, was selected for development because of activity in the murine P388 leukemia model. Route and schedule dependency have been demonstrated. It is believed that the antitumor activity of the drug is mediated via antimitotic effects and chromosomal damage. However, the active metabolic species responsible for these antitumor properties is not yet known. The major toxic effect was myelosuppression. Phase I clinical trials have arrived at recommended doses for further study. Colon carcinoma has been found to be possibly responsive, and several tumor types were reported stable during phase I testing. In a single phase II study in refractory leukemia, there were three responses, including one complete response, among seven patients. Phase II studies in all panel tumors are indicated, especially colon carcinoma and leukemias.
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PMID:Indicine-N-oxide: a new antitumor agent. 693 84

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (CL 216942; bisantrene hydrochloride; NSC 337766), a member of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental murine tumor systems. The compound produced significant increases in life span (LS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of greater than 173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of greater than 85% in mice with Lieberman plasma cell tumor, and an ILS of greater than 200, 150, and 63%, respectively, in mice with B16 melanoma, colon tumor 26, and Ridgway osteogenic sarcoma. An adriamycin-resistant subline of P388 leukemia showed complete cross-resistance to CL of 216942. The compound was active when administered by the i.p., i.v., and s.c. routes, but p.o. activity was not observed. Significant schedule dependency was not observed when the drug was administered once daily for 9 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. CL 216942 was a potent inhibitor of DNA and RNA synthesis in L5178Y lymphoma cells cultured in vitro, and preliminary studies indicated the drug was a DNA-intercalating agent. The drug was cytotoxic for rapidly proliferating and nonproliferating (G0) human colon carcinoma WiDR cells in vitro.U
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PMID:Activity of a novel anthracenyl bishydrazone, 9,10-anthracenedicarboxyaldehyde Bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride, against experimental tumors in mice. 705 99

Previous studies from this laboratory demonstrated that a potent inhibitor of nucleoside transport, nitrobenzylthioinosine (NBMPR), protected cultured cells against cytotoxic nucleosides (nebularine, tubercidin, and toyocamycin). NBMPR and its 5'-monophosphate (NBMPR-P) also protected mice against potentially lethal dosage of these agents. This report describes protection of mice from potentially lethal dosages of tubercidin by administration of NBMPR-P and the use of combinations of these agents in treatments of mice bearing transplanted neoplasms. Treatment of mice bearing i.p. implants of the Ehrlich ascites carcinoma, leukemia L1210/TG8, and colon carcinoma 26 with potentially lethal dosages of tubercidin administered together with host-protecting dosages of NBMPR-P resulted in substantial kill of neoplastic cells and long-term survivors. In these experiments, therapeutic effects were achieved at optimal dosages of NBMPR-P, which protected host vital tissues but did not protect neoplastic cells in ascitic fluids (Ehrlich ascites carcinoma cells and leukemia L1210/TG8 cells). However, at supraoptimal dosages of NBMPR-P, the occurrence of therapeutic failures which were neoplastic deaths indicated that NBMPR-P also protected the neoplastic ascites cells against tubercidin cytotoxicity. Thus, the selectivity of tubercidin toxicity toward cells of the Ehrlich ascites carcinoma and leukemia L1210/TG8 was modified by NBMPR-P dosage.
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PMID:Treatment of mouse neoplasms with high doses of tubercidin. 724 75

Among events limiting the effectiveness of cancer chemotherapy are the general lack of preferential uptake of anticancer drugs by tumor cells and the occurrence of drug resistance. An approach has been undertaken to explore whether or not such events can be favorably altered or circumvented therapeutically by development of a new class of anticancer molecules, cytotoxic liponucleotide analogs. The design of cytotoxic liponucleotide analogs encompasses both biochemical and biophysical aspects of liponucleotide and glycerophospholipid structure and metabolism. Several cytotoxic liponucleotide analogs of cytidine diphosphate diacylglycerol (CDPdiacylglycerol/dCDPdiacylglycerol), containing the 1-beta-D-arabinofuranosyl moiety, were tested for antitumor activity. Multispecies ara-CDPdiacylglycerol (1-beta-D-arabinofuranosylcytosine 5'-diphosphate diacylglycerol), which contains egg lecithin-derived mixed fatty acyl chains, was more active than 1-beta-D-arabinofuranosylcytosine (ara-C), a clinically used anticancer drug, against leukemia L5178Y and P388 ascites cells in mice. At identical single doses (50 mg/kg per day times 4) administered intraperitoneally, ara-CDPdiacylglycerol prolonged the life spans of L5178Y tumor-bearing mice 93%, while ara-C prolonged life by 18%. Ara-CDPdiacylglycerol increased life spans of P388 tumor-bearing mice by 357% at doses of 50 mg/kg per day times 4; the maximum increase with ara-C was 159% (85 mg/kg per day times 4). Against a P388 ara-C-resistant cell line (P/Ara-C, kinase deficient) in mice, ara-CDPdiacylglycerol prolonged survival times by 34% at a dose of 50 mg/kg per day times 4 and by 55% at 75 mg/kg per day times 4; the drug was not active against two other ara-C-resistant murine leukemia mutants (CA 55, CA5b). With cell line-derived human colon carcinoma HCT-15 grown in mice immunosuppressed with anti-thymocyte serum, ara-CDPdiacylglycerol at a single daily dose of 50 mg/kg per day times 4 significantly reduced tumor weights to 21% of the controls; the same dose schedule of ara-C caused no observable reduction of tumor weights. Results of these preliminary antitumor evaluations indicate that cytotoxic liponucleotide analogs should be investigated further to determine their potential as antineoplastic molecules.
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PMID:Cytotoxic liponucleotide analogs. II. Antitumor activity of CDP-diacylglycerol analogs containing the cytosine arabinoside moiety. 745 69

Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalato Pt(II); 1R,2R-dach, l-OHP), its trans-d isomer (1S,2S-dach) and cis-dach (1R,2S-dach) isomers were compared in in vitro testing against human ovarian carcinoma cell lines A2780, A2780/CP (cisplatin resistant), A2780/l-OHP (oxaliplatin resistant), colon carcinoma cell line HT-29, and murine leukemia cell lines L1210, L1210/CP (cisplatin resistant), and L1210/dach (tetraplatin resistant). The relative molar potency of the three complexes in all the cell lines except A2780/l-OHP and L1210/dach are trans-l > trans-d > cis-dach; in A2780/l-OHP they are trans-l = trans-d > cis-dach; in L1210/dach trans-l > trans-d = cis-dach. The A2780/l-OHP selected for trans-l resistance is 3.6-fold resistant to oxaliplatin, showed no resistance to trans-d isomer and is 6-fold resistant to cis-dach. However, L1210/dach which is selected for carboxyphthalato 1,2-dach (trans-dl) platinum(II) is 140-fold resistant to oxaliplatin, 73-fold resistant to trans-d, and 41-fold resistant to cis-OHP. The accumulation and DNA binding of platinum following a 2-h treatment of A2780 cells with each of the isomers (60 microM) is in the order of trans-l > cis-dach > trans-d which corresponded to the cytotoxicity of trans-l, but not the others. The data suggest that other processes, such as differential formation of specific adducts and/or repair may be involved. Of the three isomers l-OHP is the superior and its accumulation and DNA binding are consistent with its cytotoxicity.
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PMID:Cytotoxicity, cellular accumulation and DNA binding of oxaliplatin isomers. 749 60

The expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene can be down-regulated by inflammatory stimuli such as phorbol myristate acetate (PMA). Since the respiratory manifestations of cystic fibrosis (CF) are characterized by intense chronic airway inflammation very early in life, successful gene therapy for CF will require that expression of the transferred normal CFTR gene be resistant to down-regulation by inflammatory mediators. To evaluate the concept that a viral promoter--human CFTR cDNA unit would be resistant to this form of down-regulation, a retrovirus promoter (5' long terminal repeat of the Moloney murine leukemia virus)--human CFTR cDNA unit was transferred to T84 human colon carcinoma cell line using a retrovirus vector. Exposure of the retrovirus-modified T84 cells to PMA resulted in down-regulation of the endogenous CFTR mRNA transcripts (6.5 kb), but did not affect the level of exogenous CFTR transcripts (8.0 kb). Importantly, in parallel with the persistence of the exogenous CFTR transcripts, the modified cells still maintained cAMP-regulated CI- secretion in the presence of PMA. These in vitro data suggest that a constitutive viral promoter--CFTR cDNA unit should be resistant to modulation by inflammatory stimuli, a likely requirement for successful gene therapy for CF.
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PMID:Transfer of a constitutive viral promoter-cystic fibrosis transmembrane conductance regulator cDNA to human epithelial cells conveys resistance to down-regulation of cAMP-regulated Cl- secretion in the presence of inflammatory stimuli. 752 42

We compared the influence of exogenous N-ras oncogene and treatment with PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA) on P-glycoprotein (Pgp) function in various human, rat and dog cell lines. Two approaches were used: (a) flow cytometry analysis of Rhodamine 123 (Rh123) exclusion; and (b) sensitivity to cytotoxic action of colchicine. We have found that in Rat1 fibroblasts, rat IAR2 epithelial cells and rat McA RH 7777 (hepatoma), ras activates Pgp function, while in MDCK (dog kidney), K562 (human chronic myelogenous leukaemia) and LIM1215 (human colon carcinoma) cells it either has no effect or even acts in opposite direction. TPA-induced Pgp function shows dissimilar pattern of cell specificity. It is assumed that PKC and ras oncogene regulate mdr1 gene expression through at least partially distinct signalling pathways.
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PMID:Cell-specific effects of RAS oncogene and protein kinase C agonist TPA on P-glycoprotein function. 762 41

A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (+/-)-2-(Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 microM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 microM) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 microM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids.
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PMID:Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids. 764 Feb 6

The microbial product wortmannin has previously been shown to be a potent inhibitor of phosphatidylinositol-3-kinase. In view of the potential role of this enzyme in transduction of mitogenic signals, we determined the cytotoxic activity of wortmannin against several human tumor cell lines in vitro. The most sensitive lines included GC3 colon carcinoma, IGROV1 ovarian carcinoma, and CCRF-CEM leukemia (IC-50s ranging from 0.7-2.1 microM). The cytotoxicity of wortmannin was decreased approximately 10-fold by serum-free conditions. Wortmannin was generally less active in low passage human breast cancer cell lines that overexpress either epidermal growth factor receptor or Her2/neu. Wortmannin was also tested for in vivo antitumor activity against seven murine tumor and ten human tumor xenograft models. Activity (> 60% inhibition of tumor growth) was observed in only the C3H mammary carcinoma and the human BxPC-3 pancreatic carcinoma xenograft. In vivo antitumor activity did not correlate with in vitro sensitivity to wortmannin cytotoxicity.
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PMID:In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. 765 91


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