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)

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
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PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

Seven different tumor cell lines (human melanoma SK MEL 28; hamster melanoma HM29; murine melanomas B16F10 and amelanotic melanoma B16a; human colon carcinoma HCT8; murine colon carcinoma CT26; and murine Lewis lung carcinoma) were treated with thrombin at 0.5-1 unit/ml and examined for their ability to bind to adherent platelets; HM29 was studied for its ability to bind to fibronectin and von Willebrand factor; CT26, B16F1, B16F10, and B16a were studied for their ability to form pulmonary metastasis after i.v. injection of thrombin-treated tumor cells; CT26 was studied for its ability to grow s.c. Five of 7 thrombin-treated tumor cell lines increased their adhesion to adherent platelets 2-to 3-fold. HM29 increased its adherence to fibronectin and von Willebrand factor 2- to 3-fold. CT26, B16F1, B16F10, and B16a increased experimental pulmonary metastasis 10- to 156-fold. Thrombin-treated CT26 cells demonstrated 2-fold greater growth in vivo after s.c. injection. The mechanism of enhanced adhesion of thrombin-treated tumor cells to platelets required the platelet integrin GPIIb-GPIIIa since it could be inhibited by agents known to block adhesion of ligands to GPIIb-GPIIIa (monoclonal antibody 10E5, tetrapeptide RGDS, disintegrin Albolabrin); as well as a "GPIIb-GPIIIa-like" structure on tumor cells since it could be inhibited by treatment of thrombin-treated tumor cells with 10E5 and RGDS. The thrombin effect on tumor cells was optimum at 1 h of incubation with thrombin, did not require active thrombin on the tumor cell surface, and did not require protein synthesis (not inhibited by cycloheximide). Thus, thrombin-treated tumor cells markedly enhance pulmonary metastasis. It is suggested that this may be secondary to thrombin-induced enhanced adhesion as well as growth of tumor cells.
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PMID:Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. 159 84

Interactions between the extracellular matrix macromolecules and tumor cells are critical in the process of metastasis formation. We show here that elastins (both mature insoluble elastin and a 75-kDa soluble peptide: K-elastin) adhere rapidly to two cell lines with high metastatic capacities: a metastatic lung carcinoma cell line (3LL-HM) and a human amelanotic melanoma cell line (A-2058); by contrast the low-metastatic Lewis lung carcinoma cell line variant as well as a rhabdomyosarcoma cell line with a low metastatic potential bind to elastins to a much lower extent. 3H-labelled K-elastin was used in order to study elastin--3LL-HM interaction. It was found to be saturable (2 ng 3H-labelled K-elastin/10(6) cells), with one class of high-affinity binding sites having Kd equal to 1.3 nM and 16,000 sites/cell. The binding of K-elastin to 3LL-HM cells at its receptor triggered several cell responses; (a) increase of intracellular Ca2+ concentration; (b) induction of 3LL-HM chemotaxis toward the K-elastin gradient; (c) stimulation of the adherence of mature insoluble elastin. In contrast to non-transformed cells such as fibroblasts and smooth muscle cells, the adhesion kinetics of insoluble elastin to 3LL-HM did not exhibit a lag period; the rapid binding of insoluble elastin to the tumor cells was followed by its slow detachment from the cells, which lasted for 6 h. 3LL-HM cells but not human skin fibroblasts were shown to secrete elastinolytic activity inhibitable by metal-chelating agents. In vivo studies were performed in order to evaluate the influence of K-elastin binding to 3LL-HM cells on their ability to form lung colonies in mice. It was shown that pretreatment of 10(4) 3LL-HM cells with 10 microM K-elastin and the simultaneous i.v. injection into mice of 750 micrograms K-elastin together with the highly metastatic cells was able to reduce the number of lung colonies by more than 70% after 12 days.
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PMID:Interaction between elastin and tumor cell lines with different metastatic potential; in vitro and in vivo studies. 185 64

Aliphatic triazenes, such as 1,3-dimethyltriazene, are potent biological alkylating agents because they form alkyldiazonium ions. They are also subject to very rapid proteolytic decomposition, even at physiological pH. The acylated analogues 1,3-dialkyl-3-acyltrizenes are much more stable in aqueous solution, but they also give rise to alkyldiazonium ions. Four acylated 1,3-dimethyltriazenes, where the acyl groups were diethylphosphoryl (DMP), carbethoxy (DMC), acetyl (DMA), and N-methylcarbamoyl (DMM), were studied kinetically. Rate-pH profiles indicated that the acyl group had a profound effect on the mechanism of decomposition. The cytotoxic potential of all four compounds was studied in vitro by using the MTT-tetrazolium assay. The compounds had fair-to-good activity against some cell lines, particularly those deficient in methylation repair. In vivo assays of DMC and DMM against several tumor xenografts in nude mice showed promising activity for some cancers, particularly in the case of DMM. In vitro assays were also carried out on three 1-(2-chloroethyl)-3-methyl-3-acyltriazenes. The acyl groups were carbethoxy (CMC), acetyl (CMA), and N-methylcarbamoyl (CMM). The activity of these compounds largely paralleled that of bis(2-chloroethyl)-N-nitrosourea (BCNU), except for those cell lines which exhibited the Rem phenotype; triazenes were more active in those lines than BCNU. The in vivo activity of CMC, CMA, and CMM was tested in the P388 leukemia assay. All three were active but CMC and CMA proved to be rather toxic. CMM was well tolerated and was examined in several tumor xenografts in nude mice. Significant activity was found against MX-1 mammary carcinoma, against LX-1 small cell lung carcinoma, and particularly against LOX amelanotic melanoma, where complete cures were effected. The antineoplastic activity of the acyltriazenes is well-correlated with their chemical behavior.
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PMID:1,3-Dialkyl-3-acyltriazenes, a novel class of antineoplastic alkylating agents. 239 96

Our laboratories have previously demonstrated that the malignancy of human and animal tumors is associated with increases in cathepsin B activity, due in part to increases in cathepsin B-specific RNA transcripts and in part to decreased regulation by the endogenous low molecular weight cysteine proteinase inhibitors (CPIs). In this study we have extended these observations to tumor cell subpopulations of B16 amelanotic melanoma (B16a) and Lewis lung carcinoma (3LL) isolated by centrifugal elutriation. B16a subpopulations exhibited a 10-fold differential in lung colonization potential, whereas 3LL subpopulations exhibited no differential. In the B16a subpopulations, cathepsin B activities, total cellular and plasma membrane-associated, corresponded positively (4- and 10-fold increase, respectively) with their lung colonization potentials. CPI activities, total cellular and plasma membrane-associated, corresponded inversely (2- and 5-fold decrease, respectively) with the lung colonization potential of the B16a subpopulations. In the 3LL subpopulations, neither cathepsin B nor CPI activities changed. In the plasma membrane fractions of all 3LL subpopulations the ratio of cathepsin B activity to CPI activity was less than 1, whereas in the plasma membrane fractions of all B16a subpopulations the ratio was 1 or greater. In the plasma membrane fractions of the B16a subpopulations of higher lung colonization potential the ratios were 2.5 and 7, indicating that the levels of endogenous CPIs in these fractions may not be sufficient to regulate cathepsin B activity. Cathepsin B mRNA levels were not increased in the B16a subpopulations expressing increased cathepsin B activity. Thus increased cathepsin B activity in these subpopulations was apparently due not to increased synthesis but to decreased regulation by the endogenous CPIs. These results suggest that membrane-associated cathepsin B and CPIs may both play a role in the expression of the experimental metastatic phenotype.
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PMID:Cathepsin B to cysteine proteinase inhibitor balance in metastatic cell subpopulations isolated from murine tumors. 240 Sep 91

RSU 1069 and RSU 1164 are electron affinic agents that contain a nitro group together with a weakly basic alkylating aziridine moiety, and they represent lead compounds in the development of dual-function, bioreductive, hypoxic cell radiosensitizers. We studied the pharmacokinetics of these drugs in mice carrying KHT sarcoma. Lewis lung carcinoma, and B16 melanoma. Following an i.p. dose of 80 mg/kg, absorption was rapid and the elimination t1/2 was in the region of 30 min for both agents. Maximal tumour levels were 91, 16 and 19 microgram/ml for RSU 1069 and 109, 26 and 28 microgram/ml for RSU 1164 in. the B16, KHT and Lewis lung tumours, respectively. In B16 melanoma these levels corresponded to tumour:plasma ratios of 3.8 for RSU 1069 and 3.7 for RSU 1164. Cellular uptake of RSU 1069, RSU 1164 and a related compound, RB 7040, was measured in vitro as a function of extracellular pH. Melanotic cells from both B16 melanoma and HX118, a human tumour xenograft, showed substantially greater accumulation of these weakly basic sensitizers than any other cell type examined. Ratios of intra-:extracellular concentration (Ci/Ce) for RSU 1069 were around unity and independent of pH for Lewis lung cells and HX34 amelanotic melanoma cells, whereas ratios of up to 3 and 5 were obtained in B16 and HX118 cells, respectively. The highest measured value of Ci/Ce was 15 for RSU 1164 in HX118 cells at pH 8.4; this compares with a ratio of 1.5 for HX34 cells at the same pH. These studies indicate that the high levels of uptake of the weakly basic sensitizers into melanotic melanoma in vivo is a cell-mediated phenomenon and may be due to a lower average intracellular pH in the melanotic cells.
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PMID:High uptake of RSU 1069 and its analogues melanotic melanomas. 254 36

Our earlier studies indicated a role for polyamines (namely, putrescine, spermidine, and spermine) not only in tumor growth but also in tumor metastases. We have observed that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, resulted in significant inhibition of visually detectable pulmonary metastases in mice implanted with Lewis lung carcinoma. The objective of the present study is to investigate the effect of DFMO on other spontaneous and experimental metastatic models and also to determine which step(s) in the tumor metastatic cascade is sensitive to DFMO. The results presented in this study with malignant mouse B16 amelanotic melanoma (B16a) showed a dose-dependent effect of DFMO on the inhibition of both tumor growth and grossly detectable pulmonary metastases. DFMO, when administered as 0.5, 1, and 2% solution in drinking water, resulted in 0, 24.5, and 60% inhibition of tumor growth, respectively, whereas at the same doses an inhibition of 55, 83, and 96% of visible metastases was observed. At treatment levels of 1 and 2% DFMO, 30 and 65% of the animals were free of metastases. DFMO, at 0.5%, did not show any effect on tumor growth, while a significant 55% inhibition of visible pulmonary metastasis was observed, suggesting a specific role for polyamines in tumor metastasis. DFMO treatment also resulted in a significant reduction of putrescine and spermidine levels with a slight increase in spermine concentration in the tumor tissue. DFMO administration did not inhibit the experimental metastases induced as a result of i.v. injection of B16 melanoma (line F10) tumor and Lewis lung carcinoma cells into the tail vein. These results provide preliminary evidence to indicate that tumor cell polyamine depletion by DFMO might affect the first step in the metastatic cascade, intravasation (i.e., prevent the invasion of metastatic tumor cells into lymphatics or blood vessels), although the effect of DFMO on other steps in the metastatic cascade cannot be ruled out.
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PMID:Antimetastatic activity of DL-alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, in mice. 310 31

Resistance to cisplatin is a relative term and is at least partially attributable to its narrow therapeutic index. It is often not possible to successfully treat tumors exhibiting even a small inherent resistance to cisplatin by increasing the dose level of cisplatin, because such therapies may be fatally toxic to a patient. Thus, combination therapy with an agent which enhances cisplatin's antitumor effects with little or no enhancement of cisplatin's toxicities, may be of value in the treatment of human tumors which fail to respond to treatment with cisplatin alone. We recently reported that nifedipine, a dihydropyridine class calcium channel blocker, enhances the antitumor actions of cisplatin against a cisplatin-sensitive murine amelanotic melanoma. We now report that nifedipine enhances cisplatin's antitumor effects against a murine carcinoma (Lewis lung carcinoma) that is inherently resistant to cisplatin.
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PMID:Cisplatin and nifedipine: synergistic antitumor effects against an inherently cisplatin-resistant tumor. 337 Jun 29

Aggregation of rat platelets was induced in vitro by homologous rat Walker 256 carcinosarcoma cells and the extent of tumor cell-platelet interactions examined ultrastructurally. By 30s there was surface contact between unstimulated platelets and tumor cell microvilli. By midphase aggregation (2-3 min) tumor cells became enmeshed within expanding platelet aggregates. Tumor cell microvilli and platelet pseudopodia interdigitated as aggregation progressed. During the later stages of aggregation (6-10 min) tumor cells formed large processes which penetrated deep into the aggregate. Platelet activation (i.e. degranulation) occurred in gradient fashion and was concentrated near tumor cell membrane sites involved in process formation. At these later stages tumor cells near the aggregate periphery were found to have engulfed platelets or platelet fragments. Tumor cell-platelet interactions in the pulmonary microvasculature were also studied in vivo following injection of murine Lewis lung carcinoma, 16C mammary adenocarcinoma, and B16 amelanotic melanoma tumor cells into the tail vein. Platelets demonstrated a biphasic association with arrested tumor cells with peak interactions occurring at 10-30 min and 4-24 h. Ultrastructurally, tumor cells exhibited newly formed processes which interdigitated with the platelet aggregate. Such processes formed only in areas of contact with platelets and not in areas of contact with endothelial cells or other blood elements (i.e. erythrocytes, polymorphonuclear leukocytes). Numerous tumor cell mitochondria were concentrated in the areas of greatest platelet-tumor cell process activity. At early time intervals (2-10 min), intravascular platelet degranulation was observed primarily in platelets associated with tumor cell processes. Tumor cells also were found to have engulfed platelet fragments in vivo.
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PMID:Tumor cell-platelet interactions in vitro and their relationship to in vivo arrest of hematogenously circulating tumor cells. 382 98

The interaction between metastasizing tumor cells and the hemostatic system of the host has been implicated in successful tumor cell dissemination. Prostacyclin (PGI2) decreases metastasis from tail vein injected B16 amelanotic melanoma (B16a) cells when administered 15 min prior to tumor cells. This effect is potentiated by a phosphodiesterase inhibitor. Initial trapping of 125I Udr labelled tumor cells in pulmonary vascular beds is unaltered by PGI2 but retention time is decreased. PGI2 decreases retention time even when administered 60 min post tumor cells. Structurally unrelated thromboxane (TX) synthetase inhibitors and a TXA2 receptor antagonist also reduce metastasis from tail vein injected B16a cells. Furthermore, one inhibitor, 1-(7-carboxyheptyl)imidazole, when injected intraperitoneally reduced spontaneous metastasis from subcutaneous B16a and Lewis lung carcinoma tumors. These results suggest that selective manipulation of PGI2 and TXA2 can reduce the hematogenous spread of tumor cells.
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PMID:Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. 624 6


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