Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine. However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600 mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction. To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines. The N-[(N,N-dimethylamino)ethyl]carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the non-carboxamide compounds, were still low and little selectivity for hypoxic cells were observed. A series of carboxamides of 2,4-dinitroaniline mustard was also prepared. These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells. The most selective compounds were 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-[(N,N-dimethylamino)ethyl]carboxamide analogue. These showed selectivities of 60- to 70-fold for hypoxic UV4 cells. The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system. Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase). Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23.
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PMID:Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells. 150 7

Genomic and gene-specific DNA interstrand cross-links produced by nitrogen mustard (HN2) were measured in the human tumor cell line Colo320HSR. Following exposures that produced greater than or equal to 1 log cell kill, it was found that HN2-induced DNA interstrand cross-links were produced and processed in a heterogeneous fashion within the genome. Cross-links were detected in the amplified, overexpressed c-myc oncogene, whereas in the weakly expressed N-ras gene and the nontranscribed, high copy number alpha-satellite sequence (of chromosome 20), cross-links were not detected. The cross-links in the c-myc oncogene disappeared more rapidly than total genomic cross-links. These results suggest that HN2-induced DNA interstrand cross-links are produced and processed in the genome in a nonrandom fashion.
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PMID:Gene-specific DNA interstrand cross-links produced by nitrogen mustard in the human tumor cell line Colo320HSR. 151 67

A number of highly lipophilic dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidyl-glycerol at a molar ratio of 7:3. The entrapment efficiency and stability of liposomal platinum (L-Pt) preparations was greater than 90%. The subacute mouse LD50 of L-Pt preparations tested ranged from 60 to 104 mg/kg. All L-Pt preparations tested had no significant nephrotoxicity at the LD50 dose except for L-Pt 5, which caused renal dysfunctions (as evidenced by elevated blood urea nitrogen levels) at the LD50 dose. L-Pt preparations had shown good in vivo antitumor activity against i.p. L1210 leukemia when an optimal dose was administered i.p. to mice on days 1, 5 and 9 (% T/C 230-300; cisplatin 220). L-Pt preparations were also markedly active, by the i.p. route, against L1210 leukemia resistant to cisplatin (% T/C 237-355; cisplatin 112). All L-Pt preparations exhibited significant antitumor activity against B16 melanoma when administered i.p. on day 1 (% T/C 144-155; cisplatin 161). L-Pt 1, 3 and 5 were all tested by the i.v. route on days 4, 8 and 12 against M5076 reticulosarcoma, but none of these preparations showed any significant antitumor activity against this tumor system (% T/C 120-127; cisplatin 173). Current studies aimed at optimizing the liposomal formulation of these compounds should result in the selection of a single isomeric L-Pt formulation for clinical development.
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PMID:Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes. 152 98

Cytolytic activity of mineral oil elicited rat peritoneal macrophages activated by lipopolysaccharide (LPS) and/or rIFN-gamma, rIL-2, Zymosan and PMA (4-beta-phorbol-12-beta-myristate 13-alpha-acetate) was detected in the presence of various concentrations of L-arginine. This paralleled the NO2- production in the presence, but not in the absence, of L-arginine. Significant amount of NO2- was detected in the peritoneal macrophages cultured with 0.4 mmol of L-arginine 8 days and the last 24 h with LPS at a concentration of 1 microgram/ml. No significant differences were found between activated peritoneal macrophages obtained from normal (healthy) and/or from tumor bearing rats to induce tumoricidal activity and NO2- production under the same experimental conditions. The results showed that the major cytolytic mechanism against BP6-Tu2 and U 937 tumor cell lines is L-arginine-dependent nitrogen oxide synthesis of activated rat peritoneal macrophages.
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PMID:Tumoricidal properties of rat peritoneal macrophages activated with various activators depend on nitrogen oxid synthesis. 152

The very rapid growth rate (1 population doubling/day) of normal human epidermal keratinocytes (HK) cultured in serum-free medium can be utilized for wound closure in burn treatment. However, rapid growth in vitro may present the possibility of neoplastic transformation. To investigate this possibility, HK were cultured from primary isolation to large populations in MCDB 153 medium supplemented with epidermal growth factor (EGF, 10 ng/ml), insulin (5 micrograms/ml), hydrocortisone (0.5 micrograms/ml), and Bovine Pituitary Extract (BPE, 70 micrograms/ml). HK were studied for their ability to form tumors in athymic mice after subcutaneous inoculation. Sixteen separate HK strains were inoculated from primary cultures, or from secondary cultures either before or after storage in liquid nitrogen. Transformed cell lines, SCC 13 and FL, derived from human epithelial carcinomata were used as controls for tumor formation. HK formed no tumors (0/79) after 26 weeks incubation, SCC 13 formed nodular tumors (3/5) after 20 weeks incubation, and FL formed tumors (5/5) after 4 weeks incubation. HK cells were not found by histological examination of inoculation sites of keratinocyte cultures derived from primary culture from skin. In contrast, palpable tumors from both SCC 13 and FL were returned to tissue culture and continued to proliferate. These results support the conclusion that the rapid growth rate of human epidermal keratinocytes in vitro can be attributed to permissive culture conditions, and not to neoplastic transformation.
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PMID:Absence of tumorigenicity in athymic mice by normal human epidermal keratinocytes after culture in serum-free medium. 154 Sep 41

Two tumor cell lines were established from each of three human malignant glioma biopsy specimens (M059, M067, M071) and sensitivity to treatment with radiation or chemotherapeutic agents (BCNU, nitrogen mustard) was determined. The effects of recombinant human interferon-alpha (rIFN) on the radiation response and of buthionine sulfoximine (BSO) on the drug response were investigated as well. For tumor M059, two cell lines that differed significantly in radiosensitivity were isolated (surviving fractions at 2 Gy = 0.02 and 0.64). The chemosensitivity and response to chemical modification differed as well. Cell lines established from tumor M071 differed in their response to rIFN only and were not sensitized by BSO. M067 cell lines showed little difference and were not sensitized by either agent. These results suggest that differences may exist both within and among human malignant gliomas with regard to their sensitivity to drugs, radiation, and the ability of chemical agents to modify treatment responses.
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PMID:Heterogeneity in response to treatment with buthionine sulfoximine or interferon in human malignant glioma cells. 154 50

Antifolate inhibitors of thymidylate synthase (TS) have primarily been based on the structure of folic acid. This paper describes the identification and development of novel 6,7-imidazotetrahydroquinoline TS inhibitors by iterative ligand design, synthesis, and crystallographic analysis of protein-inhibitor complexes. Beginning with a high-resolution crystal structure of E. coli TS (TS, EC 2.1.1.45), an imidazotetrahydroquinoline inhibitor was designed de novo to occupy the folate binding pocket. Structural modifications of the initial compound 1h (Ki approximately 5 microM human/E. coli TS) were then made on the basis of feedback from additional cocrystal structures and activity data. An amino group in the 2-position of the imidazole was found to increase the potency of the series by 1-2 orders of magnitude. Other substitutions on the imidazole ring (1-CH3, 2-CH3, 2-NHCH3, 2-SCH3) generally led to weaker inhibition. Additional improvements in activity were obtained by modification of the substituents on the tetrahydroquinoline nitrogen, bringing the Ki of three of the compounds below 15 nM against the human TS enzyme. The compounds were tested for cytotoxicity and were shown to inhibit the growth of three tumor cell lines in vitro.
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PMID:Design and synthesis of novel 6,7-imidazotetrahydroquinoline inhibitors of thymidylate synthase using iterative protein crystal structure analysis. 154 76

High-resolution 1H NMR spectroscopy has been used to measure the concentrations of metabolites (alanine, N-acetylaspartate, gamma-aminobutyric acid, glutamate, glutamine, aspartate, taurine, glycine, succinate, creatine, cholines, inositol, and glucose) in perchloric acid extracts of human epileptic cortex and brain tumors. All tissue was obtained by surgical biopsy, excised before thermal coagulation, and immediately frozen in liquid nitrogen. Lower levels of N-acetylaspartate and gamma-aminobutyric acid and a shift in the glutamate/glutamine ratio toward glutamine in the tumors reflect neuronal loss. Abnormal glucose metabolism (aerobic glycolysis) in the tumors gives decreased levels of succinate, glutamate, aspartate, glutamine, and creatine and generally increased concentrations of glycine and alanine. Differences in metabolite concentrations that may be of use in differential tumor diagnosis include lower creatine and inositol in meningiomas than in astrocytomas. Lower taurine differentiates benign from malignant astrocytomas. Malignant astrocytomas and metastatic tumors are more regionally heterogeneous than meningiomas or benign astrocytomas. Mannitol, administered perioperatively to all patients from whom tissue was obtained, was observed only in the spectra of extracts of tissue from tumors which enhanced on computerized tomographic imaging.
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PMID:High-resolution 1H NMR spectroscopy studies of extracts of human cerebral neoplasms. 155 19

(-)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP) were compared for their antitumor effects and nephrotoxicity-inducing activities at the same dosage (1/8, 1/4, 1/3, 1/2, 2/3 or 3/4 of the LD10 or LD10) on the basis of their intravenous lethal doses in mice. DWA2114R was effective against murine tumor lines, Colon 26 and Colon 38 carcinomas, M5076 ovarian sarcoma and P388 L1210 leukemias, implanted subcutaneously (s.c.). Triple injection every other day of DWA2114R was more effective than a single injection at each sublethal dose. The antitumor effects of DWA2114R against these tumors were more effective than or were similar to those of CBDCA and CDDP. The antitumor effect against CDDP-resistant L1210 leukemia implanted s.c. was only observed in the treatment of DWA2114R, but not in CBDCA and CDDP. No excellent antitumor effects of three platinum complexes were observed against Lewis lung carcinoma and B16 melanoma implanted s.c. even at triple injection every other day, and no effect was obtained against Meth-A fibrosarcoma under similar conditions. While the treatment of CDDP showed marked increases in levels of blood urea nitrogen and of urinary protein and sugar at effective doses in the antitumor evaluations, the treatment of DWA2114R as well as CBDCA showed no increase in these parameters. These results indicate that DWA2114R represents a desirable second generation antitumor platinum complex.
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PMID:Antitumor effects of three platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate (DWA2114R), cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP), in mice. 156 81

This study describes the synthesis and in vitro antitumor activity of inhibitors of purine de novo biosynthesis that are analogues of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl) propyl]amino]benzoyl-L-glutamic acid (5-DACTHF). Benzene ring substituted analogues were synthesized from a protected pyrimidinyl propionaldehyde and a substituted benzoyl glutamate moiety by a key reductive amination step. Pyrimidine and linking chain substituted analogues were built up stepwise from p-aminobenzoic acid or analogues. The compounds were tested as inhibitors of methotrexate uptake as a measure of binding to the reduced folate transport system, as inhibitors of glycinamide ribonucleotide transformylase, as substrates for folylpolyglutamate synthetase, and as inhibitors of tumor cell growth in cell culture. With the exception of 2'-F substituent, the ring-substituted analogues are less active than the parent compound. Replacement of the 10-nitrogen by carbon, sulfur, or oxygen produced less than 2-fold changes to biological activity in vitro. A four-atom linking chain and an amino group at the 2-position on the pyrimidine ring are important for good activity.
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PMID:Synthesis and biological activity of open-chain analogues of 5,6,7,8-tetrahydrofolic acid--potential antitumor agents. 157 33


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