Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through the extensive investigation of new mitomycin C (MMC) derivatives, several compounds with disulfide at N-7 were found to show activities superior to MMC against murine Sarcoma 180 solid tumor. Among them, 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]- mitomycin C (KW-2149) was selected for further evaluation of antitumor activity and toxicity in mice. KW-2149 exhibited activity superior to MMC in increasing survival of i.p. inoculated P388 leukemia-, M5076 sarcoma-, and B16 melanoma-bearing mice. KW-2149 administered i.v. also exhibited superior activity in inhibiting the growth of s.c. inoculated P388 leukemia, M5076 sarcoma, and colon 26 adenocarcinoma and in increasing survival of i.v. inoculated P388 leukemia- and M5076 sarcoma-bearing mice. Furthermore, KW-2149 remarkably increased the life span of MMC-resistant P388 leukemia- and L1210 leukemia-bearing mice. KW-2149 and MMC inhibited the growth of human tumors inoculated into nude mice. The activity of KW-2149 was prominent in human lung carcinoma Lu-65 and Lu-99, bladder carcinoma T24, and epidermoid carcinoma A431. KW-2149 was comparable to MMC in decreasing the number of WBC in the peripheral blood, and the thrombopenia induced by KW-2149 was mild and recovery was rapid. The in vitro anticellular spectrum of KW-2149 against 23 human tumor cell lines was similar to that of MMC. However, KW-2149 inhibited the growth of the cell lines at concentrations of 10- to 100-fold lower than MMC and showed efficient cytotoxicity against MMC-insensitive tumor cell lines. These included lung epidermoid carcinoma Calu-1, stomach carcinoma MKN-28, colon adenocarcinoma DLD-1, colon adenocarcinoma LoVo, bladder carcinoma HT-1197, sarcoma G-292, and melanoma SK-MEL-28 cells. These results indicate that KW-2149 bears interesting characteristics as a new anticancer drug and warrants further development.
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PMID:Antitumor activity of 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]-mitomycin C. 198 76

Base propenals arise from DNA by a Fe(II)-bleomycin-mediated reaction which leads to strand scission. These compounds undergo addition-elimination reactions with thiols and other nucleophilic groups under physiological conditions and form an addition product with glutathione. Thymine- and adenine-N1-propenals inhibit DNA synthesis in HeLa cells; both compounds are cytotoxic [50% inhibiting concentration (IC50) = 1 to 2 microM]. A structurally related nucleoside, thymidine-N3-propenal, designed as a metabolic pathway inhibitor, inhibits growth of HeLa, L1210 leukemia, Lewis lung carcinoma, B16 melanoma, and DLD-1 human colon carcinoma cells in culture (IC50 = 1 to 6 microM). A single injection of this compound, administered on the first day following transplant of L1210 leukemia cells, increased the mean survival time of mice by 50% (T/C = 154). Thymidine-N3-propenal selectively blocks DNA synthesis in HeLa cells and inhibits thymidine kinase (Ki = 5.1 microM) and DNA polymerase-alpha. We suggest that base propenals, rather than damaged DNA, account for some of the cytotoxic effects of bleomycin and that nucleoside propenals represent a novel class of site-directed inhibitors.
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PMID:Origin and cytotoxic properties of base propenals derived from DNA. 257 72

The responses of two heterogeneous human cancer cell lines and their derivative clones to graded single doses of X-rays were examined in vitro. One system consisted of the human colon carcinoma line DLD-1 and two subpopulations (clones A and D). The second system consisted of the human lung carcinoma line (LX1) and four subpopulations (LX1-1, LX1-2, LX1-3, and LX1-9). These subpopulations have previously been shown to be markedly heterogeneous in terms of such characteristics as karyotype, morphology, drug sensitivity, tumorigenicity, and expression of membrane glycoproteins (such as carcinoembryonic antigen and tumor colonic mucoprotein antigen). Exponentially growing cultures were irradiated with graded single doses of 100-kVp X-rays. Survival was assessed using colony formation as the end point, and responses from multiple experiments were fitted to the single-hit, multitarget equation of cell survival. Values for the mean lethal dose (D0, grays), quasithreshold dose (Dq, grays), and extrapolation number (n) were obtained. For the human colon adenocarcinoma system, these values for the three tumor lines were: DLD-1, 0.95, 2.34, and 11.7; clone A, 1.06, 2.23 and 8.20; and clone D, 1.08, 1.89, and 5.80. For the human lung carcinoma system, these values for the five sublines were: LX1, 1.14, 0.19, and 1.20; LX1-1, 0.96, 2.06, and 8.54; LX1-2, 0.98, 0.88, and 2.48; LX1-3, 0.68, 2.05, and 20.3; and LX1-9, 1.12, 0.00, and 1.00. These two human tumor systems therefore exhibit variability in their intrinsic sensitivity to X-irradiation. The data indicate that failure of some human carcinomas to respond to physical treatment modalities can be due to preexisting resistant subpopulations.
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PMID:Differential responses to x-irradiation of subpopulations of two heterogeneous human carcinomas in vitro. 708 48

Adozelesin (Ado), a CC-1065 analog, shows significant antineoplastic activity in vivo against several types of murine tumors and human tumor xenografts. Ado is a DNA alkylating agent. One objective of this study was to investigate the cytotoxic action of Ado against the human colon (HT-29, DLD-1) and the lung (SK) carcinoma cell lines. The concentrations of Ado that produced 50% cell kill for a 4 and 24 h exposure were in the range of 0.001-0.02 ng/ml for both colon and lung carcinoma cells, indicating that this analog was a very potent cytotoxic agent. Since most clinical regimens for tumor therapy consist of several drugs, we investigated the antineoplastic action of Ado in combination with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation or cytosine arabinoside (Ara-C), a potent inhibitor of DNA synthesis. The Ado plus 5-Aza-CdR combination showed a synergistic effect on cytotoxicity of DLD-1 colon carcinoma cells for both a 6 and 24 h exposure. However, combination of Ado and Ara-C for a 6 h exposure showed an antagonistic effect, whereas a 24 h exposure showed a synergistic effect. These preclinical results provide some preliminary data on possible drugs that can be selected for use in combination with Ado in future clinical trials in patients with cancer.
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PMID:Evaluation of the antineoplastic activity of adozelesin alone and in combination with 5-aza-2'-deoxycytidine and cytosine arabinoside on DLD-1 human colon carcinoma cells. 768 64

DMP 840, a novel bis-naphthalimide, was evaluated for antitumor efficacy in several tumor models in mice. As measured by a tumor growth inhibition assay, i.v. administration of DMP 840 to athymic nude mice at doses at or below the maximum tolerated dose resulted in curative activity against four human solid tumor xenografts, MX-1 mammary carcinoma, CX-1 and DLD-2 colon adenocarcinomas, and LX-1 lung carcinoma, producing full or incomplete regressions and/or percent tumor growth inhibition of > or = 96%. The efficacy of DMP 840 in the models was dose dependent. The activity of DMP 840 against the human tumors surpassed that demonstrated by several clinically used and investigational anticancer agents. In long-term growth delay studies, DMP 840 induced full regressions in 20 of 20 mice bearing MX-1 tumors, and tumors in one-half of these mice remained regressed for over 5 months. In addition, DMP 840 was curative against exponentially growing DLD-2 tumors staged at 500 mg and MX-1 tumors staged at 1000 mg. The bis-naphthalimide was equally efficacious when administered i.v. or i.p. but was slightly less active after oral dosing. Against both the MX-1 mammary carcinoma and the DLD-2 colon adenocarcinoma, some measure of schedule dependence was observed; the optimum schedule was daily for 9 days. Against L1210 and P388 murine leukemias, DMP 840 demonstrated little or no activity and was inactive against B16 murine melanoma. Overall, these results suggest that DMP 840 may be a human solid tumor selective cytotoxic agent.
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PMID:Efficacy of DMP 840: a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity. 826 36

Members of the Janus kinase (Jak) family of protein tyrosine kinases have recently been implicated in the proximal signal transduction events of cytokine receptors. Jak3, a newly discovered member of this family, is believed to be normally limited in its expression to cells of the lymphoid and myeloid lineages. Herein we show that Jak3 is expressed in primary human vascular cells, as well as other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed at low levels in human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1 (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells. Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC-1, and these levels increased significantly with cytokine treatment. Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4. This work shows that Jak3 is expressed or inducible in human vascular endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid cells, suggesting a broader role for Jak3 in the cytokine signal transduction of these cells.
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PMID:Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. 866 78

The inhibitory effect of acyclothymidine[AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl) uracil], a potent pyrimidine nucleoside phosphorylase (PyNPase) inhibitor, on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in human and mouse tumor cell homogenates was measured. Competitive inhibition was observed in MKN-74 and Lewis lung carcinoma (LLC), whereas non-competitive inhibition was observed in HeLa. The strength of the inhibitory effect by AcyT showed the following pattern: HeLa < human normal intestine < mouse normal intestine < Colon 26 < LLC < MKN-74 < DLD-1. From the kinetic parameter obtained, we simulated the inhibitory effect of AcyT on 5'-DFUR phosphorolysis in tumor cells and the intestine. These data indicated that AcyT was more sensitive in normal mouse intestine than in Colon 26 and LLC, and that orally administered AcyT can reduce the intestinal toxicity of 5'-DFUR without reducing the antitumor effect in the mouse. The present finding may have an important implication for attempts to introduce AcyT, a potent PyNPase inhibitor, into the clinic.
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PMID:Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclothymidine in tumor cell homogenates. 930 Jan 47

We investigated the effects of UFT and its metabolites, GHB and GBL, on angiogenesis induced by tumor cells in a dorsal air sac (DAS) assay in mice. Five tumor cell lines (murine renal carcinoma; RENCA, human gastric cancer; 4-1ST, human small-cell lung carcinoma; LX-1, and human colon carcinoma; DLD-1, KM-20C) were used in the DAS assay. In this model, UFT demonstrated a significant anti-angiogenic activity in a dose-dependent manner while 5-FU (19 mg/kg/day) and 5'-DFUR (200 mg/kg/day) were less effective. Moreover, tegafur (FT), a component of UFT, and gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL), in vivo metabolites of UFT, inhibited angiogenesis induced by RENCA cells. The inhibitory effects of 5-FU, GHB, and GBL on angiogenesis were increased with administration by continuous infusion, providing a suitable pharmacokinetic profile. These results suggest that GHB and GBL are involved in the expression of anti-angiogenic activity of UFT.
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PMID:[Anti-angiogenic activities of UFT and its metabolites, GHB and GBL, in the dorsal air sac (DAS) model in mice]. 1066 Jul 38

Human tumor cell lines that are sensitive to the effects of farnesyl transferase inhibitors accumulate in G(2) --> M (except for cells with an activated Ha-ras that accumulate in G(1)). A search for CAAX box proteins from Swiss-Prot revealed more than 300 peptides. Of these, the centromeric proteins CENP-E and CENP-F are preferentially expressed during mitosis and are implicated as mediators of the G(2) --> M checkpoint. Experiments performed here show that peptides from the COOH-terminal CAAX box of CENP-E and CENP-F are substrates for farnesyl transferase but not geranylgeranyl transferase-I. Although both proteins are prenylated in the human tumor cell line DLD-1, their prenylation is completely inhibited by the farnesyl transferase inhibitor, SCH 66336. Immunohistochemical data with the lung carcinoma cell line, A549, showed that preventing the farnesylation of CENP-E and CENP-F by treatment with the farnesyl transferase inhibitor SCH 66336 does not affect their localization to the kinetochores. However, the presence of farnesyl transferase inhibitors alters the association between CENP-E and the microtubules. Our results imply that the inhibition of CENP-E farnesylation results in the alteration of the microtubule-centromere interaction during mitosis and results in the accumulation of cells prior to metaphase.
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PMID:Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. 1085 15

Hederacolchisid A1, a new oleanolic acid monodesmoside, isolated from Hedera colchica K. Koch, an ivy species endemic in Georgia, was evaluated in vitro for antiproliferative activity on cancer cells versus normal cells in comparison to cisplatin. Investigations were made on six human cell lines (colon adenocarcinoma DLD-1, ovarian teratocarcinoma PA 1, lung carcinoma A 549, breast adenocarcinoma MCF7, prostatic adenocarcinoma PC 3 and malignant melanoma M4 Beu) versus normal human fibroblasts, by assaying both cellular metabolic activity (RTT test) and DNA content in living cells (test with Hoechst 33,342) after 48 h continuous contact. Results demonstrated the strong cytotoxicity of hederacolchisid A 1 on all cancer cells (IC50 from 4.5 to 12 microM). The antiproliferative effects on malignant melanoma M4 Beu (IC50 ca 4.5 microM) versus normal cells (IC50 ca 7.5 microM) suggests that, despite a lack of specificity for cancer cells, hederacolchisid A1 has potential anti-tumor applications. Comparison of the cytotoxicity of hederacolchisid A 1 with that of five other saponins from H. colchica, offers some new information about structure-activity relationships. It was observed that i) for a same sugar sequence, monodesmosides with oleanolic acid as aglycone exhibit higher cytotoxicity than those containing hederagenin, ii) the sugar sequence O-alpha-L-rhamnopyranosyl (1 --> 2)-alpha-L-arabinopyranoside at C3 induces strong cytotoxicity and might be identified as a basic sequence for anti-tumor activity of oleanolic acid monodesmosides. iii) a complementary glucopyranosyl moiety branched at C1 of arabinose increases the cytotoxicity against malignant melanoma M4 Beu, prostatic adenocarcinoma PC 3 and normal fibroblasts in a different manner for each type of monodesmoside. A slight increase whose amplitude was quite similar on cancers and normal cells, was observed with oleanolic acid monodesmoside. This increase was much higher with hederagenin monodesmoside and markedly elevated in normal cells than in cancer cells.
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PMID:In vitro activity of hederacolchisid A1 compared with other saponins from Hedera colchica against proliferation of human carcinoma and melanoma cells. 1222 85


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