Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 60 derivatives of anguidin were prepared for evaluation of antitumor activities. Positions 3, 4, 8-10, and 15 were modified, and the resultant derivatives were screened against P-388 leukemia. It was found that introduction of the C3-keto and C3,C8-diketo groups markedly improved the antileukemic activity, whereas epoxidation of the C9-C10 double bond or oxidation of the C15 position diminished its activity. Selected derivatives were further tested in the L1210, B16, Lewis lung, Colon 36, and Colon 38 tumor lines. Among these compounds, 4 beta, 15-diacetoxyscirpene-3,8-dione (54) and 4 beta-(chloroacetoxy)-15-acetoxyscirpene-3,8-dione (55) were found to be most active in various tumors. Inhibitory action of several analogues on protein synthesis was also examined using H-HeLa cells.
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PMID:Structural modifications of anguidin and antitumor activities of its analogues. 708 45

The effect of intratumoral administration of BRMs in Meth-A solid tumor has been analyzed in BALB/c mice. The effect of BRMs on in vitro invasion by murine RL male-1 leukemia cells was studied using Biocoat Matrigel Invasion Chamber (Becton Dickinson Labware). We determined the ability of tumor cells to penetrate matrigel-coated filters in the presence or absence of BRM. PSK or OK-432 inhibited tumor cell invasion of matrigel-coated filters in a dose-dependent manner. PSK, OK-432 and Cepharanthin inhibited invasion of murine Colon 26 carcinoma cells and human A 375. S2 melanoma cells. On the other hand, polysaccharide preparations without protein, Lentinan or Sonifilan inhibited neither tumor growth nor tumor cell invasion.
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PMID:[Antitumor effect of intratumoral administration of BRM: inhibition of tumor cell invasion in vitro]. 757 77

5-Fluorouracil (5-FU) is an effective antitumor agent used in treating various cancers. Because of its metabolism by intestinal and other cells, 5-FU has an inconsistent bioavailability that limits its oral use. 5-Fluoro-2-pyrimidione (5-FP), a 5-FU prodrug, was synthesized and found to be converted to 5-FU by aldehyde oxidase, an enzyme present in high concentrations in the livers of mice and humans but not in the gastrointestinal tract. Using BDF1 mice, the pharmacokinetics of 5-FP were studied and compared with those of 5-FU. The bioavailability of 5-FP given orally was 100% at a dosage of 25 mg/kg and 78% at a dosage of 50 mg/kg. The half-lives of both doses of 5-FP were at least 2-fold longer than the half-lives of the same doses of 5-FU, and the clearance rates of 5-FP were 3-fold slower. 5-FP was converted rapidly to 5-FU, in vivo. The resulting 5-FU was measured at a steady-state level of 40-70 microM in plasma, at a dosage of 25 mg/kg, that was sustained for at least 4 hr. Also, when given orally, 5-FP was shown to have potent activity against Colon 38 tumor cells and P388 leukemia cells in mice. The therapeutic index of 5-FP was similar to that of 5-FU in these mouse tumor models. The potential clinical use of 5-FP as a prodrug of 5-FU should be considered.
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PMID:5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil. 774 92

The antitumor effects of 6-O-(3-ethoxypropionyl)-3',4'-O-exo- benzylidenechartreusin (IST-622), a new synthetic derivative of chartreusin (CT), were investigated. Following oral administration, IST-622 showed marked antitumor effects against various mouse tumors such as P388 and L1210 leukemias, B16 melanoma, Lewis lung carcinoma, Colon 26 and Colon 38 adenocarcinomas, and M5076 reticulum-cell sarcoma. The best antitumor effects were obtained by five intermittent treatments given every 4 days. In addition, IST-622 showed a significant growth-inhibitory effect against two human tumor xenografts, a large-cell lung cancer (Lu-116) and a gastric adenocarcinoma (St-4), among the seven lines tested. IST-622, which was rapidly metabolized into 3',4'-O-exo-benzylidenechartreusin (A-132) and not into CT in vivo or in culture medium, exhibited remarkable growth-inhibitory activity against P388 leukemia in vitro, its 50% growth-inhibitory concentration (IC50) being over 20-fold lower than that of CT. IST-622 showed an in vivo antitumor effect superior to that of authentic A-132, possibly resulting from a higher absorption ratio of IST-622 through the gastrointestinal tract. IST-622 is now under clinical phase I study in Japan.
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PMID:Antitumor effects of IST-622, a novel synthetic derivative of chartreusin, against murine and human tumor lines following oral administration. 803 94

Methyl(1S)-1-bromomethyl-7-methyl-5-[(4-methylpiperazinyl)-carb onyloxy]- 3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrolo[3, 2-e] indole-8-carboxylate hydrobromide (KW-2189), a novel derivative of duocarmycin B2, was selected for extensive evaluation based on its improved antitumor activity, water solubility, and stability in the culture medium, as compared with duocarmycin B2. Although the in vitro cell growth-inhibitory activity of KW-2189 was less potent than that of duocarmycin B2, it significantly inhibited the growth of five murine solid tumors including Colon 26 adenocarcinoma, Colon 38 adenocarcinoma, and B16 melanoma in vivo. KW-2189 was also effective against murine P388 leukemia and L1210 leukemia not only by local administration (i.p.-i.p. system), but also by systemic administration (i.p.-i.v. or i.v.-i.v. system). The most remarkable feature of KW-2189 was its efficacy against various human xenografts, which was observed in 14 tumors among 16 tested tumors including drug-insensitive tumors by single i.v. administration. Tumor regression was observed in mice bearing LC-6 lung, St-4 and St-40 stomach, Li-7 liver, PAN-2 pancreas, and MX-1 breast carcinomas. In many cases, the activities of KW-2189 were more than those of clinically active agents, mitomycin C, Adriamycin, cisplatin, and cyclophosphamide. Delayed lethal toxicity, which was reported in mice treated with CC-1065 whose structure was similar to KW-2189, was not observed in mice treated with KW-2189. KW-2189 inhibited DNA synthesis more significantly than RNA or protein synthesis, although DNA strand breaks were not observed. KW-2189 was activated by porcine liver esterase, mouse liver homogenate or Hep G2 homogenate, and DU-86-DNA adducts were detected in KW-2189-treated HeLa S3 cells, suggesting that KW-2189 was converted to DU-86 in the cells. These results indicate that KW-2189 is an interesting candidate for further development as a novel antitumor agent.
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PMID:Characteristics of antitumor activity of KW-2189, a novel water-soluble derivative of duocarmycin, against murine and human tumors. 816 88

The antitumor activity of navelbine (vinorelbine ditartrate, KW-2307) against murine and human transplantable tumors was compared with those of other vinca alkaloids, vindesine (VDS), vincristine (VCR) or vinblastine (VLB). KW-2307 and VDS increased the life span of mice bearing ascitic tumors (P 388 leukemia, L 1210 leukemia, EL-4 lymphoma, Colon 26, FM 3 A mammary carcinoma and M 5076 sarcoma) slightly more than VCR or VLB. A significant difference was not found in the antitumor activities against 6 murine solid tumors (B 16 melanoma, Colon 26, FM 3 A mammary carcinoma, Lewis lung carcinoma, M 5076 sarcoma and Sarcoma 180). However, a remarkable difference was observed in the antitumor activities against 11 human tumors inoculated into nude mice. The activity of KW-2307 was more than those of other 3 drugs against 4 human non-small cell lung carcinomas (Lu-65, Lu-99, LC-6 and L-27) and 2 stomach carcinomas (St-4 and St-40). KW-2307 and VDS were also effective in inhibiting the growth of 2 human breast carcinomas (MX-1 and Br-10).
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PMID:[Antitumor activity of navelbine (vinorelbine ditartrate), a new vinca alkaloid analog]. 842 87

We investigated the significance of milky spots for malignant cells in peritoneal dissemination using three mouse carcinomatous peritonitis models. P388 leukemia and Colon 26 cancer cells were labeled with bromodeoxyuridine (BrdU) and mice were inoculated intraperitoneally. After 24 h the greater omentum and the mesenterium were removed and stained immunohistochemically with anti-BrdU antibody. The labeled cells were found to have preferentially infiltrated into the milky spots in these specimens. Next, using B16 PC melanoma cells, which can be easily distinguished from the other cells by the intrinsic black melanin, the distribution of the melanoma cells was observed macro- and microscopically following intraperitoneal inoculation. The melanoma cells were similarly found to have selectively infiltrated into the milky spots in the omentum and mesenterium after 1 day. Moreover, the melanoma cells were growing and forming distinct metastic lesions within the milky spots 1 week later.
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PMID:Role of milky spots as selective implantation sites for malignant cells in peritoneal dissemination in mice. 887 56

FR901463, FR901464 and FR901465, novel antitumor substances, were isolated from the fermentation broth of Pseudomonas sp. No. 2663. Their antitumor activities were examined in three mouse tumor systems and one human tumor system. The three FR compounds prolonged the life of mice bearing murine ascitic tumor P388 leukemia (T/C values were 160%, 145% and 127% for FR901463, FR901464 and FR901465, respectively), and inhibited the growth of a human solid tumor, A549 lung adenocarcinoma, with different effective dose ranges. FR901464 exhibited most prominent effects on these tumor systems among the three FR compounds. FR901464 also inhibited the growth of murine solid tumors, Colon 38 carcinoma and Meth A fibrosarcoma. To address the involvement of transcriptional activation ability of the three FR compounds in the antitumor effect, we selected FR901464 as a candidate compound and investigated cell cycle transition, chromatin status and endogenous gene expression in FR901464-treated tumor cells having elevated transcriptional activity. FR901464 induced characteristic G1 and G2/M phase arrest in the cell cycle and internucleosomal degradation of genomic DNA with the same kinetics as activation of SV40 promoter-dependent cellular transcription in M-8 tumor cells. In contrast to the potent activation of the viral promoter, FR901464 suppressed the transcription of some inducible endogenous genes but not house keeping genes in M-8 cells. These results suggest that FR901464 may induce a dynamic change of chromatin structure, giving rise to strong antitumor activity, and therefore may represent a new type of drug for cancer chemotherapy.
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PMID:New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. 903 65

CI-994, a substituted benzamide derivative, is a compound that showed solid tumor selectivity for a variety of solid tumor models compared to L1210 leukemia. Due to its lack of aqueous solubility, it requires oral administration. Female B6D2F1 mice were treated with CI-994 once daily by oral administration of 50 mg/kg for 14 days. Following treatment mice were evaluated for pharmacodynamic effects as well as the pharmacokinetic behavior of CI-994 and the de-acetylated derivative dinaline. Mice samples (plasma, urine, feces) were analyzed using solid phase extraction, reverse phase HPLC and ultraviolet detection. The plasma distribution and elimination half-lives for CI-994 were 51 minutes and 9.4 hours, respectively, on D-1; 31 minutes and 3.4 hours, respectively on D-14. The apparent plasma distribution and elimination half-lives for dinaline were 27 minutes and 2.4 hours, respectively, on D-1; 40 minutes and 7.3 hours, respectively on D-14. The CI-994 AUC on D-1 and D-14 were 2879 and 2407 micrograms/ml x minutes, respectively; while the dinaline AUC on D-1 and D-14 were 87 and 92 micrograms/ml x minutes, respectively. Urinary excretion for CI-994 and dinaline was higher on D-14, while the fecal excretion was the same on both days. The Colon #38 tumor growth in treated mice was reduced to 22% of that observed in the controls by D-19. The levels of all blood cells were reduced in the treated mice when compared to controls and the total WBC was the most affected (median 38%). Recovery to pretreatment levels occurred quickly following treatment cessation. Phase I evaluation of chronic oral administration of CI-994 is currently ongoing.
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PMID:Preclinical pharmacokinetic, antitumor and toxicity studies with CI-994 (correction of CL-994) (N-acetyldinaline). 938 41

Ecthyma gangrenosum is a cutaneous gangrenous disorder which usually follows Pseudomona aeruginosa infection and is found mainly in immunosuppressed children. We describe a case of a five-year-old female with leukemia with a severe perineal ecthyma gangrenosum resulting in a cloaca-like deformity. One year later a perineoplasty with puborectalis interposition and overlapping external anal sphincteroplasty was successfully performed, achieving satisfactory continence.
Dis Colon Rectum 1999 Jul
PMID:Perineal reconstruction for severe sequela of ecthyma gangrenosum: report of a case. 1041 47


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