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)

Carbodiimide-mediated condensation of 4-amino-4-deoxy-N10-methylpteroic acid (APA) with several alkyl, aralkyl, and aryl amines, in the presence or absence of N-hydroxysuccinimide, was employed in order to prepare new lipid-soluble bis(amide) derivatives of methotrexate (MTX) as potential prodrugs. MTX dianilide was likewise prepared, in comparable yield, from APA and L-glutamic acid dianilide via the mixed carboxylic--carbonic anhydride method. Dihydrazide and bis(N-methylhydrazide) derivatives of MTX were formed readily from MTX diethyl ester. However, reaction with hydroxylamine led to MTX gamma-monohydroxamic acid as the sole isolated product. The bis adduct appears to form, but is unstable during workup. The identity of the product was confirmed by independent mixed anhydride synthesis from APA and the gamma-monohydroxamate of L-glutamic acid. Treatment of MTX dimethyl ester with N,N-dimethylhydrazine unexpectedly yielded MTX gamma-monomethyl ester. MTX dianilide was active against L1210 leukemia in mice, with a +155% increase in life span at a dose of 160 mg/kg given ip in 10% Tween 80 on a q3d X 3 schedule. The bis(p-chlorobenzylamide), bis(p-methoxybenzylamide), and dihydrazide were also active against L1210 leukemia in vivo, but to a lesser extent than the dianilide. The gamma-monohydroxamic acid derivative showed activity (+111% ILS at 40 mg/kg) similar to that of MTX and was found to bind to a partially purified dihydrofolate reductase preparation from L1210 cells with an ID50 of 0.005 microM as compared to 0.007 microM for MTX. In vivo experiments in mice indicated that the pharmacokinetic properties of this compound and of MTX are similar but failed to demonstrate any advantage over MTX in terms of selective uptake into tumor (sc implanted P388 leukemia) or improved penetration of the central nervous system. The activities of the dianilide, bis(benzylamide), and dihydrazide derivatives in vivo are of interest in view of their low toxicity relative to MTX against cells in culture, which suggests that these derivatives are probably acting as prodrugs in the intact animal.
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PMID:Methotrexate analogues. 13. Chemical and pharmacological studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side chain. 678 99

New modifications of 10-[[3-(diethylamino)propyl]amino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]i sisoquinoline (1b) and 1-[[3-(diethylamino)propyl]amino]-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carba zole (4b), which display important antitumor properties, were performed either on the side chain or on the intercalating heterocycle. Side chains were introduced by direct substitution of the corresponding chloro derivatives and 6-N-methyl-9-hydroxypyrido[4,3-b]carbazoles analogues were prepared via 9-O-benzoyl-1-chloroellipticines. Evaluation of all new compounds shows no significant increase of in vitro cytotoxicity and percent ILS on the L1210 leukemia system by comparison with the model compounds 1b and 4b.
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PMID:Antitumor amino-substituted pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines and pyrido[4,3-b]carbazole derivatives: synthesis and evaluation of compounds resulting from new side chain and heterocycle modifications. 682 34

The glycosidation products of O-alpha-L-cinerulosyl-(1 leads to 4)-O-(3-O-acetyl-2-deoxy-alpha-L-fucosyl)-(1 leads to 4)-alpha, beta-L-rhodosamine with aklavinone, daunomycinone, adriamycinone and carminomycinone were synthesized and the resulting products were deacylated, yielding anthracyclines having the trisaccharide. We further synthesized N-monomethyl and N-didemethyl derivatives of daunomycinone trisaccharide by photolysis with sunlight. 3"-O-Acyl derivatives of daunomycinone, carminomycinone and aklavinone glycosides showed a marked antitumor activity against L1210 leukemia in mice with ILS 110, 86 and 86%, respectively, while 3"-O-acetyladriamycinone glycoside was highly toxic with a ILS of 44%.
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PMID:Chemical modification of anthracycline antibiotics IV. Synthesis of new anthracyclines with trisaccharide. 695 27

A series of substituted 4'-(9-acridinylamino)methanesulfonanilide (AMSA) derivatives have been tested for mutagenicity using Salmonella typhimurium strain TA 1537 and for antitumor activity against the L1210 leukemia in mice. Two measures of mutagenic activity were determined and quantitative structure--activity relationships (QSAR) developed for them. M50, the percentage of drug-induced mutant colonies observed at the concentration providing 50% inhibition of bacterial growth, is a measure of mutagenic efficiency. The lowest molar drug concentration (1/C) needed to induce a fixed proportion of revertants (chosen as 50 per 10(8) bacteria) is a measure of mutagenic effectiveness. The two measures of antitumor activity modeled were ILSmax (the percent increase in life span observed for each derivative at its LD10 dose), a measure of tumor cell selectivity, and 1/D40 (the dose of drug to provide an ILS of 40%), a measure of dose potency. These measures of bioactivity were intercompared and modeled in terms of a number of drug physicochemical properties. The results show that drug lipophilic/hydrophilic balance is the dominant factor in determining both mutagenic and antitumor activity, although other factors are involved. The two different types of activity can be readily separated in the AMSA drug series by appropriate choice of substituent and adjustment of overall drug lipophilic/hydrophilic balance.
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PMID:Potential antitumor agents. 33. Quantitative structure--activity relationships for mutagenic activity and antitumor activity of substituted 4'-(9-acridinylamino)methanesulfonanilide derivatives. 698 89

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

Chemotherapy with 4'-O-tetrahydropyranyladriamycin (THP-ADM), a new derivative of Adriamycin, was equally or more effective against several experimental mouse tumors than it was with Adriamycin (ADM). When mice with P388 leukemia were given i.p. injections of THP-ADM or ADM daily for 9 consecutive days, the maximum increases in life span (ILSs) of the mice were 190 and 175%, respectively. Eight of 24 mice treated with THP-ADM were free of tumor, while one of 24 mice treated with ADM was free of tumor. A single i.p. injection of either drug was also effective; maximum ILS was 170% for mice treated with THP-ADM and 240% for those treated with ADM. Nine of 12 mice were found to be free of tumor. THP-ADM was equally or slightly more effective against P388 leukemia than was ADM when either drug was given i.v. The maximum ILS was 106% with THP-ADM and 77% with ADM when the drug was given for 9 consecutive days. Single i.v. injections of THP-ADM or ADM were almost equally (ILS, 100%) effective. Chemotherapy with THP-ADM was also very effective against L1210 leukemia. THP-ADM administered i.p. five times, every other day starting from Day 1, was more effective than ADM was against Lewis lung carcinoma, B16 melanoma, and colon adenocarcinoma 38 inoculated s.c. In the study with Lewis lung carcinoma, metastasis to the lungs was well suppressed by THP-ADM. ADM was more effective than was THP-ADM against colon adenocarcinoma 26. Because THP-ADM was more cytotoxic than or almost equally as cytotoxic as ADM against the established cell lines from the above mouse tumors, we suggest that THP-ADM is more efficiently transported into cultured cells.
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PMID:4'-O-tetrahydropyranyladriamycin as a potential new antitumor agent. 706 20

Three new antibiotics isolated from broth cultures of a Pseudomonas were evaluated for antitumor activity against murine leukemias L1210 and P388. The antibiotic with the dichloromethyl group at the 3 position of actinobolin, an antibiotic produced by a Streptomyces, is the major product (Y-12278), and two analogs of Y-12278 are minor. When these antibiotics were administered i.p. on days 1 to 4 to mice bearing ascitic leukemias, the most effective was Y-12278, which increased the lifespan of mice implanted with leukemias L1210 and P388 by 88 and 110% over controls, respectively. On the same treatment schedule, less than 60% ILS (increase in lifespan) was obtained by oral and s.c. administration of Y-12278 to mice implanted i.p. with these leukemias, and by its i.p. injection to mice implanted i.c., i.v. and s.c. with leukemia L1210. With i.p. administration of Y-12278, a single injection on day 1 only was less effective in increasing the lifespan of mice bearing ascitic leukemias L1210 and P388 than the prolonged treatment schedules such as daily on days 1 to 4. Y-12278 administered i.p. on days 3 to 6 was shown to possess antitumor activity against i.p. implanted rat hepatomas. More than 200% ILS was seen in hepatomas AH44 and AH7974F.
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PMID:Antitumor activity of newly isolated antibiotics, 3-dichloromethylactinobolins. 720 39

Daunoblastin in free and liposome-encapsulated form was tested in the L1210 murine leukemia and the intramuscularly transplanted 276A sarcoma. Both therapeutic (% ILS, tumor volume inhibition) and toxicologic (leukocytes, body weight difference) parameters were evaluated. The liposome preparations showed similar therapeutic effects as the free substance but caused a lower toxicity with a lower mortality rate, higher leukocyte values and smaller body weight reduction. Longer sonication time with the output of more smaller unilamellar vesicles had no influence on the parameters in the solid model, but resulted in shorter ILS values in the L1210 model. Administration of empty liposomes immediately before liposomal Daunoblastin did not result in better antineoplastic activity but yielded higher leukocyte values.
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PMID:Therapeutic evaluation of liposome-encapsulated Daunoblastin in murine tumor models. 725 32

The accumulation of amino acid and dipeptide derivatives of DNR has been studied in vitro on L1210 cells. Only Leu-DNR reaches accumulation levels close to DNR, while Val-DNR, Ile-DNR, and Leu-Leu-DNR reach intermediate values. Intracellular DNR was found when the L1210 cells were incubated in the presence of DNR, Leu-Leu-DNR, Leu-Ala-DNR, and Leu-DNR. The cytostatic activity of the derivatives in vitro on L1210 cells cannot be correlated with their uptake or conversion into DNR. At equitoxic doses given iv on the iv inoculated form of L1210 leukemia, all the derivatives are less active than DNR. When given iv on the sc inoculated L1210 leukemia, Leu-DNR, Ala-Leu-DNR and Leu-Leu-DNR are much more active than DNR with a striking increase in ILS and reduction of tumor progression. The superiority of those compounds could be due to their greater hydrophobicity and to their hydrolysis in situ by enzymes secreted by tumor cells or present on the tumor cells surface.
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PMID:Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity on L1210 leukemic cells in vitro and in vivo. 745 66

The synthesis of a series of 1-amino-substituted pyrido[4,3-b]carbazole derivatives, based on the substitution of corresponding 1-chloroellipticines, is reported. The cytotoxic properties on tumor cells grown in vitro, the in vivo acute toxicity of the most potent in vitro cytotoxic compounds, and the antitumor properties toward the L1210 leukemia system are described. No correlation between the apparent association constant to DNA and the in vitro cytotoxicity or the in vito antitumor efficiency could be observed in this series. 9-Hydroxylated derivatives were more cytotoxic in vitro than the corresponding 9-methoxylated compounds. However, their antitumor efficiencies on the in vivo experimental systems do not confirm the advantage of demethylation. The presence of a [(dialkylamino)alkyl]amino side chain at the 1 position of ellipticines increases the antitumor potency: 1-[[3-(diethylamino)propyl]amino]-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (5) is a very potent antitumor compound (% ILS of 134 on the L1210 leukemia system).
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PMID:Structure-activity relationships in a series of newly synthesized 1-amino-substituted ellipticine derivatives. 745 70


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