Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several N-substituted sulfonamides and N'-substituted sulfonylhydrazides have been prepared as sulfur analogues of L-asparagine with the potential of acting as inhibitors of L-asparagine synthetase (ASase, from Novikoff hepatoma). L-Cysteine was converted in known steps to N-carboxy-3-(sulfonylchloro)-L-alanine dibenzyl ester (1). Condensation of 1 with O-benzylhydroxylamine, p-(fluorosulfonyl)benzylamine, or monoethyl fumarylhydrazide (9), followed by deblocking with HF, gave 3-(hydroxysulfamoyl)-L-alanine (3a), 3-[p-(fluorosulfonylbenzyl)]sulfamoyl-L-alanine (3c), and 3-sulfo-L-alanine S-[2-[(E)-3-(ethoxycarbonyl)acryloyl]hydrazide] (3e), respectively. Similarly, 1 with 2-chloroethylamine and deblocking with H2-Pd gave 3-[(2-chloroethyl)sulfamoyl]-L-alanine (3b). tert-Butyl carbazate was allowed to react with 1 and the tert-butyl group was removed with HCl. The resulting sulfonylhydrazide 7 was condensed with p-(fluorosulfonyl)benzoyl chloride and then deblocked with HF to give 3-sulfo-L-alanine S-[2-[P-(fluorosulfonyl)benzoyl]hydrazide] (3d). The inhibition of ASase by 3a-e at 2 mM was 97, 0, 30, 43, and 37%, respectively, and 3a was competitive with L-aspartic acid. Neither 3a nor 3e was effective in increasing the life span of mice bearing P-388 lymphocytic leukemia.
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PMID:Potential inhibitors of L-asparagine biosynthesis. 4. Substituted sulfonamide and sulfonylhydrazide analogues of L-asparagine. 2 54

The toxicity of the bis-succinyl derivative of the protein antibiotic, neocarzinostatin, was compared with the parent compound, neocarzinostatin (NCS), in rats. The derivative was found to be about two to five fold more active than NCS in vivo. The antitumor activity in rats bearing eleven distinct Yoshida hepatoma ascitic cell lines was tested under four possible combinations with regard to sites of drug and tumor cell administration. The results indicate that the antitumor spectrum of the derivative had changed slightly. Antitumor activity in mice was also tested with L1210 and P388 lymphatic leukemia, and with B16 melanocarcinoma. When the effect of the derivative was compared with parental NCS at the molecular level with respect to the inhibition of DNA synthesis in vitro, the specific activities of the two were found to be almost identical. These results were interpreted to indicate that the succinyl derivative of NCS was more stable to inactivation and proteolytic break-down in vivo than NCS as observed previously in in vitro studies.
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PMID:Evaluation of succinyl neocarzinostatin in vivo. 14 81

A newly synthesized water-soluble nitrosourea derivative, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU; NSC-254157) has marked activities against experimental tumors such as lymphoid leukemia L-1210, ascites sarcoma- 180, ascites hepatoma AH-130, and Walker carcinosarcoma-256. A single intraperitoneal injection of the compound is more effective than successive injections on the L-1210 system. An especially interesting point is that both the single intraperitoneal and single oral administrations 2 days after tumor implantation showed a high effectiveness. In addition, growth of the mammary adenocarcinoma transplanted subcutaneously on the back of mice was also considerably suppressed by successive intraperitoneal injections of the compound.
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PMID:Effect of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea on experimental tumors. 20 35

Immunization of rabbits with rat leukemia DBLA-6 resulted in the production of antisera which upon absorption with hepatoma cells were specific for rat immature T lymphocytes. The antisera showed cytotoxicity against thymocytes and killed 75 approximately 90% of them, whereas the antisera had no cytotoxic effect on peripheral lymphocytes from the spleen, lymph node, and bone marrow of rats. The antisera also showed cytotoxicity against rat lymphatic leukemia and lymphoma cells of all lines tested but not against rat myelogenous leukemia and erythroleukemia cells. The cytotoxic activity of anti-DBLA-6 serum was completely absorbed with rat brain or thymocytes.
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PMID:Heterologous antiserum to a subpopulation of thymocytes and lymphomas in rats. 31 55

Transplantability of mouse tumors superinfected with various kinds of membrane viruses was investigated in syngeneic hosts. Methylcholanthrene-induced fibrosarcomas in BALB/c mice, Meth A, and in C57BL/6 mice, BMT-, superinfected with Friend lymphatic leukemia virus in mice given neonatal injection of the virus, grew more slowly than uninfected tumors. The retardation of growths was not observed in mice that had been given injections of the virus at birth. Similarly, Meth A and a hepatoma in C3H/He mice, MH134, superinfected with Moloney murine sarcoma virus in nu/nu mice, had reduced their transplantability in respective syngeneic mice. Further, Meth A and MH134 superinfected with endogenous rat leukemia virus and human measles virus, respectively, in nu/nu mice also showed reduced transplantability, and some of the former were actually rejected by normal syngeneic hosts. On the other hand, the reduced transplantability was not found in irradiated mice, suggesting that the phenomenon was due to immunological events. However, a myelogenous leukemia in C57BL/6 mice, C1498, superinfected with Moloney sarcoma virus in nu/nu mice grew like uninfected tumor and did not show reduced transplantability at all.
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PMID:Reduced transplantability of syngenic mouse tumors superinfected with membrane viruses in nu/nu mice. 100 77

Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 microM, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 microM and an IC50 of 29 microM being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.
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PMID:Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells. 145 Dec 38

Physalin F and physalin D were isolated and characterized from the ethanolic extract of the whole plant of Physalis angulata L. (Solanaceae). Systematic fractionation of the ethanolic extract of the plant led to characterization of physalin F from the fraction PAIV-2 as an active ingredient which showed cytotoxicity in vitro by DEA and MTT assays on 8 cancer cell lines, five human cancer cell lines: HA22T(hepatoma), HeLa(cervix uteri), KB(nasopharynx), Colo-205(colon) and Calu-1(lung); and three animal cancer cell lines: H1477(melanoma), Hep-2(laryngeal) and 8401(glioma). It was found that the anti-hepatoma action is the strongest, and the anti-HeLa is the next. Physalin F also had an antitumor effect in vivo against P388 lymphocytic leukemia in mice whereas physalin D was inactive both in vitro and in vivo.
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PMID:Antitumor agent, physalin F from Physalis angulata L. 162 43

With the object of providing an oligomeric prodrug of 5-fluorouracil (5FU) with reduced side-effects, affinity for tumor cells and high antitumor activity, 5FU was covalently attached to three chito-oligosaccharides (COS) through hexamethylene spacer groups via carbamoyl bonds. The ability of these conjugates to prolong the life of lymphocytic leukemia mice (following their intraperitoneal administration) and their tumor-inhibitory effects on Meth-A fibrosarcoma or MH-134 hepatoma mice (following their subcutaneous administration) were assessed. The conjugates caused a significant increase in the survival time of the p-388 leukemia mice, and higher growth-inhibitory effects against the solid tumor than either 5FU, COS, or blends of 5FU and COS. At the highest dose levels, the conjugates did not cause acute toxicity, and did not cause rapid decrease in body weight.
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PMID:Synthesis and antitumor activity of conjugates of 5-fluorouracil and chito-oligosaccharides involving a hexamethylene spacer group and carbamoyl bonds. 208 29

The chemical synthesis of three close analogues (2-4) of N10-propargyl-5,8-dideazafolate (PDDF) is described. The quinazoline ring of 2 and 4 was constructed from the pivotal intermediate 9 in a novel and unambiguous manner during the final step of the synthesis under very mild conditions. 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolate (DMPDDF) (2) was a strong inhibitor of human and Lactobacillus casei thymidylate synthases, whereas 2-desamino-2-(trifluoromethyl)-N10-propargyl-5,8-didezafolate (3) and 2-desamino-2,3-dimethyl-N10-propargyl-5,8-dideazafolate (4) were only weak inhibitors of this enzyme. DMPDDF exhibited excellent growth inhibition of Manca human lymphoid leukemia and H35 hepatoma cells in culture. The inhibitor activities of 2 were 43- and 65-fold greater than that of PDDF, respectively, in these cell lines. H35R cells that are resistant to methotrexate by virtue of a transport defect were cross resistant to DMPDDF but not to PDDF. H35FF cells which have 70-fold greater amounts of thymidylate synthase compared to H35N cells were 130-fold resistant to DMPDDF. Furthermore, the toxicity of DMPDDF to H35 hepatoma cells could be completely reversed by thymidine, establishing its locus of action as thymidylate synthase. Transport studies in vitro established that DMPDDF effectively inhibits MTX influx into H35 hepatoma cells, whereas PDDF has no effect on MTX transport in this cell line. These data suggest that the greater activity of DMPDDF relative to PDDF is partly due to the ability of the former compound to enter cells via the MTX/reduced folate transport system. Enzyme inhibition data of 4 suggest that the presence of N3H in DMPDDF is essential for binding to thymidylate synthase.
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PMID:Folate analogues. 32. Synthesis and biological evaluation of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid and related compounds. 254 57

VP-16-213 (etoposide) is an orally and parenterally active antineoplastic agent synthesized from podophyllum extracts of a common North American plant, the May apple or mandrake. The drug delays and kills cells in the G2 phase of the cell cycle and is active in a variety of animal tumors and leukemias. Major therapeutic activity for the drug has been found in small cell bronchogenic carcinoma, germ cell malignancies, acute non-lymphocytic leukemia, Hodgkin's disease and non-HOdgkin's lymphoma. Minor therapeutic activity of the drug occurs in non-small cell bronchogenic carcinoma, pediatric neoplasms, hepatocellular carcinoma and gastric cancer. Toxicity is primarily hematologic, with alopecia, nausea and vomiting occurring less frequently.
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PMID:VP-16-213 (etoposide): the mandrake root from Issyk-Kul. 627 88


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