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

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemistry of reduction of nitro heterocycles. 293 68

A method based on detection of drug-induced cell cycle perturbation by flow cytometric DNA analysis has previously been described in Ehrlich ascites tumors as a way to estimate chemosensitivity. The method is extended to test human small-cell carcinoma of the lung. Three tumors with different sensitivities to melphalan in nude mice were used. Tumors were disaggregated by a combined mechanical and enzymatic method and thereafter have incubated with different doses of melphalan. After incubation the cells were plated in vitro on agar, and drug induced cell cycle changes were monitored by flow cytometric DNA analysis. Melphalan produced a dose-related S phase accumulation in the two sensitive tumors, whereas no changes in the cell cycle distribution were found in the resistant tumor. The size of S phase accumulation correlated to the chemosensitivity in vivo. For low concentrations of melphalan, the S phase accumulation was accompanied by G2 + M accumulation. The results indicate that the method may be extended to sensitivity testing of human solid tumors, including screening for new agents.
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PMID:Chemosensitivity of human small cell carcinoma of the lung detected by flow cytometric DNA analysis of drug-induced cell cycle perturbations in vitro. 301 70

Survival curves and dose escalation studies of four representative human tumor cell lines exposed to the various alkylating agents are presented. With HN2, at a level of one log of cell kill there was a fivefold range in drug concentration required to achieve this degree of cell kill among the cell lines, from 4.5 microM for the SL6 lung adenocarcinoma to 22 microM for the SW2 small-cell lung carcinoma. Four logs of SCC-25 squamous carcinoma cells were killed by 100 microM CDDP; however, there was only about one log of SL6 cells killed by 500 microM CDDP. To kill one log of G3361 melanoma cells required 24 microM 4-HC and to kill one log of SCC-25 cells required 24 microM, approximately a 16-fold difference. The curves for cell kill by L-PAM appeared to be biphasic, with a break at about 100 microM. There was about a threefold range in drug concentration required to achieve one log of cell kill with L-PAM, from 60 microM in the SCC-25 cell line to 18 microM in the SW2 line. To kill one log of SCC-25 cells required 295 microM BCNU and to kill one log of SW2 cell required 120 microM, about a 2.5-fold difference. The range of maximally tolerated HN2 concentrations were from 1200 microM for the SL6 cell line, 48 times the initial concentration, to 300 microM for the SCC-25 line, 16 times the initial concentration. The G3361 line tolerated the highest level of CDDP, 1900 microM, 48 times the initial concentration. The SCC-25 line, on the other hand, tolerated only 600 microM, 30 times the initial concentration. The SL6 cell line maximally tolerated 36 times the initial concentration of 4-HC (1450 microM), whereas the SCC-25 cell line tolerated only 18 times the initial concentration (720 microM). The G3361 melanoma tolerated 1555 microM, 30 times the initial concentration of L-PAM, and the SCC-25 cell line tolerated 700 microM, 14 times the initial concentration. The SL6 cell line tolerated the highest concentration of BCNU, 4200 microM, 24 times the initial concentration. The SCC-25 cell line tolerated 1450 microM, 8 times the initial concentration. In all cases, the SCC-25 cell line was least able to tolerate exposure to increasing concentrations of alkylating agents. The SL6 and G3361 cell lines showed the greatest tolerance for increasing concentrations of alkylating agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of alkylating agent-resistant human tumor cell lines. 337 Jul 36

The ability of amphotericin B (AmB) to potentiate the cytotoxicity of several different anticancer agents against two murine tumor models was examined. A spleen colony assay was used to quantitate the cytotoxicity of BCNU, CCNU, and L-PAM, either alone or in combination with AmB against the MOPC-315 plasmacytoma. A high level of potentiation of the effects of CCNU and L-PAM by AmB occurred, but AmB did not increase the cytotoxicity of BCNU. Tumor growth curves and calculation of cell survival demonstrated significant potentiation of the cytotoxicity of CCNU by AmB against SC Lewis lung carcinoma.
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PMID:Potentiation by amphotericin B of the cytotoxicity of anticancer agents against MOPC-315 plasmacytoma and Lewis lung carcinoma. 646 97

The in vivo response of B16 melanoma and Lewis lung carcinoma to combinations of hyperthermia and graded doses of CCNU or Melphalan was studied. To obtain dose-response curves and quantitative comparisons of different treatments, an agar-colony assay was used to measure survival of cells from excised tumours. For heating experiments, the use of 2 tumours per animal, one heated and one not, allowed all other factors to be kept constant. When tumours were immersed in a water-bath at 43 degrees C for 1 h, Thermal Enhancement Ratios (TER) measured from the slopes of the dose-response curves were up to 1.6 for CCNU and 2.4 for Melphalan. Direct heat killing of about 1 decade was seen for 1 h at 43 degrees C. The anaesthetic Saffan also enhanced drug cell kill; the largest Dose Modifying Factor (2.7) was measured for Melphalan in the Lewis lung tumour. The duration of heating, and waterbath temperature, both influenced the enhancement of cell killing by CCNU, as did the time of excision of tumours between 0 and 3 1/2 h after treatment. There was no difference in effect between 3 1/2 and 24 h. The interaction between heat and CCNU varied if the interval between them was altered. The maximum effect was found if the heat and drug were given in close sequence.
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PMID:Response of two mouse tumours to hyperthermia with CCNU or melphalan. 705 61

Bombesin (BN) and bombesin-like peptides are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. Six peptides belonging to a new class of alkylating BN analogues have been selected according to their characteristics evidenced on Swiss 3T3 fibroblasts: high binding affinity to BN receptor, relevant inhibition (> 60%) of the proliferative stimulus induced by BN, long-lasting effect and specificity for BN receptor. The six peptides were able to bind BN receptors on SCLC cells and to inhibit the growth of two SCLC cell lines: NCI-H69 and NCI-N592. Conversely, they did not inhibit the growth of tumor cell lines devoid of BN receptors. Two of them were tested in vivo on N592 cells transplanted into nude mice. The peptide carrying a Cab [p-bis(2 chloroethyl)aminobenzoyl] moiety proved to be completely inactive. The second peptide, with a Melphalan moiety (Mel), showed a moderate activity (33-45% of tumor growth inhibition) without any toxicity. The low solubility of this compound prevented the use of the higher doses in vivo.
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PMID:In vitro and in vivo activity of alkylating bombesin receptor antagonists on small cell lung carcinoma. 838 97

In mice bearing immunogenic tumors, adding thymic humoral factor-gamma 2 (THF-gamma 2)1 immunotherapy as an adjunct to anticancer chemotherapeutic regimens not only potentiates the antitumor activity of each drug but also repairs tumor/chemotherapy-induced damage to T-cell populations and functions. The Lewis lung carcinoma (3LL) is a weakly immunogenic, highly metastatic tumor in C57BL/6 mice. To investigate whether the immunoregulatory octapeptide is also effective against a tumor that does not elicit an antitumor immune response, we assessed the effect of combination THF-gamma 2 immunotherapy and chemotherapy in 3LL-bearing mice. The results indicate that THF-gamma 2 combined with either Melphalan or 5-Fluorouracil was more effective in reducing metastatic load than either chemotherapeutic drug alone and was characterized by massive infiltration of lymphatic cells. The combined chemoimmunotherapy treatment also prolonged the survival time in all treated animals and repaired T-cell defects and impaired in vitro cellular immune response parameters, induced either by the tumor or by chemotherapy. THF-gamma 2 immunotherapy reversed the decrease in the number of bone-marrow myeloid colonies (GM-CFU) induced by chemotherapy treatment of tumor-bearing mice, supporting the hypothesis that THF-gamma 2 directly stimulates the proliferation of myeloid stem cells. The overall results imply, that when administered as an adjunct to chemotherapy, THF-gamma 2 immunotherapy is equally effective against immunogenic and nonimmunogenic tumors.
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PMID:Thymic humoral factor-gamma 2 (THF-gamma 2) immunotherapy reduces the metastatic load and restores immunocompetence in 3LL tumor-bearing mice receiving anticancer chemotherapy. 877 68

Modulation of glutathione has been proposed as a mechanism to alter the efficacy and toxicity of chemotherapeutic agents. We investigated in vitro cytoenhancement of chemotherapy toxicity by reducing cellular glutathione levels with L-buthionine-[S,R]-sulfoximine (BSO), and chemoprotection with small molecular weight sulfur-containing agents that mimic or replace glutathione. Cytotoxicity, caspase-2 enzymatic activity, and in situ DNA staining for apoptosis were assessed in cultured human small cell lung carcinoma cells and fibroblasts. BSO treatment reduced the half-maximal cytotoxic dose of the alkylating chemotherapeutics melphalan, carboplatin, and cisplatin, and increased the total magnitude of cell death. Melphalan was more sensitive than carboplatin or cisplatin to BSO. The chemoprotective agents sodium thiosulfate, N-acetylcysteine, and glutathione ethyl ester reduced the cytotoxicity of all three alkylating chemotherapeutics regardless of BSO treatment, but D-methionine was effective only against the platinum agents. N-Acetylcysteine was the most effective protectant tested. Chemoprotection against melphalan toxicity was maximally effective only if administered concurrent with chemotherapy, whereas chemoprotection for the platinum agents remained effective if delayed 4 h after chemotherapy. BSO enhancement and N-acetylcysteine chemoprotection for melphalan toxicity occurred at least partially through an apoptotic mechanism. Modulation of glutathione levels will be valuable in the clinical setting if chemotherapy and chemoprotectant can be physically and/or temporally separated. Cytoenhancement and chemoprotection may be particularly useful in the central nervous system where the blood-brain barrier of the cerebral vasculature creates two compartments, for cytoenhancement in brain tumors and systemic chemoprotection.
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PMID:Rescue from enhanced alkylator-induced cell death with low molecular weight sulfur-containing chemoprotectants. 1118 9