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)

Interest in the formulation of quantitative structure-activity relationships (QSAR) for antitumor drugs has begun to develop in the past decade. The work in this area has been reviewed briefly, using as examples studies on nitrosoureas, aniline mustards, and aryl triazenes. A salient conclusion from this analysis is that the present drugs in clinical use are more hydrophilic than one might expect. The reason for this may be that they have been developed using leukemia as the test system which may in part account for the fact that while the currently used drugs are effective against leukemia, they are not effective in general against solid tumors.
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PMID:QSAR in cancer chemotherapy. 39 23

A set of 23 aniline mustards [X-C6H4N(CH2CH2Cl)2] have been tested for their activity against B-16 melanoma in mice. The following quantitative structure-activity relationship (QSAR) correlates the data well: log 1/C = -2.06 sigma - 0.15 pi - 0.13 pi2 + 4.13 (r = 0.936). When this equation is compared with those formulated for aniline mustards acting against leukemia, it is found that log P0 (ideal lipophilicity) is higher for solid tumors. The QSAR brings out the unique activity of phenylalanine aniline mustard.
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PMID:Structure-activity relationship of aniline mustards acting against B-16 melanoma in mice. 51 75

Quantitative structure-activity relationships (QSAR) have been formulated for the hydrolysis of aniline mustards and their antitumor activity against Walker 256 tumor and L1210 and P388 leukemia. In general, the antitumor activity parallels hydrolysis under the conditions defined by Ross; toxicity (LD50) parallels antitumor efficacy. Chlorambucil is an exception. A most important finding is that ideal lipophilicity for effectiveness against Walker tumor appears to be much higher than for the leukemias which suggests that solid tumors may, in general, require more lipophilic drugs than leukemias.
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PMID:Structure-activity relationships in antitumor aniline mustards. 61 46

For the rational design of more specific alkylating agents, we suggested new biological platforms able to deliver the alkylating moieties to specific target site and on the other hand we hoped to lead in compounds with synergistic activity. As biological platforms have been used steroidal lactams of A and D- ring and as alkylating agents carboxylic derivatives of N,N-bis (2-Chloroethyl) aniline which combine to the steroid by an easily cleaved ester bond. These homo-aza-steroidal esters gave satisfactory results in early and advanced P388, L1210 leukemias and solid tumors. Whereas unmodified steroidal esters have generally been reported to be inactive in treatment of L1210 leukemia. The steric arrangement of the alkylating moiety greatly effects toxicity and activity of the drugs, while the steric arrangement of the hydrogen atom at position 5 influences these parameters. Isosterism of alkylating agent is the factor for biological action. The amide group of the lactam molecule may be essential for activity.
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PMID:Hybrid anticancer compounds. Steroidal lactam esters of carboxylic derivatives of N,N-bis (2-chloroethyl) aniline (review). 176 51

A series of 4-anilinoquinoline-linked aniline mustards of widely varying mustard reactivity were prepared and evaluated for their antitumor activity. The compounds were designed as minor grove binding agents, where the aniline mustard ring is itself part of the DNA-binding ligand. While there was a general trend for cytotoxicity to correlate with mustard reactivity, this was much less pronounced than with untargeted mustards. The compounds were much more cytotoxic than the parent diols, and were also at least 10-fold more cytotoxic than the corresponding aniline mustards themselves. Comparative cell line studies suggested that the mechanism of cytotoxicity varied with mustard reactivity. The most reactive mustards cross-linked DNA, while cell killing by the less reactive compounds appeared to be by the formation of bulky monoadducts. The compounds were active but not particularly dose-potent against P388 leukemia in vivo. The modest potency may be related to their poor aqueous solubility, since the more soluble methyl quaternary salts were equally active at much lower doses.
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PMID:DNA-directed alkylating agents. 4. 4-anilinoquinoline-based minor groove directed aniline mustards. 203 80

Melphalan and analogous aniline mustard derivatives were tested on antitumor activity in vitro. All compounds showed similar antiproliferative effects against melanoma B16, sarcoma 180 and leukemia P388D1. Thus, the singular clinical efficiency of melphalan may not simply be explained by a selective uptake employing amino acid carrier systems of tumor cells.
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PMID:[In vitro studies of the antitumor effect of melphalan and analogous aniline mustard derivatives]. 261 May 85

The uptake by Escherichia coli of a series of bisquaternary experimental anti-tumour agents (quinolinium 4-[p-9(-pyridylamino)phenylcarbamoyl]-aniline-bisalkyl dibromides) has been measured both by association of radiolabelled compounds and their inhibition of the vegetative replication of bacteriophage lambda (after heat inactivation of the phage repressor) as a measure of biologically effective intracellular drug concentration. Uptake of these compounds was correlated with biological effect, and was a function of both incubation temperature and the lipophilic-hydrophilic balance of the compound. At 30 degrees C uptake was drug concentration-dependent and was not readily reversible. No saturation of uptake was apparent over the concentration range tested. Preliminary experiments indicated that time-dependent drug uptake was also related to growth inhibition in cultured L1210 murine leukaemia cells. These results are consistent with the hypothesis that uptake occurs by diffusion across the plasma membrane followed by strong binding to cell constituents such as DNA. The approximate range of uptake of the most active compounds, using an external drug concentration of 1 microM, are 100 and 2400 molecules/s respectively for bacteria and murine leukemia cells. For bacteria, the uptake of approx. 2 X 10(5) molecules of drug/cell inhibits the yield of phage lambda by 90%.
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PMID:The relationship between lipophilic-hydrophilic balance, uptake and anti-bacteriophage lambda activity of experimental anti-tumour bisquaternary salts. 296 83

Study of a series of aniline-substituted 9-anilinoacridines related to the antileukemic drug amsacrine showed that a 1'-carbamate group provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar, with 3-halo-5-methyl and 3-halo-5-methoxy compounds proving the most active. This substitution pattern also provided the highest DNA binding. Such compounds (particularly the 3-chloro-5-methyl and 3-chloro-5-methoxy) have in vivo activity against wild-type P388 and Lewis lung comparable to that of the best amsacrine analogues previously developed (greater than 50% cures), as well as P388/ADR activity. This work essentially completes the development of the amsacrine series of antitumor agents.
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PMID:Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia. 362 6

Sudan III treatment of Long-Evans rats results in increased hepatic monooxygenase activity using ethoxycoumarin and aniline as substrates. Monooxygenase activity towards amino-pyrine and nitrosodimethylamine is not affected. Sudan III treatment results in increased microsomal cytochrome P448 and increased amounts of a protein band which comigrates with purified cytochrome P448 during SDS polyacrylamide gel electrophoresis. The proportions of the different dihydrodiols formed during the incubation of 7,12-dimethylbenz[a]anthracene with microsomes vary between untreated and treated animals. Thus, extracts of microsomes from untreated rats were found to contain materials with chromatographic properties identical to those of the 3,4-dihydrodiol and the 5,6-dihydrodiol when examined on two different h.p.l.c. systems. Extracts of microsomes from Sudan III treated animals were found to contain materials with chromatographic properties identical to those of the 5,6-dihydrodiol and the 8,9-dihydrodiol when similarly examined. These findings suggest that the protective effect of Sudan III against DMBA induced leukaemia is mediated by an alteration in monooxygenase activity.
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PMID:Alterations in the metabolism of 7,12-dimethylbenz[a]anthracene and various xenobiotics by rat hepatic microsomes following Sudan III treatment in vivo. 391 57

Some new di-n-butyltin and tin(IV) complexes of the type Bu2SnL, Bu2SnL2 and SnL2 (where L = anions of Schiff bases derived from S-substituted dithiocarbazates and fluoro-aniline) have been prepared and screened for their antitumor activity in P 388 Lymphocyte Leukaemia system. These complexes do not show any toxicity at low dose levels and display T/C values in the range 94-124. Di-n-butyltin complex derived from salicylaldehyde-S-methyl dithiocarbazate has been found to be the most active in this series.
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PMID:Antitumor activity of some diorganotin and tin(IV) complexes of Schiff bases. 685 May 71


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