Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.
...
PMID:Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. 150 76

5-Chlorodeoxycytidine (CldC), coadministered with modulators of pyrimidine metabolism, is an effective radiosensitizer of murine tumors. Past studies that utilized RIF-1 tumors in C3H mice and Lewis lung carcinoma (LLC) in BDF1 mice have been extended with an emphasis on using multiple cycles of drug administration followed by irradiation of LLC and the use of two additional tumor models. Four of seven cures of BDF1 mice bearing LLC were obtained with three doses of 20 Gy irradiation, in which the first and third dose were preceded by a "Standard Protocol" that includes N-(phosphonacetyl)-L-aspartic acid (PALA), 5-fluorodeoxycytidine (FdC), tetrahydrouridine, and the radiosensitizer, 5-chlorodeoxycytidine. No cures were obtained in groups of mice receiving radiation alone or drugs alone, and there were no "no takes" in untreated control groups (six mice/group). Extensive tumor inhibition, exceeding that obtained with drugs or radiation alone, was obtained with two cycles of drugs and radiation combined when a dimethybenzanthracene-induced mammary adenocarcinoma was used in BALB/c mice. With the EMT-6 tumor in BALB/c mice, doses of 10 and 20 Gy were administered 9 and 16 days after tumor implantation, each preceded with the Standard Protocol; this resulted in a tumor growth delay of 24 days. No tumor growth delay occurred with drugs or radiation alone. The omission of PALA, FdC or CldC from the Standard Protocol resulted in loss of tumor control, which was obtained with the complete protocol. The fact that 5-chlorodeoxycytidine is an effective radiosensitizer in four rodent tumor systems is compelling evidence that it has potential as a radiosensitizer of human tumors, especially in view of its tumor selectivity and its resistance to catabolism when used with modulators of its metabolism, and in view of the high levels of the key enzymes in human tumors, which can convert 5-chlorodeoxycytidine to 5-chlorodeoxyuridine triphosphate, the proximate radiosensitizer.
...
PMID:5-chlorodeoxycytidine, a radiosensitizer effective against RIF-1 and Lewis lung carcinoma, is also effective against a DMBA-induced mammary adenocarcinoma and the EMT-6 tumor in BALB/c mice. 173 88

Clinical Stage III (N2) non-small cell carcinoma of the lung encompasses a large group of patients, frequently treated with radiation therapy alone, who are now considered to have borderline-resectable tumors. Pilot studies are proceeding which use combinations of resection, radiation therapy, and chemotherapy. To place trials of combination therapy in perspective with contemporary results of radiation therapy alone, recently completed trials of the RTOG were analyzed specifically for clinical Stages T1-3N2. A prospective randomized trial of hyperfractionated radiation therapy (HFX), conducted from 1983 through 1987, compared total doses of 60.0, 64.8, and 69.6 Gy using 1.2 Gy bid with greater than or equal to 4 hr interval. After acute and late effects were considered tolerable, 74.4 Gy and 79.2 Gy arms supplanted the two lowest dose arms. Survival was compared among the five total dose arms, and with 60 Gy in 30 fractions in 6 weeks (standard fractionation-STD) from earlier RTOG studies. Of 516 HFX patients analyzed, 296 (57.3%) with Performance Status (PS) 70-100 and less than 5% weight loss (favorable) had a significantly (p = .001) better survival than those with PS 50-69 or weight loss greater than 5%. Patients with RTOG Stage III (361, 70.0%) experienced better survival (p = .027) than RTOG Stage IV M0. The 69.6 Gy total dose arm was significantly (p = .031) better in favorable RTOG Stage III patients than all other total dose arms: the 1-year survival rate was 58% and the 3-year rate was 20%. The 69.6 Gy HFX results were significantly (p = .002) better than results with STD fractionation in comparable patients from earlier RTOG trials (1-year survival = 30%, 3-year survival = 7%). A prospective, randomized Phase III comparison of STD with 60 Gy versus HFX with 69.6 Gy is underway. These results provide benchmarks for studies of surgical resection combined with chemotherapy and/or radiation therapy until results of prospective comparisons with concurrent controls are available.
...
PMID:N2 (clinical) non-small cell carcinoma of the lung: prospective trials of radiation therapy with total doses 60 Gy by the Radiation Therapy Oncology Group. 184 26

The toxicity of 1-[2-(diethylamino)ethyl]reserpine (DL-152) has been measured for 4 transplantable mouse tumors. DL-152 was found to be toxic to cells of all the tumor models tested (KHT fibrosarcoma, RIF-1 fibrosarcoma, EMT-6 adenocarcinoma and Lewis lung carcinoma) when the drug was given by intraperitoneal injection to the tumor-bearing mouse and cell survival was measured by excision assay. For the KHT tumor, hypoxic cells were found to be more sensitive to the drug in vivo than were aerated cells, and a similar response to hypoxia was observed in vitro, suggesting that sensitization occurred at the cellular level. Neither EMT-6 nor RIF-1 tumors showed increased sensitivity to the drug when cells were exposed under hypoxic conditions in vivo or in vitro. However, when the response of aerated cells of the 3 tumors was compared, the relative sensitivities for tumors exposed in vivo did not show the same ranking as the results of in vitro toxicity assays. This difference in in vitro and in vivo response in the different tumor models did not appear to be related to pharmacokinetic factors since the maximum tissue concentration and the rate of clearance of the drug were similar for all the tumors studied.
...
PMID:Factors influencing the toxicity of diethylaminoethylreserpine to tumor cells: studies with four transplantable tumors. 368 80

CAI (NSC 609974; L651582), a new agent that has demonstrated antimetastatic activity in vitro and in vivo, was not very cytotoxic toward EMT-6 mouse mammary carcinoma cells in culture or toward FSaIIC fibrosarcoma cells in vivo. Coexposure of EMT-6 cells to CAI and antitumor alkylating agents under various environmental conditions did not markedly increase the cytotoxicity of cisplatin (CDDP), melphalan, or carmustine (BCNU). However, the combination of CAI and 4-hydroperoxycyclophosphamide (4-HC) produced much greater than additive killing of EMT-6 cells. CAI also increased the sensitivity of hypoxic EMT-6 cells to X-rays. CAI increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells when animals were treated with single doses of both drugs. The effect of CAI on tumor cell killing by cyclophosphamide was greatest at high doses of the antitumor alkylating agent. CAI administration appeared to result in increased serum levels of prostaglandin E2 and leukotriene B4 in animals bearing the Lewis lung tumor. Administration of CAI on days 4-18 did not alter the growth of the Lewis lung carcinoma but did result in an increase in the tumor-growth delay produced by treatment with CDDP, cyclophosphamide, melphalan, BCNU, and fractionated radiation. Although CAI did not reduce the number of lung metastases present in Lewis lung carcinoma-bearing mice on day 20, it did appear to reduce the number of large (vascularized) metastases present on that day.
...
PMID:CAI: effects on cytotoxic therapies in vitro and in vivo. 792 63

Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.
...
PMID:beta-cyclodextrin tetradecasulfate/tetrahydrocortisol +/- minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic Lewis lung carcinoma. 826 4

Recent studies have demonstrated the importance of E-cadherin, a homophilic cell-cell adhesion molecule, in contact inhibition of growth of normal epithelial cells. Many tumor cells also maintain strong intercellular adhesion, and are growth-inhibited by cell- cell contact, especially when grown in three-dimensional culture. To determine if E-cadherin could mediate contact-dependent growth inhibition of nonadherent EMT/6 mouse mammary carcinoma cells that lack E-cadherin, we transfected these cells with an exogenous E-cadherin expression vector. E-cadherin expression in EMT/6 cells resulted in tighter adhesion of multicellular spheroids and a reduced proliferative fraction in three-dimensional culture. In addition to increased cell-cell adhesion, E-cadherin expression also resulted in dephosphorylation of the retinoblastoma protein, an increase in the level of the cyclin-dependent kinase inhibitor p27(kip1) and a late reduction in cyclin D1 protein. Tightly adherent spheroids also showed increased levels of p27 bound to the cyclin E-cdk2 complex, and a reduction in cyclin E-cdk2 activity. Exposure to E-cadherin-neutralizing antibodies in three-dimensional culture simultaneously prevented adhesion and stimulated proliferation of E-cadherin transfectants as well as a panel of human colon, breast, and lung carcinoma cell lines that express functional E-cadherin. To test the importance of p27 in E-cadherin-dependent growth inhibition, we engineered E-cadherin-positive cells to express inducible p27. By forcing expression of p27 levels similar to those observed in aggregated cells, the stimulatory effect of E-cadherin-neutralizing antibodies on proliferation could be inhibited. This study demonstrates that E-cadherin, classically described as an invasion suppressor, is also a major growth suppressor, and its ability to inhibit proliferation involves upregulation of the cyclin-dependent kinase inhibitor p27.
...
PMID:E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). 967 52

A model system has been used to test the efficacy of vascular targeting of alpha-particle emitter 213Bi for therapy of small, 'artificial' metastases in mouse lung. Specific monoclonal antibody (mAb) 201 B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific 213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6-6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours--epidermoid carcinoma A431 and lung carcinoma A549--growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control 213Bi MAb or EDTA complexed 213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived alpha-particle emitter 213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from alpha-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two.
...
PMID:Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi. 1038 94

The anticancer activity of the boronic acid dipeptide proteasome inhibitor PS-341 was examined in vitro and in vivo. PS-341 was a potent cytotoxic agent toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 microM on 24 h of exposure to the drug. In the EMT-6 tumor cell survival assay, PS-341 was equally cytotoxic administered p.o. or by i.p. injection up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colony-forming unit-granulocyte macrophage. PS-341 increased the tumor cell killing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Parent tumor, but was not able to overcome the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP tumors. In the tumor growth delay assay, PS-341 administered p.o. had antitumor activity against the Lewis lung carcinoma, both primary and metastatic disease. In combination, regimens with 5-fluorouracil, cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily additive tumor growth delays against the s.c. tumor and was highly effective against disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants continued investigation in cancer therapy.
...
PMID:The proteasome inhibitor PS-341 in cancer therapy. 1049 43

An important component in the development of a new anticancer drug is an understanding of its potential for inclusion in combination treatment regimens. LY231514, a multitargeted antifolate (MTA), was tested in combination with cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin, LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT 116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as xenografts in nude mice. Isobologram methodology was used to determine the additivity or synergy of the combination regimens. MTA administered with cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced additive to greater than additive tumor response by tumor cell survival assay and tumor growth delay. While an additive tumor response was observed when MTA was administered with methotrexate, synergistic tumor responses were seen when MTA was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I inhibitor, irinotecan. MTA was administered in combination with full doses of each anticancer agent studied, with no evidence of increased toxicity resulting from the combination.
...
PMID:MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma. 1059 56


1 2 3 4 5 6 7 8 9 10 Next >>

---