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)

The present paper describes 4-amino-N-(2'-aminophenyl)benzamide (GOE1734) with regard to synthesis; toxicity in mice, rats, and dogs; and differential therapeutic efficacy in slowly and rapidly proliferating rat tumors. GOE1734, an analog of a group of compounds known for other than antitumor effects with relatively simple N-acyl-O-phenylenediamine structure, is characterized by a low bacterial mutagenic potential after in vitro metabolic activation and DNA-DNA crosslinking activity after in vivo treatment. Maximum tolerated doses in rats and dogs amount to 4 and 1 mg/kg, respectively. High growth-inhibiting efficacy was obtained in intratibially implanted osteosarcoma, in methylnitrosourea-induced primary mammary carcinoma, and in acetoxymethyl-methylnitrosamine-induced colorectal adenocarcinoma. GOE1734 proved to be ineffective in transplanted Yoshida sarcoma and Walker 256 carcinosarcoma when single or multiple doses were administered at dose levels that were moderately toxic or not toxic. Some antitumor effects were observed in L5222 leukemia after ip transplantation, but no effect could be observed after ic implantation or in vitro incubation and subsequent retransplantation of these cells. Since the latter three rat tumors are characterized by relatively short tumor volume doubling times (0.5-2 days), whereas the first three grow slower (tumor volume doubling time, 11-19 days), the remarkable differential antitumor activity of GOE1734 in fast and slowly growing malignancies is striking.
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PMID:Synthesis, toxicity, and therapeutic efficacy of 4-amino-N-(2'-aminophenyl)-benzamide: a new compound preferentially active in slowly growing tumors. 384 Oct 25

A group of folate analogs of the 10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program, have been examined in therapy experiments utilizing a group of murine tumor models. These new analogs were found to be markedly superior to methotrexate against four of five ascites tumors (L1210 leukemia, Sarcoma 180, Ehrlich carcinoma and Tapper carcinosarcoma) and against four of five solid tumors (S180, Tapper carcinosarcoma, E0771 mammary adenocarcinoma, Lewis lung carcinoma, and T241 sarcoma). Analogs alkylated (methyl or ethyl) at the 10 position of 10-deaza-aminopterin were found to be the most effective of the group. These analogs achieved log10 reduction in tumor burden several-fold greater in magnitude than methotrexate against L1210 and S180 ascites tumors and there were also long-term survivors. 10-Deaza-aminopterin itself gave a result intermediate between those obtained with the 10-alkyl derivatives and methotrexate. Against the solid forms of the Tapper tumor some partial regressions were obtained with methotrexate and 10-deaza-aminopterin, but a far greater number, extending over a longer period were obtained with the 10-ethyl derivative of 10-deaza-aminopterin. Against the E0771 tumor, 10-deaza-aminopterin was 2-fold and the ethyl derivative of 10-deaza-aminopterin was greater than 5-fold more effective than methotrexate in retarding tumor growth. Evidence for partial regressions and marked effects against metastatic disease were also obtained in the case of the 10-alkyl derivative. Similar results were also obtained with the T241 sarcoma. For Lewis lung carcinoma the relative potency was about the same but overall antitumor effects were more modest.
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PMID:New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models. 669 70

The metabolism, antitumor activity, and acute toxicity of 5-fluoro-1,3-bis-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FD-1) were investigated in animals, compared with 5-fluoro-1-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FT). It was found that after oral administration of FD-1, the level of 5-fluorouracil (5-FU) was maintained higher and longer than after administration of FT, and that a large amount of 5-FU was released from FD-1 by liver microsomal drug-metabolizing enzymes or spontaneous hydrolysis via 5-fluoro-3-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (3-FT) and FT. FD-1 had a significant activity against the solid form of Ehrlich carcinoma, sarcoma-180, hepatoma AH130, Yoshida sarcoma, Walker carcinosarcoma-256, and leukemia L1210 and P388, but not the ascitic forms, and it produced greater inhibition of tumor growth than FT. The acute toxicity of FD-1 was less than that of FT.
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PMID:Metabolism, antitumor activity, and acute toxicity of 5-fluoro-1,3-bis(tetrahydro-2-furanyl)-2,4-pyrimidinedione by oral administration to animals. 676 37

Succinylacetone (SA, 4,6-dioxoheptanoic acid) inhibits d-aminolevulinic acid dehydrase, the second enzyme of the heme biosynthetic pathway and thereby inhibits heme biosynthesis. In the present study SA is shown to inhibit the growth of the Walker carcinosarcoma (W256) in vitro and in vivo, the Novikoff hepatoma in vivo, and L1210 leukemia in vitro, but only slightly in vivo. Rats can tolerate significantly larger doses of SA for at least twice as long as were administered in the present study without gross evidence of toxicity. In contrast to findings in previously published studies with murine erythroleukemia cells, the inhibition of growth of L1210 and W256 cells by SA in vitro is not accompanied by a decrease in cellular heme and is not reversed by addition of hematin to the medium. This suggests a second mechanism of growth inhibition of tumor cells unrelated to heme biosynthesis. Although the growth of both W256 and L1210 cells was markedly inhibited by the same concentration of SA in culture, there was a great difference in responsiveness in vivo, in that much greater inhibition of the growth of the Walker tumor was produced by SA.
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PMID:Growth inhibitory activity of succinylacetone: studies with Walker 256 carcinosarcoma, Novikoff hepatoma and L1210 leukemia. 682 92

When injected at tracer levels into the blood, radiogallium as 67Ga-citrate binds to, and it transported to the site of the tumor by, transferrin. The process by which transferrin-bound Ga is converted to tumor-bound Ga is not fully understood, but may involve the differential physiology of neoplasms compared with normal tissues. Based on the slight acidity known to be exhibited by the extracellular fluid of many animal and human tumors, we have studied the effect of pH on stability and dissociation of the Ga-transferrin complex and on the uptake of Ga by tumor cells in vitro and animal tumors in vivo. When plasma from rabbits injection 67Ga-citrate was dialyzed at pH 6.5-7.5, dissociation of Ga from transferrin showed an inverse pH-dependence. A similar inverse dependence on pH was observed for the uptake of Ga by L1210 leukemia cells and Ehrlich ascites cells incubated with Ga-transferrin complex. Tumor uptake of Ga in rats bearing Walker-256 carcinosarcoma or Murphystum lymphosarcoma whose tumor pH had been further lowered by administration of glucose showed a statistically significant increase over control rats receiving no glucose. These results demonstrate that the stability of the Ga-transferrin complex is pH-dependent and suggest that dissociation of this complex due to decreased pH at the tumor site may be one factor involved in tumor localization and binding of Ga.
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PMID:Effect of pH on tumor cell uptake of radiogallium in vitro and in vivo. 689 27

The antitumor activity of 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077), a novel water-soluble nitrosourea derivative, against leukemia L1210, Ehrlich carcinoma, sarcoma 180, Lewis lung carcinoma, Yoshida sarcoma, rat ascites hepatomas and Walker 256 carcinosarcoma was examined and compared with those of 3 reference nitrosourea antitumor agents, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. TA-077 exhibited a broad antitumor spectrum against the above tumors. Among these 4 nitrosoureas, TA-077 produced the best therapeutic ratios (OD/ILS30) against leukemia L1210, irrespective of the administration route and schedule employed. The ratio obtained by consecutive treatment (ip) was superior to that by single administration, a unique characteristic of this novel nitrosourea agent. The inhibitory effect of TA-077 on the growth of non-syngenic tumors (solid form) was also significant in all administration routes employed (ip, iv and po). Furthermore, TA-077 showed a marked life-prolonging effect on both early and advanced forms of Lewis lung carcinoma.
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PMID:Effect of 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea on experimental tumors. 712 12

The pharmacological properties (toxicity and antitumor activity against W256 carcinosarcoma and L1210 leukemia) of thirty five new triazenes derived both from amides and esters of 3-methyl-4-amino-benzoic acid and from aromatic dipeptidic esters were investigated. The new compounds proved to be moderately effective against W256 carcinosarcoma and totally devoid of activity against L1210 leukemia, except for ethyl,4-(3,3-dimethyltriazenophenyl)-N-alpha-(9-fluorenyl)-acetyl-L-alanine ester which exhibited borderline activity against this leukemia. The pharmacological data thus obtained were correlated with the physico-chemical parameters of the new triazenes in a quantitative structure-activity relationship (QSAR approach). The results of the computed equations suggested that the electronic and the lipophilicity factors alone are not sufficient to give a satisfactory picture of the in vivo behavior of such compounds.
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PMID:Potential anticancer agents. XXII. Pharmacological properties of some new triazene derivatives. 727 57

The antitumor effect of some N alpha-benzyloxycarbonyl-N,N-bis-(2-halogenethyl)hydrazide derivatives of lysine, glycine, cystine, phenylalanine and p-chlorophenylalanine, was studied. Six of eight newly synthesized compounds show considerable antitumor effect on solid Walker carcinosarcoma 256 (about 95% tumor growth inhibition). Three of these compounds under study increased the lifespan of mice with leukemia L1210. The investigation of the effect of N alpha-benzyloxycarbonyl,D,L-phenylalanine-N,N-bis(2-chloroethyl)hydrazine on various mouse tumors showed remarkable growth inhibition of the Ehrlich ascites carcinoma, sarcoma 37, colon adenocarcinoma akatol and lesser antitumor effect also on solid adenocarcinoma 755, Lewis lung carcinoma and melanoma B16. All investigated compounds exhibited depression of leukocyte count--their toxicity being, however, lower than that of sarcolysine in parallel experiments.
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PMID:Antitumor effect of N alpha-benzyloxycarbonyl-N,N-bis-(2-halogenethyl)-hydrazide derivatives of amino acids. 739 53

Arachidonate lipoxygenases (LOX) and their products play an important role in mediating growth factor-supported tumor cell proliferation and growth. The LOX pathway may also be critical in regulating tumor cell survival and apoptosis. Blocking the 12-LOX gene expression with sequence-specific antisense oligos or its activity with general or isoform-specific LOX inhibitors induces a strong apoptotic response in rat W256 carcinosarcoma cells of the monocytoid origin (Tang et al., 1996, Proc. Natl. Acad. Sci. U.S.A., 93:5241-5246). In the present study, several molecular approaches confirmed the predominant expression of platelet-type 12-LOX in W256 cells, with no or little expression of 5- and 15-LOX. NDGA, a general LOX inhibitor and BHPP, a 12-LOX-selective inhibitor, induced rapid and dose-dependent apoptosis of serum-cultured W256 cells as well as several other tumor (in particular leukemia) cell lines, thus suggesting a potential role for LOX in mediating serum-supported tumor cell survival. The molecular mechanism of NDGA-induced W256 cell death was subsequently investigated. NDGA-induced apoptosis could be significantly postponed by overexpression of 12-LOX, thus suggesting that the NDGA effect is, at least partly, dependent on its inhibition of LOX (i.e., 12-LOX). W256 cell apoptosis induced by NDGA could also be effectively inhibited by GSH-elevating or thiol agents as well as by lipid peroxidation inhibitors and an inhibitor of mitochondria respiratory chain rotenone. Further experiments demonstrated that NDGA treatment triggered rapid lipid peroxidation leading to the depletion of cytosolic and mitochondrial GSH pools. Interestingly, the lipid peroxidation induced by NDGA could not be inhibited by conventional free radical scavengers nor by cyclooxygenase or cytochrome P-450 monooxygenase inhibitors. In summary, the present work suggests a role of 12-LOX in regulating serum (growth factor)-supported survival of certain tumor cells.
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PMID:Apoptosis of W256 carcinosarcoma cells of the monocytoid origin induced by NDGA involves lipid peroxidation and depletion of GSH: role of 12-lipoxygenase in regulating tumor cell survival. 925 37

beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.
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PMID:[Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use]. 1147 85


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